OXO-SUBSTITUTED COMPOUND

20230287009 · 2023-09-14

Assignee

Inventors

Cpc classification

International classification

Abstract

Provided is a novel compound that has an excellent β-lactamase inhibitory effect. More specifically, provided is a compound represented by formula (1a), (1b) or (11) having an excellent β-lactamase inhibitory effect or a pharmaceutically acceptable salt thereof. By using this compound either in combination with a β-lactam drug or alone, a useful preventive or therapeutic agent for bacterial infections is provided. Also provided are useful preventive or therapeutic agents for treating various diseases with the combined use of the aforesaid compound and β-lactam drugs.

Claims

1-54. (canceled)

55. A compound represented by formula (11): ##STR01096## or a pharmaceutically acceptable salt thereof, wherein R.sup.G is a hydroxyl group, a thiol group, or —NHR.sup.a1, G is an oxygen atom, a sulfur atom, or —NR.sup.a1—, X is a hydroxyl group, an optionally substituted C.sub.1-6 alkoxy group, or —NR.sup.a2R.sup.b1, R.sup.a1, R.sup.a2, and R.sup.b1 are the same or different, each independently 1) a hydrogen atom, 2) a C.sub.1-6 alkyl group, 3) a C.sub.3-10 alicyclic group, 4) C.sub.6-10 aryl 5) 5- or 6-membered heteroaryl, 6) a 4- to 10-membered non-aryl heterocycle, 7) a C.sub.1-6 alkylcarbonyl group, 8) a C.sub.3-10 alicyclic carbonyl group, 9) a C.sub.6-10 arylcarbonyl group, 10) a 5- or 6-membered heteroarylcarbonyl group, 11) a C.sub.1-6 alkylsulfonyl group, 12) a C.sub.3-10 alicyclic sulfonyl group, 13) a C.sub.6-10 arylsulfonyl group, 14) a 5- or 6-membered heteroarylsulfonyl group, or 15) —OR.sup.c1, wherein each substituent from 2) to 14) is optionally substituted, wherein R.sup.a2 and R.sup.b1 together may form an optionally substituted 4- to 10-membered nitrogen-containing non-aryl heterocycle, R.sup.c1 is 1) a hydrogen atom 2) a C.sub.1-6 alkyl group, 3) a C.sub.3-10 alicyclic group, 4) C.sub.6-10 aryl, 5) 5- or 6-membered heteroaryl, or 6) a 4- to 10-membered non-aryl heterocycle, wherein each substituent from 2) to 6) is optionally substituted, L.sup.1 is a single bond, an oxygen atom, a sulfur atom, —SO—, —SO.sub.2—, —NR.sup.d—, —NR.sup.dC(═O)—, or —NR.sup.dSO.sub.2—, L.sup.2 is a single bond or an optionally substituted C.sub.1-6 alkylene group, Z is 1) a hydrogen atom, 2) a hydroxyl group, 3) a cyano group, 4) a carboxyl group, 5) a C.sub.3-10 alicyclic group, 6) C.sub.6-10 aryl, 7) 5- or 6-membered heteroaryl, 8) a 4- to 10-membered non-aryl heterocycle, 9) a C.sub.1-6 alkoxy group, 10) a C.sub.3-10 alicyclic oxy group, 11) a C.sub.6-10 aryloxy group, 12) a 5- or 6-membered heteroaryloxy group, 13) a 4- to 10-membered non-aryl heterocyclyl oxy group, 14) a C.sub.1-6 alkylthio group, 15) a C.sub.3-10 alicyclic thio group, 16) a C.sub.6-10 arylthio group, 17) a 5- or 6-membered heteroarylthio group, 18) a 4- to 10-membered non-aryl heterocyclyl thio group, wherein each substituent from 5) to 18) is optionally substituted, 19) —SO.sub.2—NR.sup.e1R.sub.f1, 20) —NR.sup.e1—C(═O)OR.sup.f1, 21) —NR.sup.g1—C(═O)NR.sup.e1R.sup.f1, 22) —NR.sup.e1—C(═S)R.sup.f1, 23) —NR.sup.e1—C(═S)OR.sup.f1, 24) —NR.sup.g1—C(═S)NR.sup.e1R.sup.f1, 25) —NR.sup.g1—CR.sup.e1(═NR.sup.f1), 26) —NR.sup.g1—CR.sup.e1(═N—OR.sup.f1), 27) —NR.sup.h1—C(═NR.sup.g1)NR.sup.e1R.sup.f1, 28) —NR.sup.h1—C(═N—OR.sup.g1)NR.sup.e1R.sup.f1, 29) —NR.sup.i1—C(═NR.sup.h1)NR.sup.g1—NR.sup.e1R.sup.f1, 30) —NR.sup.i1—C(═N—OR.sup.h1)NR.sup.g1—NR.sup.e1R.sup.f1, 31) —NR.sup.e1—SO.sub.2—R.sup.f1, 32) —NR.sup.g1—SO.sub.2—NR.sup.e1R.sup.f1, 33) —C(═O)OR.sup.e1, 34) —C(═S)OR.sup.e1, 35) —C(═S)NR.sup.e1R.sup.f1, 36) —C(═S)NR.sup.e1OR.sup.f1, 37) —C(═S)NR.sup.g1—NR.sup.e1R.sup.f1, 38) —C(═NR.sup.e1)R.sup.f1, 39) —C(═N—OR.sup.e1)R.sup.f1, 40) —C(═NR.sup.h1)NR.sup.g1—NR.sup.e1R.sup.f1, 41) —C(°N—OR.sup.h1)NR.sup.g1—NR.sup.e1R.sup.f1, 42) —NR.sup.e1R.sup.f1, 43) —NR.sup.g1—NR.sup.e1R.sup.f1, 44) —NR.sup.e1OR.sup.f1, 45) —NR.sup.e1—C(═O)R.sup.f1, 46) —C(═O)NR.sup.e1R.sup.f1, 47) —C(═O)NR.sup.e1OR.sup.f1, 48) —C(═O)NR.sup.g1—NR.sup.e1R.sup.f1, 49) —C(═O)R.sup.e1, 50) —C(═NR.sup.g1)NR.sup.e1R.sup.f1, or 51) —C(═N—OR.sup.h1)NR.sup.e1R.sup.f1, one of R.sup.1, R.sup.2, and R.sup.3 is a group represented by formula (2): ##STR01097## wherein Y is an oxygen atom, a sulfur atom, or —NR.sup.j—, ring A is an optionally substituted 4- to 20-membered non-aryl heterocycle, L.sup.3 is —C(═O)—, —S(═O), or —S(═O).sub.2—, L.sup.4 is 1) a single bond, 2) a C.sub.1-6 alkylene group, 3) a C.sub.3-10 cycloalkylene group, 4) a C.sub.6-10 arylene group, 5) a 5- or 6-membered heteroarylene group, 6) a 4- to 10-membered non-aryl heterocyclylene group, or 7) —C(═N—OR.sup.h1), wherein each substituent from 2) to 6) is optionally substituted, and R.sup.5 is 1) a hydrogen atom 2) a C.sub.1-6 alkyl group, 3) a C.sub.3-10 alicyclic group, 4) a 4- to 10-membered non-aryl heterocycle, 5) C.sub.6-10 aryl, 6) 5- or 6-membered heteroaryl, 7) a C.sub.1-6 alkylthio group, wherein each substituent from 2) to 7) is optionally substituted, or 8) —NR.sup.e1OH, the remaining two, which are without the structure of formula (2) among R.sup.1, R.sup.2 and R.sup.3, are the same or different, each independently a hydrogen atom, a halogen atom, an optionally substituted C.sub.1-6 alkyl group, an optionally substituted C.sub.1-6 alkoxy group, an optionally substituted C.sub.1-6 (alkylthio group, an optionally substituted 5- or 6-membered heteroaryl, or —NR.sup.a3R.sup.b2, R.sup.d, R.sup.e1, R.sup.e2, R.sup.f1, R.sup.f2, R.sup.g1, R.sup.g2, R.sup.h1, R.sup.h2, R.sup.i1, R.sup.i2 and R.sup.j are the same or different, each independently a hydrogen atom, an optionally substituted C.sub.1-6 alkyl group, an optionally substituted C.sub.3-10 alicyclic group, optionally substituted C.sub.6-10 aryl, optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 4- to 10-membered non-aryl heterocycle, a combination of R.sup.e1 and R.sup.f1 or R.sup.e2 and R.sup.f2, when attached to the same nitrogen atom, together may form an optionally substituted 4- to 10-membered nitrogen-containing non-aryl heterocycle, R.sup.4 is 1) —C(═O)R.sup.8, 2) —SO.sub.2-L.sup.6-R.sup.8, wherein R.sup.8 in 1) and 2) is —NR.sup.a5R.sup.b4, —NR.sup.a5-L.sup.7-B(OR.sup.m1).sub.2, —OR.sup.m1, or an optionally substituted C.sub.1-6 alkyl group, and L.sup.6 is a single bond or —NR.sup.a6—, 3) —NR.sup.a4R.sup.b3, 4) —B(OR.sup.m1), 5) —PO(OR.sup.m1)(OR.sup.m2), 6) optionally substituted 5-membered heteroaryl, 7) an optionally substituted 5-membered non-aryl heterocycle, or 8) a bioisostere of one of 1) to 7), wherein the formulas of 2), 4), 5), and 6) include a carboxylic acid isostere, and 8) may include them in duplicates, R.sup.a3, R.sup.a4, R.sup.a5, R.sup.a6, R.sup.b2, R.sup.b3, and R.sup.b4 are the same or different, each independently having the same definition as R.sup.a1, R.sup.a2, and R.sup.b1, wherein a combination of R.sup.a3 and R.sup.b2, R.sup.a4 and R.sup.b3, or R.sup.a5 and R.sup.b4, when attached to the same nitrogen atom, together may form an optionally substituted 4- to 10-membered nitrogen-containing non-aryl heterocycle, R.sup.m1 is 1) a hydrogen atom, 2) a C.sub.1-6 alkyl group, 3) a C.sub.3-10 alicyclic group, 4) C.sub.6-10 aryl, 5) 5- or 6-membered heteroaryl, or 6) a 4- to 10-membered non-aryl heterocycle, wherein each substituent from 2) to 6) is optionally substituted, wherein if R.sup.m1 is attached to a boron atom via an oxygen atom, two R.sup.m1, as C.sub.2-4 alkylene, together with the boron atom and two oxygen atoms, may form a 5- to 7-membered non-aryl heterocycle, wherein an alkylene moiety is optionally substituted in the non-aryl heterocycle, R.sup.m2 is a hydrogen atom, an optionally substituted C.sub.1-6 alkyl group, or an optionally substituted C.sub.3-10 alicyclic group, and L.sup.7 is an optionally substituted C.sub.1-3 alkylene group.

56. The compound or the pharmaceutically acceptable salt thereof according to claim 55, wherein the compound of formula (11) is represented by formula (12): ##STR01098##

57. The compound or the pharmaceutically acceptable salt thereof according to claim 55, wherein the compound of formula (12) is represented by formula (13): ##STR01099##

58. The compound or the pharmaceutically acceptable salt thereof according to claim 57, wherein X and R.sup.G are hydroxyl groups, R.sup.4 is a carboxyl group, and ring A is an optionally substituted 4- to 6-membered nitrogen-containing non-aryl heterocycle.

59. The compound or the pharmaceutically acceptable salt thereof according to claim 58, wherein the compound of formula (13) is represented by formula (14): ##STR01100##

60. The compound or the pharmaceutically acceptable salt thereof according to claim 55, wherein R.sup.G is a hydroxyl group or a thiol group.

61. The compound or the pharmaceutically acceptable salt thereof according to claim 60, wherein R.sup.G is a hydroxyl group.

62. The compound or the pharmaceutically acceptable salt thereof according to claim 55, wherein X is a hydroxyl group or a C.sub.1-6 alkoxy group.

63. The compound or the pharmaceutically acceptable salt thereof according to claim 55, wherein X is a hydroxyl group.

64. The compound or the pharmaceutically acceptable salt thereof according to claim 63, wherein m is 1 or 2, n is 1 or 2, and m+n is 2 or 3.

65. The compound or the pharmaceutically acceptable salt thereof according to claim 64, wherein m is 1, and n is 1.

66. The compound or the pharmaceutically acceptable salt thereof according to claim 55, wherein L.sup.3 is —C(═O)—.

67-69. (canceled)

70. A medicament comprising the compound or the pharmaceutically acceptable salt thereof according to claim 55.

71. The medicament according to claim 70, which is a therapeutic drug or a prophylactic drug for a bacterial infection.

72. A β-lactamase inhibiting agent comprising the compound or the pharmaceutically acceptable salt thereof according to claim 55 as an active ingredient.

73. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof according to claim 55 and a pharmaceutically acceptable carrier.

74. The pharmaceutical composition according to claim 73, further comprising an additional agent.

75. The pharmaceutical composition according to claim 74, wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, and an anti-allergic agent.

76. The pharmaceutical composition according to claim 74, wherein the additional agent is a β-lactam agent.

77. The pharmaceutical composition according to claim 75, wherein the β-lactam agent is selected from the group consisting of amoxicillin, ampicillin (pivampicillin, hetacillin, bacampicillin, metampicillin, and talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethyl penicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin and flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, tomopenem, razupenem, cefazolin, cefacetrile, cefadroxil, cephalexin, cefaloglycin, cefalonium, cefaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicide, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefovecin, aztreonam, tigemonam, carumonam, RWJ-442831, RWJ-333441, and RWJ-333442.

78. The pharmaceutical composition according to claim 77, wherein the β-lactam agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem.

79. The pharmaceutical composition according to claim 77, wherein the β-lactam agent is selected from the group consisting of aztreonam, tigemonam, BAL30072, SYN2416, and carumonam.

80. The pharmaceutical composition according to claim 74, wherein the additional agent is included in the pharmaceutical composition such that the additional agent is concomitantly administered with the compound or the pharmaceutically acceptable salt thereof.

81. The pharmaceutical composition according to claim 80, wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, and an anti-allergic agent.

82. The pharmaceutical composition according to claim 81, wherein the additional agent is a β-lactam agent.

83. The pharmaceutical composition according to claim 82, wherein the β-lactam agent is selected from the group consisting of amoxicillin, ampicillin (pivampicillin, hetacillin, bacampicillin, metampicillin, and talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethyl penicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin and flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, tomopenem, razupenem, cefazolin, cefacetrile, cefadroxil, cephalexin, cefaloglycin, cefalonium, cefaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicide, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefovecin, aztreonam, tigemonam, carumonam, RWJ-442831, RWJ-333441, and RWJ-333442.

84. The pharmaceutical composition according to claim 83, wherein the β-lactam agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem.

85. The pharmaceutical composition according to claim 83, wherein the β-lactam agent is selected from the group consisting of aztreonam, tigemonam, BAL30072, SYN2416, and carumonam.

86. The compound or the pharmaceutically acceptable salt thereof according to claim 55, which is suitable for treating a bacterial infection.

87. The compound or the pharmaceutically acceptable salt thereof according to claim 86, wherein the bacterial infection is a bacterial infection in which a bacteria that can have a β-lactamase is involved.

88. The compound or the pharmaceutically acceptable salt thereof according to claim 87, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, a urinary tract infection, a genital infection, eye infection, or an odontogenic infection.

89. A medicament comprising a combination of the compound or the pharmaceutically acceptable salt thereof according to claim 55 and at least one agent selected from the group consisting of therapeutic agents for sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, a urinary tract infection, a genital infection, eye infection, and an odontogenic infection.

90. (canceled)

91. A method for treating a bacterial infection, comprising administering a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 55 to a patient in need thereof.

92. The method according to claim 91, wherein the bacterial infection is a bacterial infection in which a bacteria that can have a β-lactamase is involved.

93. The method according to claim 92, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, a urinary tract infection, a genital infection, an eye infection, or an odontogenic infection.

94. The method of claim 93, wherein an additional agent is concomitantly administered.

Description

EXAMPLES

[2402] While the present invention is described more specifically with Reference Examples, Examples, and Test Examples hereinafter, the preset invention is not limited thereto.

[2403] Compounds were identified using proton nuclear magnetic resonance spectrum (.sup.1H-NMR), liquid chromatography-mass spectrometry (LCMS), or the like. Tetramethylsilane was used as an internal standard for nuclear magnetic resonance spectrum.

[2404] For column chromatography in the Reference Examples and Examples, Yamazen Corporation's silica gel column, YMC's ODS-A column, and YMC's YMC-Actus Triart C18 were used. For TLC (silica gel plate) in purification using a thin layer chromatography (TLC), Silica gel 60F254 (Merck) was used, and for TLC (NH silica gel plate), TLC plate NH (Fuji Silysia) was used.

[2405] Various data described in the Reference Examples and Example was obtained with the following equipment.

[2406] NMR spectrum: [.sup.1H-NMR] 400 MHz: JEOL JNM-AL series AL400, JEOL EX270, and 500 MHz: JEOL ECA-500.

[2407] 600 Hz: Agilent DD2 600 MHz NMR Spectrometer.

[2408] LC-MS spectrum: Waters ACQUITY™ UltraPerformance LC, Waters AQUITY UPLC H-Class System, Shimadzu LCMS-2020.

[2409] The compound names described in the Reference Examples and Examples were named using ACD/Name (ACD/Labs 12.0, Advanced Chemistry Development Inc.), which are not necessarily in accordance with the IUPAC nomenclature.

[2410] The measuring conditions (hereinafter, also referred to as the measurement methods) for a high performance liquid chromatography-mass spectrometry (LCMS) system are described below. The observed mass spectrometry value [MS(m/z)] is indicated by [M+1].sup.+, and the time of retention at which the mass spectrometry value was observed is indicated by Rt (min). The measurement conditions A to C used for measurement are denoted in each actual measurement value. For example, “LCMS: [M+H].sup.+/Rt=620/1.32.sup.A” expresses that measurement was taken under measurement condition A.

Measurement Condition A

[2411] Measuring equipment: Waters ACQUITY™ UltraPerformance LC

[2412] Column: ACQUITY UPLC BEH C18 1.7 μm 2.1×30 mm column

[2413] Solvent: solution A: 0.05% HCOOH/H.sub.2O, solution B: CH.sub.3CN

Gradient Condition:

[2414] 0.0 to 1.3 minutes; A/B=90/10 to 5/95 (linear gradient)

[2415] 1.3 to 1.5 minutes; A/B=90/10

[2416] Flow rate: 0.80 mL/min

[2417] UV: 220 nm, 254 nm

[2418] Column temperature: 40° C.

Measurement Condition B

[2419] Measuring equipment: Waters AQUITY UPLC H-Class System

[2420] Column: Waters AQUITY UPLC HSS T3 1.8 μm 2.1×50 mm column

[2421] Solvent: solution A: 0.1% HCO.sub.2H/H.sub.2O, solution B: 0.1% HCO.sub.2H/MeCN

Gradient Condition:

[2422] 0.0 to 2.4 minutes; A/B=90/10 to 0/100 (linear gradient)

[2423] 2.4 to 3.2 minutes; A/B=0/100

[2424] Flow rate: 0.70 mL/min

[2425] UV: 190 to 800 nm

[2426] Column temperature: 40° C.

Measurement Condition C

[2427] Measuring equipment: Waters ACQUITY™ UltraPerformance LC

[2428] Column: ACQUITY UPLC BEH C18 1.7 μm 2.1×30 mm column

[2429] Solvent: solution A: 0.05% HCOOH/H.sub.2O, solution B: CH.sub.3CN

Gradient Condition:

[2430] 0.0 to 1.3 minutes; A/B=99/1 to 5/95 (linear gradient)

[2431] 1.3 to 1.5 minutes; A/B=99/1

[2432] Flow rate: 0.80 mL/min

[2433] UV: 220 nm, 254 nm

[2434] Column temperature: 40° C.

Measurement Condition D

[2435] Measuring equipment: Waters AQUITY UPLC H-Class System

[2436] Column: ACQUITY UPLC BEH C18 1.7 μm 2.1×50 mm column

[2437] Solvent: solution A: HCOOH/CH.sub.3CN/H.sub.2O (0.05/50/49.95), solution B: 0.05% HCOOH/CH.sub.3CN

Gradient Condition: 0.0 to 4.0 minutes; A/B=100/0 to 0/100 (linear gradient)

[2438] 4.0 to 5.0 minutes; A/B=0/100

[2439] Flow rate: 0.50 mL/min

[2440] UV: 220 nm, 254 nm

[2441] Column temperature: 40° C.

[2442] Measurement Condition E

[2443] Measuring equipment: Waters ACQUITY™ UltraPerformance LC

[2444] Column: ACQUITY UPLC BEH C18 1.7 μm 2.1×30 mm column

[2445] Solvent: solution A: 0.05% HCOOH/H.sub.2O, solution B: CH.sub.3CN

Gradient Condition:

[2446] 0.0 to 1.3 minutes; A/B=60/40 to 5/95 (linear gradient)

[2447] 1.3 to 1.5 minutes; A/B=60/40

[2448] Flow rate: 0.80 mL/min

[2449] UV: 220 nm, 254 nm

[2450] Column temperature: 40° C.

Measurement Condition F

[2451] Measuring equipment: Waters ACQUITY™ UltraPerformance LC

[2452] Column: ACQUITY UPLC BEH C18 1.7 μm 2.1×30 mm column

[2453] Solvent: solution A: 0.05% HCOOH/H.sub.2O, solution B: CH.sub.3CN

Gradient Condition:

[2454] 0.0 to 1.3 minutes; A/B=98/2 to 4/96 (linear gradient)

[2455] 1.3 to 1.5 minutes; A/B=98/2

[2456] Flow rate: 0.80 mL/min

[2457] UV: 220 nm, 254 nm

[2458] Column temperature: 40° C.

Measurement Condition G

[2459] Measuring equipment: Shimadzu LCMS-2020

[2460] Column: Phenomenex Kinetex 1.7 pim C.sub.18 (50 mm×2.10 mm)

[2461] Solvent: solution A: 0.05% TFA/H.sub.2O, solution B: CH.sub.3CN

Gradient Condition:

[2462] 0.0 to 1.9 minutes; A/B=99/1 to 1/99 (linear gradient)

[2463] 1.91 to 3.00 minutes; A/B=1/99

[2464] Flow rate: 0.50 mL/min

[2465] UV: 220 nm, 254 nm

[2466] Column temperature: 40° C.

Measurement Condition H

[2467] Measuring equipment: Shimadzu LCMS-2020

[2468] Column: Phenomenex Kinetex 1.7 μm C.sub.18 (50 mm×2.10 mm)

[2469] Solvent: solution A: 0.05% TFA/H.sub.2O, solution B: CH.sub.3CN

Gradient Condition:

[2470] 0.0 to 1.9 minutes; A/B=90/10 to 1/99 (linear gradient)

[2471] 1.91 to 3.00 minutes; A/B=1/99

[2472] Flow rate: 0.50 mL/min

[2473] UV: 220 nm, 254 nm

[2474] Column temperature: 40° C.

Measurement Condition I

[2475] Measuring equipment: Waters AQUITY™ UPLC H-Class System

[2476] Column: Waters AQUITY UPLC BEH C18 1.7 μm 2.1×50 mm column

[2477] Solvent: solution A: 0.05% HCO.sub.2H/H.sub.2O, solution B: 0.05% HCO.sub.2H/MeCN

Gradient Condition:

[2478] 0.0 to 4.0 minutes; A/B=90/10 to 0/100 (linear gradient)

[2479] 4.0 to 5.0 minutes; A/B=0/100

[2480] Flow rate: 0.50 mL/min

[2481] UV: 220, 254 nm

[2482] Column temperature: 40° C.

[2483] The abbreviations described above and the following abbreviations are used in the Reference Examples, Examples, and Test Examples in some cases to simplify the description. [2484] s: singlet [2485] d: doublet [2486] t: triplet [2487] q: quadruplet [2488] m: multiplet [2489] br: broad [2490] dd: double doublet [2491] J: coupling constant [2492] Hz: Hertz [2493] δ: chemical shift [2494] min: minute [2495] THF: tetrahydrofuran [2496] DMAP: N,N-dimethyl-4-aminopyridine [2497] TFA: trifluoroacetic acid [2498] DIPEA: N,N-diisopropylethylamine [2499] DMF: dimethylformamide [2500] DME: 1,2-dimethoxyethane [2501] NMP: N-methylpyrrolidone [2502] DMSO: dimethyl sulfoxide [2503] Me: methyl [2504] Et: ethyl [2505] MeCN: acetonitrile [2506] CPME: cyclopentyl methyl ether [2507] Boc: tert-butoxycarbonyl [2508] LBu or .sup.tBu or t-Bu: tert-butyl [2509] t-: tert- [2510] Bn: benzyl [2511] Cbz: benzyloxycarbonyl [2512] Trt: trityl(triphenylmethyl) [2513] Ms: methanesulfonyl, mesyl [2514] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate [2515] N: normal [2516] M: mol/L, molarity [2517] MEPM: meropenem [2518] MIC: minimum inhibitory concentration

Reference Example 1: tert-butyl[1-(3-hydroxyazetidin-1-yl)ethylidene]carbamate

[2519] ##STR00702## ##STR00703##

Reference Example 1-1:3-bromo-2,6-dihydroxybenzoic acid

[2520] ##STR00704##

[2521] N-bromosuccinimide (6.06 g, 34.1 mmol) was added in small portions to a dichloromethane solution (59 mL) of 2,6-dihydrobenzoic acid (5 g, 32.4 mmol) and —N,N-diisopropylethylamine (2.27 mL, 16.2 mmol) at −78° C. The reaction solution was warmed up to room temperature, and stirred for 20 hours at said temperature. The reaction solution was evaporated under reduced pressure. 1 mol/L hydrochloric acid (40 mL) was added to the resulting residue, and the mixture was stirred for 30 minutes at room temperature. The precipitated crystals were filtered out, washed with water, and dried to obtain the title compound (6.03 g).

[2522] .sup.1H-NMR (CDCl.sub.3) δ: 7.58 (1H, d, J=9.2 Hz), 6.53 (1H, d, J=8.5 Hz).

[2523] LCMS: [M+H].sup.+/Rt=233/0.412 min.sup.A

Reference Example 1-2: tert-butyl 3-bromo-2,6-bis[(tert-butoxycarbonyl)oxy]benzoate

[2524] ##STR00705##

[2525] Di-tert-butyl dicarbonate (65.2 g, 299 mmol) and DMAP (0.608 g, 4.98 mmol) were added to a THF (120 mL)/tert-butanol (60 mL) solution of the compound of Reference Example 1-1 (11.6 g, 49.8 mmol), and the reaction mixture was stirred for 18 hours at 60° C. The reaction solution was cooled to room temperature. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=99/1 to 95/5) to obtain the title compound (19.3 g).

[2526] .sup.1H-NMR (CDCl.sub.3) δ: 7.60 (1H, d, J=8.5 Hz), 7.02 (1H, d, J=8.5 Hz), 1.53 (9H, s), 1.51 (9H, s).

Reference Example 1-3: tert-butyl 2,6-bis[(tert-butoxycarbonyl)oxy]-3-ethenylbenzoate

[2527] ##STR00706##

[2528] Tri-n-butylvinyltin (2.04 mL, 6.95 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.488 g, 0.695 mmol) were added to a 1,4-dioxane (7 mL) solution of the compound of Reference Example 1-2 (1.7 g, 3.47 mmol) under a nitrogen atmosphere, and the reaction mixture was stirred for 10 hours at 110° C. After cooling the reaction solution to room temperature, the reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (1.26 g).

[2529] .sup.1H-NMR (CDCl.sub.3) δ: 7.57 (1H, d, J=9.2 Hz), 7.11 (1H, d, J=8.5 Hz), 6.73 (1H, dd, J=17.7, 11.3 Hz), 5.74 (1H, d, J=17.7 Hz), 5.37 (1H, d, J=10.4 Hz), 1.57 (9H, s), 1.54 (9H, s), 1.52 (9H, s).

Reference Example 1-4: tert-butyl 2,6-bis[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]benzoate

[2530] ##STR00707##

[2531] 1,4-bis(diphenylphosphino)butane (0.547 g, 1.28 mmol), bis(1,5-cyclooctadiene)diiridium(I) dichloride (0.431 g, 0.641 mmol), and pinacolatodiboron (1.40 mL, 9.62 mmol) were added to a dichloromethane (32 mL) solution of the compound of Reference Example 1-3 (2.8 g, 6.41 mmol) under a nitrogen atmosphere, and the reaction mixture was stirred for 17 hours at room temperature. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (3.59 g).

[2532] .sup.1H-NMR (CDCl.sub.3) δ: 7.30 (1H, d, J=8.5 Hz), 7.01 (1H, d, J=8.5 Hz), 2.66-2.58 (2H, m), 1.53 (9H, s), 1.51 (9H, s), 1.51 (9H, s), 1.20 (12H, s), 1.10-1.02 (2H, m).

Reference Example 1-5: tert-butyl 2,6-bis[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2533] ##STR00708##

[2534] (1S,2S,3R,5S)-(+)-pinanediol (0.736 g, 4.32 mmol) was added to a THF (5 mL) solution of the compound of Reference Example 1-4 (0.976 g, 1.73 mmol), and the reaction mixture was stirred for 62 hours at room temperature. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=99/1 to 85/15) to obtain the title compound (0.90 g).

[2535] .sup.1H-NMR (CDCl.sub.3) δ: 7.31 (1H, d, J=8.5 Hz), 7.01 (1H, d, J=7.9 Hz), 4.23 (1H, dd, J=8.5, 1.8 Hz), 2.69-2.60 (2H, m), 2.35-2.24 (1H, m), 2.20-2.11 (1H, m), 2.04-1.97 (1H, m), 1.91-1.76 (2H, m), 1.54 (9H, s), 1.51 (18H, s), 1.34 (3H, s), 1.26 (3H, s), 1.14-1.07 (2H, m), 1.02 (1H, d, J=11.0 Hz), 0.81 (3H, s).

[2536] LCMS: [M−H].sup.+/Rt=615/3.160 min.sup.B

Reference Example 1-6: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-hydroxy-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2537] ##STR00709##

[2538] Pyrrolidine (0.121 mL, 1.46 mmol) was added to a THF (5 mL) solution of the compound of Reference Example 1-5 (0.899 g, 1.46 mmol), and the reaction mixture was stirred for 3 hours at room temperature. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=90/10 to 70/30) to obtain the title compound (0.68 g).

[2539] .sup.1H-NMR (CDCl.sub.3) δ: 11.26 (1H, s), 7.33 (1H, d, J=8.5 Hz), 6.82 (1H, d, J=8.5 Hz), 4.24 (1H, dd, J 8.8, 2.1 Hz), 2.63-2.54 (2H, m), 2.37-2.25 (1H, m), 2.23-2.11 (1H, m), 2.04-2.00 (1H, m), 1.93-1.78 (2H, m), 1.61 (9H, s), 1.54 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.13-1.01 (3H, m), 0.83 (3H, S).

[2540] LCMS: [M−H].sup.+/Rt=515/3.175 min.sup.B

Reference Example 1-7: benzyl 3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxyl]azetidine-1-carboxylate

[2541] ##STR00710##

[2542] Under a nitrogen atmosphere, cesium carbonate (4.01 g) was added to a DMF (20.5 mL) solution of the compound of Reference Example 1-6 (2.117 g) and benzyl 3-iodoazetidine-1-carboxylic acid (1.95 g), and the reaction mixture was heated to 50° C. After 9 hours, the reaction mixture was cooled to room temperature. The reaction mixture was poured into water, extracted with a mixture solvent of ethyl acetate/hexane (1:1), and concentrated, and the residue was purified by using a silica gel column to obtain the title compound (2.46 g).

[2543] .sup.1H-NMR (CDCl.sub.3) δ: 7.36-7.26 (5H, m), 7.18 (1H, d, J=8.5 Hz), 6.36 (1H, d, J=8.5 Hz), 5.08 (2H, s), 4.91-4.84 (1H, m), 4.37-4.27 (2H, m), 4.24-4.18 (1H, m), 4.09-4.03 (2H, m), 2.58 (2H, t, J=8.2 Hz), 2.32-2.25 (1H, m), 2.18-2.08 (1H, m), 2.04-1.95 (1H, m), 1.89-1.84 (1H, m), 1.82-1.74 (1H, m), 1.53 (9H, s), 1.51 (9H, s), 1.34 (3H, s), 1.26 (3H, s), 1.08 (2H, t, J=8.2 Hz), 1.00 (1H, d, J=11.0 Hz), 0.81 (3H, s).

Reference Example 1-8: tert-butyl 6-[(azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate monohydrochloride

[2544] ##STR00711##

[2545] 1 N hydrochloric acid (0.567 mL) and 50% water containing 10% palladium on carbon (0.149 g) were added to a methanol (16 mL) solution of the compound of Reference Example 1-7 (0.4 g), and the reaction mixture was stirred for 1 hour under hydrogen atmosphere. After celite filtration, the filtrate was concentrated to obtain the title compound (0.357 g).

[2546] .sup.1H-NMR (CD.sub.3OD) δ: 7.31 (1H, d, J=8.5 Hz), 6.66 (1H, d, J=8.5 Hz), 5.14 (1H, m), 4.55-4.42 (2H, m), 4.29-4.22 (1H, m), 4.13-4.05 (2H, m), 2.55 (2H, t, J=8.2 Hz), 2.35-2.30 (1H, m), 2.17-2.13 (1H, m), 1.99-1.92 (1H, m), 1.87-1.80 (1H, m), 1.79-1.72 (1H, m), 1.56 (9H, s), 1.50 (9H, s), 1.33 (3H, s), 1.27 (3H, s), 1.04 (2H, t, J=8.2 Hz), 0.98-0.96 (1H, m), 0.83 (3H, s).

Reference Example 1: tert-butyl 6-[(1-acetylazetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2547] ##STR00712##

[2548] Acetic anhydride (0.023 mL) and triethylamine (0.057 mL) were added to a THF (0.8 mL) solution of the compound of Reference Example 1-8 (0.1 g) in an ice bath, and the reaction mixture was stirred overnight at room temperature. After concentration, the mixture was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (0.105 g).

[2549] .sup.1H-NMR (CDCl.sub.3) δ: 7.19 (1H, d, J=8.5 Hz), 6.39 (1H, d, J=8.5 Hz), 4.93-4.88 (1H, m), 4.46-4.30 (2H, m), 4.24-4.18 (1H, m), 4.16-4.00 (2H, m), 2.59 (2H, t, J=8.7 Hz), 2.35-2.23 (1H, m), 2.20-2.09 (1H, m), 2.01-1.96 (1H, m), 1.91-1.82 (4H, m), 1.82-1.73 (1H, m), 1.54 (9H, s), 1.49 (9H, d, J a 15.8 Hz), 1.32 (3H, t, J=7.0 Hz), 1.25 (3H, s), 1.10 (2H, t, J=8.7 Hz), 1.03-0.97 (1H, m), 0.81 (3H, s).

Reference Example 2: tert-butyl 6-[(1-methylsulfonylazetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2550] ##STR00713##

[2551] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 as the starting material by the same method described in Reference Example 1 to obtain the title compound.

[2552] .sup.1H-NMR (CDCl.sub.3) δ: 7.20 (1H, d, J=8.5 Hz), 6.41 (1H, d, J=8.5 Hz), 4.93-4.87 (1H, m), 4.29-4.20 (3H, m), 4.00-3.97 (2H, m), 2.89 (3H, s), 2.61-2.57 (2H, m), 2.33-2.26 (1H, m), 2.15 (1H, ddd, J=13.7, 6.1, 3.4 Hz), 2.00 (1H, t, J=5.5 Hz), 1.87 (1H, td, J=6.3, 3.9 Hz), 1.78 (1H, dt, J=14.6, 2.7 Hz), 1.55 (9H, s), 1.51 (9H, s) 1.34 (3H, s), 1.26 (3H, s), 1.11-1.06 (2H, m), 1.00 (2H, d, J=11.0 Hz), 0.81 (3H, s).

Reference Example 3: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-({1-[(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-3-{2-[(3aS,4S,6S,7aR)-3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2553] ##STR00714##

[2554] HATU was added to a DMF (0.905 mL) solution of the compound of Reference Example 1-8 (0.11 g), 4-imidazoleacetic acid hydrochloride (0.059 g), and triethylamine (0.076 mL) in an ice bath. The reaction mixture was slowly warmed up to room temperature, and stirred for 18 hours. The reaction mixture was poured into water, extracted with a mixture solvent of ethyl acetate/hexane (2:1), and concentrated, and the residue was purified by using a silica gel column to obtain the title compound (0.096 g).

[2555] .sup.1H-NMR (CDCl.sub.3) δ: 8.19 (1H, s), 7.21 (1H, d, J=8.5 Hz), 7.00 (1H, s), 6.39 (1H, d, J=8.5 Hz), 4.90 (1H, m), 4.61-4.59 (1H, m), 4.31-4.27 (1H, m), 4.23-21 (1H, m), 4.7-4.05 (1H, m), 3.81-78 (1H, m), 3.54 (2H, s), 2.58 (2H, m), 2.30-2.26 (2H, m), 2.17-2.13 (1H, m), 2.02-1.98 (1H, m), 1.88-1.87 (1H, m), 1.80-1.77 (1H, m), 1.54 (9H, s), 1.51 (9H, s), 1.33 (3H, s), 1.25 (3H, s), 1.10-1.06 (2H, m), 1.22-1.10 (1H, s), 0.81 (3H, s).

[2556] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 as the starting material by the same method described in Reference Example 3 to obtain each of Reference Example compounds 4 to 34 shown in Table 2.

TABLE-US-00002 TABLE 2 Reference Example Structural formula NMR and/or LCMS 4 [00715] embedded image .sup.1H-NMR (CDCl.sub.3) δ: 7.31- 7.23 (18H, m), 7.19 (1H, d, J = 8.5 Hz), 6.96 (1H, s), 6.56 (1H, s), 6.35 (1H, d, J = 8.5 Hz), 4.93 (1H, ddd, J = 11.3, 5.8, 3.7 Hz), 4.46 (1H, dd, J = 11.0, 6.7 Hz), 4.32 (1H, dd, J = 9.2, 6.7 Hz), 4.22 (1H, dd, J = 8.5, 1.8 Hz), 4.16- 4.04 (3H, m), 4.01 (4H, t, J = 10.7 Hz), 2.59 (2H, t, J = 8.2 Hz), 2.33-2.26 (1H, m), 2.15 (1H, tt, J = 10.7, 3.5 Hz), 1.99 (3H, t, J = 5.8 Hz), 1.89-1.85 (1H, m), 1.78 (1H, dt, J = 14.6, 2.7 Hz), 1.65 (2H, t, J = 6.1 Hz), 1.55-1.46 (19H, m), 1.37-1.29 (4H, m), 1.27 (4H, d, J = 9.8 Hz), 1.07 (2H, dd, J = 15.3, 7.3 Hz), 1.01 (1H, t, J = 7.6 Hz), 0.81 (3H, s). 5 [00716] embedded image .sup.1H-NMR (CDCl.sub.3) δ: 8.54 (1H, d, = 4.3 Hz), 8.10 (1H, d, J = 7.9 Hz), 7.79- 7.77 (1H, m), 7.35-7.32 (1H, m), 7.21 (1H, d, J = 8.5 Hz), 6.44 (1H, d, = 8.5 Hz), 5.09-5.06 (1H, m), 4.98-4.97 (1H, m), 4.70-4.67 (1H, m), 4.58- 4.55 (1H, m), 4.30-4.19 (2H, m), 2.60 (2H, t, J = 8.2 Hz), 2.31-2.28 (1H, m), 2.18-2.13 (1H, m), 2.02- 1.99 (1H, m), 1.87 (1H, br s), 1.81-1.77 (1H, m), 1.53 (9H, s), 1.51 (9H, s), 1.34 (3H, s), 1.26 (3H, s), 1.10 (2H, t, = 7.9 Hz), 1.01 (1H, d, J = 11.0 Hz), 0.81 (3H, s). 6 [00717] embedded image .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J = 8.6 Hz), 6.42 (1H, d, J = 8.6 Hz), 5.30 (2H, s), 5.00-4.90 (1H, m), 4.60-4.52 (1H, m), 4.46- 4.36 (1H, m), 4.28-4.08 (4H, m), 3.07 (2H, s), 2.66- 2.58 (2H, m), 2.39-2.24 (1H, m), 2.22-2.12 (1H, m), 2.07-1.99 (1H, m), 1.93-1.76 (2H, m), 1.57 (9H, s), 1.54 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14- 1.01 (3H, m), 0.84 (3H, s). 7 [00718] embedded image .sup.1H-NMR (CDCl.sub.3) δ: 8.19 (1H, s), 7.24 (1H, d, J = 8.6 Hz), 6.46 (1H, d, J = 8.6 Hz), 5.18-5 00 (2H, m) 4.76-4.58 (2H, m), 4.14- 4.09 (2H, m), 2.62 (2H, t, J = 8.2 Hz), 2.38-2.25 (1H, m), 2.23-2.09 (1H, m), 2.07-1.99 (1H, m), 1.93- 1.75 (2H, m), 1.56 (9H, s), 1.54 (9H, s), 1.34 (3H, s), 1.28 (3H, s), 1.12 (2H, t, J = 8.2 Hz), 1.07-1.00 (1H, m), 0.84 (3H, s). 8 [00719] embedded image .sup.1H-NMR (CDCl.sub.3) δ: 8.20- 8.17 (1H, m), 7.55-7.51 (1H, m), 7.38-7.12 (4H, m), 6.39 (1H, d, J = 8.6 Hz). 5.13-4.96 (1H, m), 4.77- 4.61 (2H, m), 4.28-4.23 (2H, m), 4.14-4.05 (1H, m), 2.72-2.55 (2H, m), 2.32- 2.25 (1H, m), 2.23-2.10 (1H, m), 2.07-1.98 (1H, m), 1.95-1.74 (2H, m), 1.56 (9H, s), 1.53 (9H, s), 1.35 (3H, s), 1.28 (3H, 2), 1.13- 1.00 (3H, m), 0.83 (3H, s). 9 [00720] embedded image .sup.1H-NMR (CDCl.sub.3) δ: 7.43- 7.28 (4H, m), 7.23-7.14 (1H, m), 6.40-6.27 (1H, m), 5.97-5.78 (1H, m), 5.22- 5.10 (1H, m), 4.99-471 (1H, m), 4.65-4.37 (1H, m), 4.35-4.18 (2H, m), 4.18- 4.04 (1H, m), 4.04-3.77 (1H, m), 2.66-2.54 (2H, m), 2.38-2.24 (1H, m), 2.205-1.98 (1H, m), 1.94- 1.85 (1H, m), 1.84-1.74 (1H, m), 1.57 (9H, m), 1.54-1.48 (9H, m), 1.42- 1.36 (9H, m), 1.35 (3H, s), 1.28 (3H, s), 1.14-0.94 (1H, m), 0.83 (3H, s). 10 [00721] embedded image .sup.1H-NMR (CDCl.sub.3) δ: 7.67- 7.59 (2H, m), 7.50-7.36 (3H, m), 7.23-7.19 (1H, d, J = 8.6 Hz), 6.41 (1H, d, J = 8.6 Hz), 5.05-4.95 (1H, m), 4.64-4.50 2H, m), 4.39-4.30 (3H, m), 2.73- 2.55 (2H, m), 2.39-2.25 (1H, m), 2.25-2.09 (1H, m), 2.08-1.96 (1H, m), 1.95-1.75 (2H, m), 1.60- 1.75 (18H, m), 1.37-1.23 (6H, m), 1.22-0.96 (3H, m), 0.86-0.80 (3H, m). 11 [00722] embedded image LCMS: [M + H].sup.+/Rt = 678/2.75 min.sup.B 12 [00723] LCMS: [M + H].sup.+/Rt = 692/2.62 min.sup.B 13 [00724] LCMS: [M + H].sup.+/Rt = 692/2.53 min.sup.B 14 [00725] LCMS: [M + H].sup.+/Rt = 828/3.06 min.sup.B 15 [00726] LCMS: [M + H].sup.+/Rt = 692/2.79 min.sup.B 16 [00727] .sup.1H-NMR (CDCl.sub.3) δ: 7.32- 7.26 (2H, m), 7.23-7.17 (1H, m), 7.16-7.00 (2H, m), 6.43-6.36 (1H, m), 4.95-4.86 (1H, m), 4.46- 4.30 (2H, m), 4.29-4.20 (1H, m), 4.18-4.06 (2H, m), 3.55-3.40 (2H, m), 2.68-2.55 (2H, m), 2.39- 2.24 (1H, m), 2.22-2.10 (1H, m), 2.08-1.98 (1H, m), 1.95-1.73 (2H, m), 1.62-1.49 (27H, m), 1.36 (3H, s), 1.28 (3H, m), 1.14-1.01 (3H, m), 0.83 (3H, s). 17 [00728] embedded image LCMS: [M + H].sup.+/Rt = 922/3.08 min.sup.B 18 [00729] LCMS: [M + H].sup.+/Rt = 682/2.63 min.sup.B 19 [00730] LCMS: [M + H].sup.+/Rt = 852/3.06 min.sup.B 20 [00731] .sup.1H-NMR (CDCl.sub.3) δ: 7.37- 7.17 (6H, m), 6.42-6.34 (1H, m), 4.94-4.84 (1H, m), 4.44-4.32 (2H, m), 4.29- 4.19 (1H, m), 4.18-4.02 (2H, m), 3.50 (2H, s), 2.68- 2.54 (2H, m), 2.38-2.26 (1H, m), 2.24-2.10 (1H, m), 2.06-1.98 (1H, m), 1.95- 1.73 (2H, m), 1.54 (9H, s), 1.54 (9H, s) 1.36 (3H, s), 1.28 (3H, m), 1.13-1.00 (3H, m), 0.83 (3H, s). 21 [00732] embedded image LCMS: [M + H].sup.+/Rt = 705/2.98 min.sup.B 22 [00733] LCMS: [M + H].sup.+/Rt = 681/2.22 min.sup.B 23 [00734] LCMS: [M + H].sup.+/Rt = 682/2.66 min.sup.B 24 [00735] LCMS: [M + H].sup.+/Rt = 683/2.62 min.sup.B 25 [00736] LCMS: [M + H].sup.+/Rt = 820/3.06 min.sup.B 26 [00737] LCMS: [M + H].sup.+/Rt = 936/3.12 min.sup.B 27 [00738] embedded image LCMS: [M + H].sup.+/Rt = 810/2.20 min.sup.B 28 [00739] LCMS: [M + H].sup.+/Rt = 772/3.01 min.sup.B 29 [00740] LCMS: [M + H].sup.+/Rt = 810/2.20 min.sup.B 30 [00741] LCMS: [M + H].sup.+/Rt = 874/2.87 min.sup.B 31 [00742] LCMS: [M + H].sup.+/Rt = 770/3.01 min.sup.B 32 [00743] LCMS: [M + H].sup.+/Rt = 770/3.01 min.sup.B 33 [00744] embedded image LCMS: [M + H].sup.+/Rt = 824/2.20 min.sup.B 34 [00745] .sup.1H-NMR (CD.sub.3OD) δ: 7.34 (2H, d, J = 8.5 Hz), 7.30- 7.29 (3H, m), 7.22-7.20 (2H, m), 7.06 (1H, d, J = 8.5 Hz), 6.89 (2H, d, J = 8.5 H), 6.84 (2H, d, J = 8.5 Hz), 6.63 (1H, d, J = 8.5 Hz), 5.07 (2H, s), 5.06 (2H, s), 5.05-5.02 (1H, m), 4.52-4.49 (2H, m), 4.27 (1H, d, J = 7.3 Hz), 4.10-4.08 (2H, m), 3.77 (3H, s), 3.74 (3H, s), 2.57 (2H, t, J = 8.2 Hz), 2.34-2.31 (1H, m), 2.16- 2.15 (1H, m), 1.97 (1H, t, J = 5.5 Hz), 1.84 (1H, br s), 1.78-1.75 (1H, m), 1.53 (9H, s), 1.51 (9H, s), 1.33 (3H, s), 1.26 (3H, s), 1.07 (2H, t, J = 7.9 Hz), 0.96-0.94 (1H, m), 0.84 (3H, s).

Reference Example 35: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-{[1-(hydroxycarbamoyl)azetidin-3-yl]oxy}-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2557] ##STR00746##

[2558] Triphosgene (14.92 mg) was added to a toluene solution of the compound of Reference Example 1-8 (76.4 mg) and DIPEA (0.066 mL) at ° C., The reaction mixture was returned to room temperature and stirred for 1.5 hours. The reaction mixture was concentrated. DMF (2.5 mL), DIPEA (0.5 mL), and hydroxylamine hydrochloride (51 mg) were added to the residue, and the reaction mixture was stirred for 3 hours at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography to obtain the title compound (56.5 mg) as a colorless solid.

[2559] .sup.1H-NMR (CDCl.sub.3) δ: 7.12 (1H, d, J=8.5 Hz), 7.04 (1H, S), 7.00 (1H, br s), 6.33 (1H, d, J=8.5 Hz), 4.87-4.83 (1H, m), 4.34 (2H, dd, J=9.8, 6.7 Hz), 4.17 (1H, dd, J=8.5, 1.8 Hz), 4.06-4.01 (2H, m), 2.53 (2H, t, J=8.5 Hz), 2.28-2.21 (1H, m), 2.13-2.07 (1H, m), 1.95 (1H, t, J=5.5 Hz), 1.83-1.81 (1H, m), 1.75-1.72 (1H, m), 1.49 (9H, s), 1.46 (9H, s), 1.29 (3H, s), 1.21 (3H, s), 1.03 (2H, t, J=8.5 Hz), 0.96 (1H, d, J=10.4 Hz), 0.76 (3H, s).

Reference Example (R)-36: tert-butyl 6-({1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Reference Example (S)-36: tert-butyl 6-({1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-(2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2560] ##STR00747## ##STR00748##

Reference Example 36-1:4-formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide

[2561] ##STR00749##

[2562] Dimethylsulfamoyl chloride (91 mL, 859 mmol) was added dropwise to a chloroform solution (750 ml) of 1H-imidazole-4-carbaldehyde (75 g, 78 mmol) and triethylamine (163 mL, 1.17 mol) over 50 minutes at room temperature. The reaction solution was stirred for 3 days and then water (900 mL) was added, and the mixture was extracted with chloroform (500 mL, 3 times). The organic phase was dried over sodium sulfate, filtered, and concentrated to obtain the title compound (161 g) as a white solid with a brownish tinge.

[2563] .sup.1H-NMR (CDCl.sub.3) δ: 9.88 (1H, br s), 7.91 (1H, t, J=7.3 Hz), 7.84 (1H, dd, J=8.5, 1.2 Hz), 2.87 (6H, dd, J=9.8, 5.5 Hz).

Reference Example 36-2: amino(1H-imidazol-4-yl)acetic acid dihydrochloride

[2564] ##STR00750##

[2565] Sodium cyanide (46.7 g, 953 mmol) was added to an ethanol solution (227 mL) of the compound of Reference Example 36-1 (161 g, 794 mmol) and 28t aqueous ammonia (371 mL) while being cooled with ice (internal temperature of 14° C.). The reaction solution was stirred for 4 hours at room temperature and then extracted with chloroform (500 mL, 4 times). The organic phase was dried over sodium sulfate, filtered, and concentrated. 6 N aqueous hydrochloric acid (850 mL) was added to the resulting solid residue, and the reaction mixture was refluxed for 4 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The resulting solid residue was stirred and washed with a THF-ethanol mixture solvent (1:1, 750 mL) and filtered to obtain the title compound (160 g) as a yellow solid with a brownish tinge.

[2566] .sup.1H-NMR (D.sub.2O) δ: 8.69 (1H, s), 7.54 (1H, s), 5.14 (1H, s).

Reference Example 36-3: [(tert-butoxycarbonyl)amino](1H-imidazol-4-yl) acetic acid hydrochloride

[2567] ##STR00751##

[2568] An aqueous 3 N sodium hydroxide solution (374 mL) was added dropwise to a methanol solution (194 mL) of the compound of Reference Example 36-2 (80 g, 374 mmol) over 45 minutes while cooling with ice. After stirring the reaction solution for 15 minutes while cooling with ice, di-tert-butyl dicarbonate was added over 15 minutes. The reaction solution was stirred for 45 minutes while cooling with ice and then warmed up to room temperature. To the reaction solution, N,N-dimethyl-4-aminopyridine (2.28 g, 18.7 mmol) and 2,2,2-trifluoroethanol (53.4 mL, 747 mmol) were added at room temperature, and the reaction solution was refluxed for 2 hours. After the reaction solution was allowed to cool down, 6 N aqueous hydrochloric acid (25 mL) was added while cooling with ice to adjust the pH of the solution to 6.0. After stirring for 1 hour while cooling with ice, the precipitated solid was filtered out, washed with acetone-water mixture solvent (1:1, 1 L), and dried and solidified under reduced pressure to obtain the title compound (40.0 g) as a white solid.

[2569] .sup.1H-NMR (D.sub.2O) 5: 8.50 (1H, d, J=1.2 Hz), 7.27 (1H, s), 5.04 (1H, s), 1.30 (9H, s).

Reference Example 36: tert-butyl 6-({1-[2-({tert-butoxycarbonyl}amino)-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2570] ##STR00752##

[2571] Triethylamine (1.54 ml, 11.1 mmol), 1-hydroxybenzotriazole (0.747 g, 5.53 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.689 g, 3.59 mmol) were added to a DMF solution (9.21 mL) of the compound of Reference Example 36-3 (1.0 g, 4.15 mmol) while cooling with ice. After stirring for 1 hour while cooling with ice, N,N-dimethyl-4-aminopyridine (0.068 g, 0.553 mmol) and the compound of Reference Example 1-8 (1.68 g, 2.76 mmol) were added to the reaction solution. After stirring for 24 hours at room temperature, an aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic phase was dried over sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to obtain the title compound (1.09 g) as a while amorphous compound.

[2572] LCMS: [M+H].sup.+/Rt=795.44/0.845 min.sup.E

[2573] The compound of Reference Example 36 (amount charged per injection: 19.6 mg) was dissolved in 0.300 mL of ethyl acetate. Isomers were obtained by optical resolution by chiral chromatography under the following conditions.

[2574] Column: CHIRALPAK IG 20 mmφ×250 mm (Daicel Corporation)

[2575] Mobile phase: diethylamine/ethyl acetate (diethylamine: 0.1%)

[2576] Flow rate: 10 mL/min

[2577] Temperature: 40° C.

[2578] Column retention times for both optical isomers were as follows. [2579] (R)-36: 6.056 min [2580] (S)-36: 4.225 min

Reference Example 37. tert-butyl 6-[(1-{[(tert-butoxycarbonyl)amino](1-methyl-1H-imidazol-4-yl)acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2581] ##STR00753##

Reference Example 37-1: [(tert-butoxycarbonyl)amino](1-methyl-1H-imidazol-4-yl) acetic acid

[2582] ##STR00754##

[2583] Sodium hydrogen carbonate (1.09 g, 13.0 mmol) and di-tert-butyl dicarbonate (1.30 mL, 5.62 mmol) were added to a methanol/water (1:1, 8.6 mL) solution of amino(1-methyl-1H-imidazol-4-yl) acetic acid (670 mg, 4.32 mmol), and the reaction mixture was stirred at room temperature. After 2 hours, the reaction solution was concentrated, and the residue was dissolved in ethanol (17 mL). Potassium hydrogen sulfate (2.35 g) was added at 0° C. to quench the reaction. Solids were filtered out, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0 to 40/60) to obtain the title compound (400 mg) as a yellow solid.

[2584] LCMS: [M+H].sup.+/Rt=255.94/0.419 min.sup.C

Reference Example 37: tert-butyl 6-[(1-{[(tert-butoxycarbonyl)amino](1-methyl-1H-imidazol-4-yl)acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2585] ##STR00755##

[2586] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 (325 mg, 0.535 mmol) and the compound of Reference Example 37-1 (205 mg, 0.803 mmol) as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound (130 mg).

[2587] LCMS: [M+H].sup.+/Rt=809.58/1.246 min.sup.C

Reference Example 38: tert-butyl 6-[(1-{[(tert-butoxycarbonyl)amino](2-methyl-1H-imidazol-4-yl)acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2588] ##STR00756##

Reference Example 38-1: [(tert-butoxycarbonyl)amino][1-(tert-butoxycarbonyl)-2-methyl-1H-imidazol-4-yl]acetic acid

[2589] ##STR00757##

[2590] Di-tert-butyl dicarbonate (1.64 g, 7.52 mmol) was added to a methanol solution (10 mL) of methyl 2-amino-2-(2-methyl-1H-imidazol-4-yl)acetate dihydrochloride (0.828 g, 3.42 mmol), N,N-dimethyl-4-aminopyridine (0.084 g, 0.684 mmol), and triethylamine (1.91 mL, 13.7 mmol) at room temperature, and the reaction mixture was stirred. After the completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate and concentrated to obtain the title compound (0.59 g).

[2591] .sup.1H-NMR (CD.sub.3OD) δ: 7.31 (1H, s), 4.91 (1H, s), 2.53 (3H, s), 1.60 (9H, s), 1.42 (9H, s).

Reference Example 38-2: potassium [(tert-butoxycarbonyl)amino](2-methyl-1H-imidazol-4-yl)acetate

[2592] ##STR00758##

[2593] Potassium carbonate (0.331 g, 2.40 mmol) was added to a methanol solution (3.2 mL) of the compound of Reference Example 38-1 (0.59 g, 1.60 mmol). After stirring for 30 minutes at room temperature, the aqueous layer was washed with ethyl acetate and concentrated to obtain the title compound (0.47 g).

[2594] .sup.1H-NMR (CD.sub.3OD) δ: 6.77 (1H, s), 4.98 (1H, s), 2.29 (3H, s), 1.43 (9H, s).

[2595] ##STR00759##

[2596] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 (0.328 g, 0.539 mmol) and the compound of Reference Example 38-2 (0.234 g, 0.799 mmol) as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound (68.3 mg).

[2597] LCMS: [M+H].sup.+/Rt=809.50/1.162 min.sup.C

Reference Example 39: tert-butyl 6-[(1-{2-[(tert-butoxycarbonyl)amino]-2-(1H-imidazol-4-yl)propanoyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2598] ##STR00760##

Reference Example 39-1: methyl amino(1H-imidazol-4-yl)acetate dihydrochloride

[2599] ##STR00761##

[2600] Thionyl chloride (75 mL, 1.21 mol) was added dropwise to a methanol solution (265 mL) of the compound of Reference Example 36-2 (44 g, 206 mmol) while cooling with ice. The reaction solution was warmed up to room temperature and then stirred for 9 hours at 50° C. The reaction solution was concentrated under reduced pressure to obtain the title compound (46.9 g) as a light yellow oily substance.

[2601] LCMS: [M+H].sup.+/Rt=155.93/0.142 min.sup.C

Reference Example 39-2: tert-butyl 4-{1-[(tert-butoxycarbonyl)amino]-2-methoxy-2-oxoethyl}-1H-imidazole-carboxylate

[2602] ##STR00762##

[2603] N,N-dimethyl-4-aminopyridine (0.113 g, 0.928 mmol), triethylamine (0.863 mL, 6.19 mmol), and di-tert-butyl dicarbonate (1.08 mL, 4.64 mmol) were added to a chloroform solution (20 mL) of the compound of Reference Example 39-1 (0.70 g, 3.09 mmol) at room temperature, and the reaction mixture was stirred for 24 hours. The reaction solution was concentrated and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (1.10 g) as a colorless oily substance.

[2604] .sup.1H-NMR (CD.sub.3OD) δ: 8.14 (1H, d, J=1.2 Hz), 7.51 (1H, s), 5.27 (1H, s), 3.73 (3H, s), 1.63 (9H, s), 1.45 (9H, s).

Reference Example 39-3: tert-butyl 4-{2-[(tert-butoxycarbonyl)amino]-1-methoxy-1-oxopropan-2-yl}-1H-imidazole-1-carboxylate

[2605] ##STR00763##

[2606] A lithium bis(trimethylsilyl)amide/THE solution (1.3 mol/L, 19.6 mL, 25.4 mmol) was added to a THF solution (43 mL) of the compound of Reference Example 39-2 (4.3 g, 12.1 mmol) at −78° C., and the reaction mixture was stirred for 30 minutes. Methyl iodide (0.832 mL, 13.3 mmol) was added to the reaction solution at −78° C. The reaction solution was warmed up to room temperature, and stirred for 4 hours. Saturated saline was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (2.15 g) as a light yellow oily substance.

[2607] .sup.1H-NMR (CDCl.sub.3) δ: 8.00 (1H, d, J=1.2 Hz), 7.35 (1H, d, J=1.2 Hz), 6.08 (1H, s), 3.73 (3H, s), 1.91 (3H, s), 1.61 (9H, s), 1.43 (9H, s).

Reference Example 39-4: 2-[(tert-butoxycarbonyl)amino]-2-(1H-imidazol-4-yl)propanoic acid

[2608] ##STR00764##

[2609] Lithium hydroxide monohydrate (0.513 g, 12.2 mmol) was added to a methanol solution (11.6 mL) of the compound of Reference Example 39-3 (2.15 g, 5.82 mmol) at room temperature, and the reaction mixture was stirred for 3 hours. 6 N aqueous hydrochloric acid (2.1 mL) was added, and the reaction mixture was stirred for 4 hours. Saturated saline was added to the reaction solution, and the solvent was evaporated under reduced pressure to obtain the title compound (1.49 g) as a crude product.

Reference Example 39: tert-butyl 6-[(1-{2-[(tert-butoxycarbonyl)amino]-2-(1H-imidazol-4-yl) propanoyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2610] ##STR00765##

[2611] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 (0.30 g, 0.493 mmol) and the compound of Reference Example 39-4 (0.176 g, 0.691 mmol) as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound (153 mg).

[2612] LCMS: [M+H].sup.+/Rt=809.17/1.139 min.sup.C

Reference Example 40: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-{[1-(1H-imidazole-4-carbonyl)azetidin-3-yl]oxy}-3-(2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl)benzoate

[2613] ##STR00766##

[2614] Palladium on carbon (20 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (3 mL) of the compound of Reference Example 1-7 (200 mg, 0.283 mmol), and the reaction mixture was stirred for 30 minutes under a hydrogen atmosphere at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methylene chloride, and the combined filtrate was concentrated. The resulting residue was dissolved in DMP (3 mL), and triethylamine (0.118 mL, 0.850 mmol) and 1H-imidazole-5-carboxylic acid chloride (40.7 mg, 0.312 mmol) were added. The reaction mixture was stirred for 20 minutes at room temperature, then water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol) to obtain the title compound (149 mg) as a light yellow solid.

[2615] .sup.1H-NMR (CDCL.sub.3) δ: 7.77-7.55 (2H, m), 7.26-722 (1H, m), 7.46 (1H, d, J=8.1 Hz), 5.12-4.90 (2H, m), 4.66-4.40 (2H, m), 4.30-4.15 (2H, m), 2.65-2.59 (2H, m), 2.36-2.26 (1H, m), 2.23-2.13 (1H, m), 2.05-2.00 (1H, m), 1.92-1.70 (2H, m), 1.59 (9H, s), 1.54 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.15-1.01 (3H, m), 0.84 (3H, s).

[2616] LCMS: [M+H].sup.+/Rt=666.7/2.49 min.sup.B

Reference Example 41: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-{[1-(4H-1,2,4-triazole-3-sulfonyl)azetidin-3-yl]oxy}-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2617] ##STR00767##

[2618] Palladium on carbon (20 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (3 mL) of the compound of Reference Example 1-7 (200 mg, 0.283 mmol), and the reaction mixture was stirred for 30 minutes at room temperature under a hydrogen atmosphere. The reaction solution was filtered through cellulose. The filtered substance was washed with methylene chloride, and the combined filtrate was concentrated. The resulting residue was dissolved in methylene chloride (3 mL), and triethylamine (0.118 mL, 0.850 mmol) was added. A methylene chloride solution (3 mL) of 1H-1,2,4-triazole-3-sulfonyl chloride (47.5 mg, 0.283 mmol) was added while cooling with ice, and the reaction mixture was stirred for 5 minutes. Water was added to the reaction solution, which was extracted with methylene chloride. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (205 mg) as a colorless solid.

[2619] .sup.1H-NMR (CDCl.sub.3) δ: 8.37 (1H, s), 7.20 (1H, d, J=8.1 Hz), 6.26 (1H, d, J=8.1 Hz), 4.43-4.37 (2H, m), 4.24 (1H, dd, J=8.1 Hz, 2.7 Hz), 4.16-4.08 (3H, m), 2.62-2.56 (2H, m), 2.36-2.27 (1H, m), 2.21-2.12 (1H, m), 2.05-2.00 (1H, m), 1.92-1.76 (2H, m), 1.55 (9H, s), 1.52 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.12-0.99 (3H, m), 0.83 (3H, s).

[2620] LCMS: [M+H].sup.+/Rt=703.6/2.75 min.sup.B

Reference Example 42: tert-butyl 6-({1-[N.SUP.2.-(tert-butoxycarbonyl)-L-asparaginyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2621] ##STR00768##

[2622] Palladium on carbon (20 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (3 mL) of the compound of Reference Example 1-7 (200 mg, 0.283 mmol), and the reaction mixture was stirred for 30 minutes at room temperature under a hydrogen atmosphere. The reaction solution was filtered through cellulose. The filtered substance was washed with methylene chloride, and the combined filtrate was concentrated. The resulting residue was dissolved in THF (3 mL), and tert-butoxycarbonyl-L-asparagine (85.6 mg, 0.368 mmol), N,N′-dicyclohexylcarbodiimide (58.5 mg, 0.340 mmol), 1-hydroxybenzotriazole monohydrate (52.1 mg, 0.340 mmol), and N-methylmorpholine (34.3 μL, 0.312 mmol) were added, and the reaction mixture was stirred for 2 hours at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (198 mg) as a colorless solid.

[2623] .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J=8.1 Hz), 6.41-6.37 (1H, m), 6.03 (1H, br), 5.72-5.61 (1H, m), 5.48-5.39 (1H, m), 4.99-4.89 (1H, m), 4.75-4.51 (2H, m), 4.44-4.31 (2H, m), 4.27-4.23 (1H, m), 4.10-4.03 (1H, m), 2.73-2.56 (4H, m), 2.36-2.27 (1H, m), 2.20-2.14 (1H, m), 2.04-2.00 (1H, m), 1.92-1.77 (2H, m), 1.57 (9H, s), 1.53 (9H, s), 1.43 (9H, s), 1.36 (3H, s), 1.26 (3H, 9), 1.14-1.01 (3H, m), 0.83 (3H, s).

[2624] LCMS: [M+H].sup.+/Rt=786.8/2.79 min.sup.B

Reference Example 43: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[(1-{[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2625] ##STR00769##

Reference Example 43-1: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-{[1-(chloroacetyl)azetidin-3-yl]oxy}-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2626] ##STR00770##

[2627] Under a nitrogen atmosphere, a dichloromethane (5.3 mL) solution of the compound of Reference Example 1-8 (160 mg, 0.263 mmol) was cooled with ice to 0° C. Chloroacetyl chloride (30 μL, 0.377 mmol) and triethylamine (0.11 mL, 0.789 mmol) were added, and the reaction mixture was stirred for 1 hour at room temperature. Subsequently, the reaction solution was cooled with ice, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous ammonium chloride solution and saturated saline, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/1) to obtain the title compound (140 mg).

[2628] .sup.1H-NMR (CDCl.sub.3) δ: 7.21 (1H, d, J=8.6 Hz), 6.40 (1H, d, J=8.6 Hz), 4.99-4.93 (1H, m), 4.64-4.58 (1H, m), 4.44-4.39 (1H, m), 4.32-4.27 (1H, m), 4.24-4.20 (1H, m), 4.15-4.09 (1H, m), 3.89 (2H, s), 2.60 (2H, t, J=8.3 Hz), 2.34-2.26 (1H, m), 2.18-2.12 (1H, m), 2.02-1.98 (1H, m), 1.91-1.85 (1H, m), 1.82-1.75 (1H, m), 1.56-1.51 (18H, m), 1.34 (3H, s), 1.26 (3H, s), 1.11-1.07 (2H, m), 1.00 (1H, d, J=10.9 Hz), 0.81 (3H, s).

Reference Example 43-2: tert-butyl 6-{[1-(azidoacetyl)azetidin-3-yl]oxy}-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2629] ##STR00771##

[2630] Sodium azide (69.0 mg, 1.06 mmol) was added to a DMSO (4.3 mL) solution of the compound of Reference Example 43-1 (140 mg, 0.216 mmol), and the reaction mixture was stirred for 1.5 hours at room temperature. Subsequently, water was added to the reaction solution, which was diluted with ethyl acetate, and the organic phase was separated. The organic phase was washed with saturated saline, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/1) to obtain the title compound (129 mg).

[2631] .sup.1H-NMR (CDCl.sub.3) δ: 7.25-7.21 (1H, M), 6.41 (1H, d, J=8.6 Hz), 5.01-4.93 (1H, m), 4.55-4.48 (1H, m), 4.48-4.40 (1H, m), 4.27-4.19 (2H, m), 4.17-4.11 (1H, m), 3.84-3.72 (2H, m), 2.61 (2H, t, J=8.3 Hz), 2.36-2.28 (1H, m), 2.20-2.13 (1H, m), 2.04-1.99 (1H, m), 1.92-1.86 (1H, m), 1.83-1.77 (1H, m), 1.59-1.51 (18H, m), 1.36 (3H, s), 1.28 (3H, s), 1.13-1.09 (2H, m), 1.04-0.99 (1H, m), 0.83 (3H, s).

[2632] ##STR00772##

[2633] 2-propyn-1-ol (47 μL, 0.788 mmol), copper iodide (24.4 mg, 0.128 mmol), and tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (24.3 mg, 46.0 μmol) were added to an acetonitrile (9.2 mL) solution of the compound of Reference Example 43-2 (300 mg, 0.458 mmol), and the reaction mixture was stirred for 2 hours at room temperature. Subsequently, a saturated aqueous potassium sodium tartrate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic phase was washed with saturated saline, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: chloroform/methanol=50/1 to 30/1) to obtain the title compound (271 mg).

[2634] .sup.1H-NMR (CDCl.sub.3) δ: 7.75 (1H, s), 7.23 (1H, d, J=8.6 Hz), 6.40 (1H, d, J=8.6 Hz), 5.13-5.05 (11H, m), 5.02-4.93 (2H, m), 4.81 (2H, s), 4.56-4.50 (1H, m), 4.47-4.38 (1H, m), 4.27-4.22 (1H, m), 4.21-4.09 (2H, m), 2.66-2.59 (2H, m), 2.38-2.28 (2H, m), 2.22-2.14 (1H, m), 2.05-1.99 (1H, m), 1.93-1.87 (1H, m), 1.84-1.77 (1H, m), 1.57 (9H, s), 1.54 (9H, s), 1.36 (3H, d, J=1.1 Hz), 1.28 (3H, s), 1.14-1.08 (2H, m), 1.06-1.01 (1H, m), 0.84 (3H, s).

[2635] LCMS: [M+H].sup.+/Rt=711.42/3.75 min.sup.D

Reference Example 44: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[(1-{[5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2636] ##STR00773##

[2637] The compound of Reference Example 43-2 (74.9 mg, 0.114 mmol) and (chloro[(1,2,3,4,5-h)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]bis(triphenylphosphine) ruthenium(II) (900 μg, 1.14 μmol) were added to a toluene (0.91 mL) solution of 2-propyn-1-ol (11.0 μL, 0.182 mmol), and the reaction mixture was stirred for 19 hours at 80° C. Subsequently, the reaction solution was cooled to room temperature, and stirred again for 4 hours at 80° C. after adding 2-propyn-1-ol (11.0 μL, 0.182 mmol) and chloro[(1,2,3,4,5-h)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]bis(triphenylphosphine)ruthenium(II) (900 μg, 1.14 μmol). Subsequently, the reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/1 to chloroform/methanol=10/1) to obtain the title compound (45.3 mg).

[2638] .sup.1H-NMR (CDCl.sub.3) δ: 7.62 (1H, s), 7.22 (1H, d, J=8.6 Hz), 6.41 (1H, d, J=8.6 Hz), 5.14-5.08 (1H, m), 5.02-4.93 (2H, m), 4.71-4.62 (3H, m), 4.42-4.36 (1H, m), 4.29-4.19 (3H, m), 2.60 (2H, t, J=8.3 Hz), 2.36-2.26 (1H, m), 2.20-2.13 (1H, m), 2.03-1.99 (1H, m), 1.92-1.76 (3H, m), 1.56 (9H, s), 1.52 (9H, s), 1.35 (3H, s), 1.27 (3H, s), 1.13-1.07 (2H, m), 1.04-0.99 (1H, m), 0.82 (3H, s).

[2639] LCMS: [M+H].sup.+/Rt=711.60/3.75 min.sup.D

Reference Example 45: tert-butyl 6-({1-[(5-{([(tert-butoxycarbonyl)(methyl)amino]methyl}-1H-1, 2, 3-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2640] ##STR00774##

[2641] A reaction, work-up, and purification were performed using the compound of Reference Example 43-2 as the starting material by the same method described in Reference Example 44 to obtain the title compound.

[2642] .sup.1H-NMR (CDCl.sub.3) δ: 7.59 (1H, s), 7.21 (1H, d, J=8.6 Hz), 6.38 (1H, d, J=8.6 Hz), 5.23-5.07 (2H, m), 5.01-4.90 (1H, m), 4.62-4.36 (4H, m), 4.29-4.19 (2H, m), 4.13-4.05 (1H, m), 2.82 (3H, s), 2.59 (2H, t, J=8.3 Hz), 2.34-2.26 (1H, m), 2.20-2.11 (1H, m), 2.04-1.96 (1H, m), 1.91-1.85 (1H, m), 1.82-1.75 (1H, m), 1.57-1.51 (18H, m), 1.43 (9H, s), 1.34 (3H, s), 1.26 (3H, s), 1.12-1.07 (2H, m), 1.01 (1H, d, J=10.9 Hz), 0.81 (3H, s).

[2643] LCMS: [M+H].sup.+/Rt=824.80/4.16 min.sup.D

Reference Example 46: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[(1-{[4-(2-tert-butoxy-2-oxoethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2644] ##STR00775##

Reference Example 46-1: benzyl[4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl]acetate

[2645] ##STR00776##

[2646] Water (12 mL) was added to a tert-butyl alcohol (12 mL) solution of benzyl 2-azidoacetate (2.50 g, 13.0 mmol). Sodium L-ascorbate (527 mg, 2.66 mmol), 3-butyn-1-ol (1.5 mL, 19.8 mmol), and copper sulfate pentahydrate (347 mg, 1.39 mmol) were added, and the reaction mixture was stirred for 2 hours at room temperature. Subsequently, water was added to the reaction solution, which was extracted with chloroform. The organic phase was washed with saturated saline, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: chloroform/methanol=100/1 to 30/1) to obtain the title compound (3.13 g).

[2647] .sup.1H-NMR (CDCl.sub.3) δ: 7.52-7.50 (1H, m), 7.38-7.31 (5H, m), 5.21 (2H, s), 5.16 (2H, s), 3.95 (2H, q, J=6.1 Hz), 2.96 (2H, t, J=5.4 Hz).

[2648] LCMS: [M+H].sup.+/Rt=262.09/1.88 min.sup.D

Reference Example 46-2: {1-[2-(benzyloxy)-2-oxoethyl]-1H-1,2,3-triazol-4-yl}acetic acid

[2649] ##STR00777##

[2650] An aqueous 0.67M sodium dihydrogen phosphate solution (28 mL) was added to an acetonitrile (28 mL) solution of the compound of Reference Example 46-1 (1.02 g, 3.90 mmol). 2,2,6,6-tetramethylpiperidine-1-oxyl (56.3 mg, 0.360 mmol), aqueous 5% hypochlorous acid solution (2.1 mL), and aqueous 80% chlorous acid solution (0.88 mL, 7.81 mmol) were added, and the reaction mixture was stirred for 23 hours at room temperature. Subsequently, an aqueous sodium thiosulfate solution was added to the reaction solution, which was then extracted with ethyl acetate. 1M hydrochloric acid was added to the aqueous layer, which was again extracted with chloroform. The organic phase was washed with saturated saline and 1M hydrochloric acid, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure to obtain the title compound (676 mg).

[2651] .sup.1H-NMR (CDCl.sub.3) δ: 7.73 (1H, s), 7.37-7.31 (5H, m), 5.21 (2H, s), 5.18 (2H, s), 3.90 (2H, s).

Reference Example 46-3: benzyl tert-butyl 2,2′-(1H-1,2,3-triazol-1,4-diyl)diacetate

[2652] ##STR00778##

[2653] Under a nitrogen atmosphere, a THE (15 mL) solution of the compound of Reference Example 46-2 (676 mg, 2.46 mmol) was cooled with ice. tert-butyl alcohol (10 mL) and N,N′-diisopropyl-O-t-butylisourea (1.8 mL, 0.789 mmol) were added, and the reaction mixture was stirred for 17 hours at room temperature. The reaction solution was evaporated under reduced pressure, and then the resulting residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=2/1) to obtain the title compound (425 mg).

[2654] .sup.1H-NMR (CDCl.sub.3) δ: 7.72 (1H, s), 7.39-7.31 (5H, m), 5.21 (2H, s), 5.16 (2H, s), 3.75 (2H, s), 1.45 (9H, s).

Reference Example 46-4: (4-(2-tert-butoxy-2-oxoethyl)-1H-1,2,3-triazol-1-yl)acetic acid

[2655] ##STR00779##

[2656] 10% palladium on carbon (88.7 mg) was added to an ethyl acetate (12 mL) solution of the compound of Reference Example 46-3 (397 mg, 1.20 mmol). Under a hydrogen atmosphere, the reaction mixture was stirred for 50 minutes at room temperature. Subsequently, the reaction solution was filtered through celite and then the filtrate was evaporated under reduced pressure to obtain the title compound (288 mg).

[2657] .sup.1H-NMR (CD.sub.3OD) δ: 7.91 (1H, s), 5.19 (2H, s), 3.70 (2H, s), 1.45 (9H, s).

Reference Example 46: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[(1-{[4-(2-tert-butoxy-2-oxoethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy)-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2658] ##STR00780##

[2659] The compound of Reference Example 1-8 (503 mg, 0.828 mmol), triethylamine (0.350 mL, 2.51 mmol), 1-hydroxybenzotriazole (231 mg, 1.71 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (237 mg, 1.71 mmol) were added to a DMF solution (8.3 mL) of the compound of Reference Example 46-4 (277 mg, 1.15 mmol) while cooling with ice. After stirring for 1.5 hours at room temperature, water was added to the reaction solution, which was then extracted with a hexane/ethyl acetate (1:1) mixture solution. The organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution, 1 N hydrochloric acid, and saturated saline, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/2 to 1/3) to obtain the title compound (394 mg).

[2660] .sup.1H-NMR (CDCl.sub.3) δ: 7.78 (1H, s), 7.22 (1H, d, J=8.6 Hz), 6.38 (1H, d, J=8.6 Hz), 5.10-4.90 (3H, m), 4.50-4.38 (2H, m), 4.27-4.10 (3H, m), 3.76 (2H, s), 2.61 (2H, t, J=8.3 Hz), 2.36-2.28 (1H, m), 2.21-2.14 (1H, m), 2.06-2.00 (1H, m), 1.92-1.87 (1H, m), 1.84-1.76 (1H, m), 1.56 (9H, s), 1.54 (9H, s), 1.46 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.08 (2H, m), 1.03 (1H, d, J=10.9 Hz), 0.84 (3H, s).

[2661] LCMS: [M+H].sup.+/Rt=795.55/4.19 min.sup.D

Reference Example 47: [4-(2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-1H-1,2,3-triazol-1-yl]acetic acid

[2662] ##STR00781##

Reference Example 47-1: tert-butyl 6-{[1-({1-[2-(benzyloxy)-2-oxyethyl]-1H-1,2,3-triazol-4-yl}acetyl)azetidin-3-yl]oxy}-2-[(tert-butoxycarbonyl)oxy]-2-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2663] ##STR00782##

[2664] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 as the starting material by the same method described in Reference Example 36-4 to obtain the title compound.

[2665] .sup.1H-NMR (CDCl.sub.3) δ: 7.77 (1H, s), 7.39-7.31 (5H, m), 7.22 (1H, d, J=8.6 Hz), 6.40 (1H, d, J=8.6 Hz), 5.22 (2H, s), 5.18 (2H, d, J=1.7 Hz), 4.96-4.89 (1H, m), 4.66-4.61 (1H, m)), 4.40-4.34 (1H, m), 4.29-4.22 (2H, m), 4.11-4.05 (1H, m), 3.72-3.58 (2H, m), 2.64-2.58 (2H, m), 2.36-2.28 (1H, m), 2.20-2.14 (1H, m), 2.04-2.00 (1H, m), 1.92-1.87 (1H, m), 1.83-1.77 (1H, m), 1.59-1.52 (18H, m), 1.36 (3H, s), 1.28 (3H, s), 1.13-1.09 (2H, m), 1.03 (1H, d, J=10.9 Hz), 0.83 (3H, 8).

[2666] LCMS: [M+H].sup.+/Rt=829.46/4.22 min.sup.D

Reference Example 47: [4-(2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S, 7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-1H-1,2,3-triazol-1-yl]acetic acid

[2667] ##STR00783##

[2668] A suspension of 10% palladium on carbon (67.9 mg) in ethyl acetate was added to a methanol (4.1 mL) solution of the compound of Reference Example 47-1 (340 mg, 0.410 mmol). Subsequently, under a hydrogen atmosphere, the reaction mixture was stirred for 2 hours at room temperature. The reaction solution was filtered through celite, and the filtrate was evaporated under reduced pressure to obtain the title compound (271 mg).

[2669] .sup.1H-NMR (CDCl.sub.3) δ: 7.78 (1H, s), 7.21 (1H, d, J=8.6 Hz), 6.39 (1H, d, J=8.0 Hz), 5.17-4.99 (2H, m), 4.98-4.88 (1H, m), 4.61-4.55 (1H, m), 4.41-4.31 (1H, m), 4.27-4.22 (1H, m), 4.14-4.01 (2H, m), 3.70-3.62 (2H, m), 2.60 (2H, t, J=8.3 Hz), 2.37-2.13 (2H, m), 2.04-1.99 (1H, m), 1.92-1.86 (1H, m), 1.83-1.77 (1H, m), 1.55 (9H, s), 1.53 (9H, 8), 1.36 (3H, s), 1.28 (3H, s), 1.10 (2H, t, J=8.3 Hz), 1.03 (1H, d, J=10.9 Hz), 0.83 (3H, s).

[2670] LCMS: [M+H].sup.+/Rt=739.28/3.84 min.sup.D

Reference Example 48: tert-butyl 6-[(1-{[(tert-butoxycarbonyl)amino][1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-4-yl]acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2671] ##STR00784##

Reference Example 48-1: methyl[(tert-butoxycarbonyl)amino](1H-imidazol-4-yl)acetate

[2672] ##STR00785##

[2673] Sodium hydrogen carbonate (1.03 g, 12.2 mmol) and di-tert-butyl dicarbonate (2.06 mL, 8.95 mmol) were added to a THF-water (3:1) mixture solution (18 mL) of the compound of Reference Example 39-1 (928 mg, 4.07 mmol). The reaction mixture was stirred for 20 hours at room temperature and then stirred for 2 days at 70° C. After allowing the reaction solution to cool, water (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol) to obtain the title compound (368 mg) as a light yellow solid.

[2674] .sup.1H-NMR (CDCl.sub.3) δ: 7.60 (1H, s), 7.06 (1H, s), 5.74 (1H, br), 5.40 (1H, d, J=8.1 Hz), 3.76 (3H, s), 1.45 (9H, s).

[2675] LCMS: [M+H].sup.+/Rt=256.2/0.93 min.sup.B

Reference Example 48-2: methyl[(tert-butoxycarbonyl)amino][1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-4-yl]acetate

[2676] ##STR00786##

[2677] Sodium hydride (23.4 mg, 60% dispersion in liquid paraffin, 0.586 mmol) was added to a DMF solution (2.1 mL) of the compound of Reference Example 48-1 (136 mg, 0.533 mmol) under a nitrogen atmosphere at 0° C., and the reaction mixture was stirred for 30 minutes at room temperature. tert-butyl bromoacetate (86.0 μL, 0.586 mmol) was added, and the reaction mixture was stirred for 3 hours. Methanol (0.1 mL) and then saturated saline (20 mL) were added to the reaction solution, which was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (155 mg) as a light yellow solid.

[2678] .sup.1H-NMR (CDCl.sub.3) δ: 7.43 (1H, s), 6.98 (1H, s), 5.76 (1H, d, J=8.1 Hz), 5.34 (1H, d, J=8.1 Hz), 4.55 (2H, s), 3.75 (3H, s), 1.47 (9H, s), 1.40 (9H, s).

[2679] LCMS: [M+H].sup.+/Rt=370.7/1.59 min.sup.B

Reference Example 48-3: [(tert-butoxycarbonyl)amino][1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-4-yl]acetic acid

[2680] ##STR00787##

[2681] Triethylamine (0.291 mL, 2.10 mmol) was added to an aqueous solution (4.2 mL) of the compound of Reference Example 48-2 (155 mg, 0.420 mmol), and the reaction mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol) to obtain the title compound (84.9 mg) as a colorless solid.

[2682] .sup.1H-NMR (CDCl.sub.3) δ: 7.82 (1H, s), 7.01 (1H, s), 5.97 (1H, s), 5.30 (1H, s), 4.62 (2H, 9), 1.48 (9H, s), 1.44 (9H, s).

[2683] LCMS: [M+H].sup.+/Rt=356.2/1.35 min.sup.B

[2684] ##STR00788##

[2685] Palladium on carbon (20 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (3 mL) of the compound of Reference Example 1-7 (200 mg, 0.283 mmol), and the reaction mixture was stirred for 30 minutes under a hydrogen atmosphere at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methylene chloride, and the combined filtrate was concentrated. The resulting residue was dissolved in DMF (3 mL). Reference Example 48-3 (131 mg, 0.368 mmol), HATU (129 mg, 0.340 mmol), and triethylamine (0.118 mL, 0.850 mmol) were added, and the reaction mixture was stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (208 mg) as a colorless amorphous compound.

[2686] .sup.1H-NMR (CDCl.sub.3) δ: 7.42 (1H, d, J=2.7 Hz), 7.20 (1H, dd, J=8.1 Hz, 5.4 Hz), 6.97 (1H, d, J=5.4 Hz), 6.36 (1H, d, J=5.4 Hz), 5.86-5.71 (1H, m), 5.26 (1H, d, J=8.1 Hz), 4.98-4.82 (1H, m), 4.76-4.05 (7H, m), 2.63-2.57 (2H, m), 2.36-2.27 (1H, m), 2.20-2.13 (1H, m), 2.04-2.00 (1H, m), 1.92-1.77 (2H, m), 1.61 (9H, s), 1.53 (9H, s), 1.48-1.42 (18H, m), 1.36 (3H, s), 1.26 (3H, s), 1.13-1.01 (3H, m), 0.83 (3H, s).

[2687] LCMS: [M+H].sup.+/Rt=910.2/2.97 min.sup.B

Reference Example 49: tert-butyl 6-[(1-{[1-(2-amino-2-oxoethyl)-1H-imidazol-4-yl][(tert-butoxycarbonyl)amino]acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2688] ##STR00789##

Reference Example 49-1: methyl[1-(2-amino-2-oxoethyl)-1H-imidazol-4-yl][(tert-butoxycarbonyl)amino]acetate

[2689] ##STR00790##

[2690] Sodium hydroxide (70.5 mg, 60% dispersion in liquid paraffin, 1.76 mmol) was added to a DMF solution (6.4 mL) of the compound of Reference Example 48-1 (409 mg, 1.60 mmol) under a nitrogen atmosphere at 0° C., and the reaction mixture was stirred for 30 minutes at room temperature. 2-bromoacetamide (243 mg, 1.76 mmol) was added, and the reaction mixture was stirred for 1.5 hours. Methanol (0.1 mL) was added to the reaction solution, and the mixture was purified by silica gel column chromatography (eluent: methylene chloride/methanol) to obtain a mixture (564 mg) of the title compound and a regioisomer thereof. The resulting mixture was further purified by silica gel column chromatography (amine silica gel, eluent: ethyl acetate/methanol). The resulting mixture (396 mg) of the title compound and a regioisomer thereof was triturated in methylene chloride, filtered, and dried and solidified under reduced pressure to obtain the title compound (198 mg) as a colorless solid.

[2691] .sup.1H-NMR (DMSO-d.sub.6) δ: 7.51 (1H, s), 7.47-7.19 (3H, m), 7.10 (1H, s), 5.19 (1H, d, J=8.1 Hz), 4.59 (2H, s), 3.62 (3H, s), 1.39 (9H, s).

[2692] LCMS: [M+H].sup.+/Rt=313.2/0.66 min.sup.B

Reference Example 49-2: [1-(2-amino-2-oxoethyl)-1H-imidazol-4-yl][(tert-butoxycarbonyl)amino]acetic acid.Math.1/2(triethylamine) salt

[2693] ##STR00791##

[2694] Triethylamine (0.204 mL, 1.47 mmol) was added to an aqueous solution (3.0 mL) of the compound of Reference Example 49-1 (92.0 mg, 0.295 mmol), and the reaction mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the title compound (123 mg) as a colorless amorphous compound.

[2695] .sup.1H-NMR (CD.sub.3OD) δ: 7.69 (1H, s), 7.08 (1H, s), 5.03 (1H, s), 4.72 (2H, s), 3.62 (3H, s), 3.18 (3H, q, J=8.1 Hz), 1.42 (9H, s), 1.29 (4.5H, t, J=8.1 Hz).

[2696] LCMS: [M+H].sup.+/Rt=299.4/0.50 min.sup.B

[2697] ##STR00792##

[2698] A reaction, work-up, and purification were performed using the compound of Reference Example 1-7 (200 mg, 0.283 mmol) and the compound of Reference Example 49-2 (109 mg, 0.312 mmol) as the starting materials by the same method described in Reference Example 42 to obtain the title compound (130 mg) as a colorless solid.

[2699] .sup.1H-NMR (CDCl.sub.3) b: 7.46 (1H, s), 7.21 (1H, dd, J=8.1 Hz, 5.4 Hz), 6.97-6.95 (1H, m), 6.41-6.37 (1H, m), 5.88-5.59 (3H, m), 5.25-5.22 (1H, m), 5.00-4.87 (1H, m), 4.83-4.57 (3H, m), 4.48-4.33 (1H, m), 4.27-4.23 (1H, m), 4.16-4.05 (2H, m), 2.63-2.57 (2H, m), 2.36-2.27 (1H, m), 2.19-2.13 (1H, m), 2.04-2.00 (1H, m), 1.92-1.77 (2H, m), 1.62-1.53 (18H, m), 1.43 (9H, s), 1.36 (3H, 9), 1.26 (3H, s), 1.13-1.00 (3H, m), 0.83 (3H, s).

[2700] LCMS: [M+H].sup.+/Rt=853.0/2.49 min.sup.B

Reference Example 50: tert-butyl 6-[(1-{[(tert-butoxycarbonyl)amino](1H-1,2,3-triazol-4-yl)acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2701] ##STR00793##

Reference Example 50-1: ethyl(1-benzyl-1H-1,2,3-triazol-4-yl)(hydroxy)acetate

[2702] ##STR00794##

[2703] After adding benzylazide (0.10 mL), copper iodide (44.6 mg, 0.234 mmol), and tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (41.4 mg, 78.0 μmol) to an acetonitrile (7.8 mL) solution of ethyl 2-hydroxy-3-butynoate (91 μL, 0.780 mmol) and stirring the reaction mixture for 5 hours at room temperature, a saturated aqueous potassium sodium tartrate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic phase was washed with saturated saline, and then dried over anhydrous sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/2) to obtain the title compound (187 mg).

[2704] .sup.1H-NMR (CDCl.sub.1) 5: 7.45 (1H, s), 7.38-7.33 (3H, m), 7.27-7.23 (2H, m), 5.50 (2H, s), 5.34 (1H, d, J=5.7 Hz), 4.33-4.18 (2H, m), 3.44 (1H, d, J=6.3 Hz), 1.24 (3H, t, J=7.2 Hz).

Reference Example 50-2: ethyl(1-benzyl-1H-1,2,3-triazol-4-yl)[(methanesulfonyl)oxy]acetate

[2705] ##STR00795##

[2706] Under a nitrogen atmosphere, triethylamine (0.12 mL, 0.856 mmol) and methanesulfonyl chloride (36 μL, 0.476 mmol) were added to a dichloromethane (1.9 mL) solution of the compound of Reference Example 50-1 (102 mg, 0.389 mmol), and the reaction mixture was stirred for 4 hours at 0° C. Subsequently, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure to obtain the title compound (110 mg).

[2707] .sup.1H-NMR (CDCl.sub.3) δ: 7.59 (1H, s), 7.39-7.36 (3H, m), 7.28-7.25 (2H, m), 6.16 (1H, s), 5.57-5.47 (2H, m), 4.33-4.22 (2H, m), 3.14 (3H, s), 1.27-1.24 (3H, m).

Reference Example 50-3: ethyl azide(1-benzyl-1H-1,2,3-triazol-4-yl)acetate

[2708] ##STR00796##

[2709] Under a nitrogen atmosphere, a DMF (4.0 mL) solution of the compound of Reference Example 50-2 (156 mg, 0.406 mmol) was cooled with ice. Sodium azide (39.6 mg, 0.609 mmol) was added, and the reaction mixture was stirred for 3.5 hours while cooling with ice. Subsequently, a saturated sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=2/1 to 1/1) to obtain the title compound (88.7 mg).

[2710] .sup.1H-NMR (CDCl.sub.3) δ: 7.56 (1H, s), 7.40-7.37 (3H, m), 7.29-7.26 (2H, m), 5.55 (2H, s), 5.14 (1H, s), 4.34-4.19 (2H, m), 1.30-1.25 (3H, m).

Reference Example 50-4: ethyl[(tert-butoxycarbonyl)amino](1H-1,2,3-triazol-4-yl)acetate

[2711] ##STR00797##

[2712] The compound of Reference Example 50-3 (101 mg, 0.349 mmol) and di-tert-butyl dicarbonate (114 mg, 0.524 mmol) were added to an ethanol (12 mL) solution of 10% palladium on carbon (10.4 mg), and then, under a hydrogen atmosphere, the reaction mixture was stirred for 2 hours at room temperature. Subsequently, 1M hydrochloric acid (0.35 mL) was added to the reaction solution, and the reaction mixture was further stirred for 44 hours at room temperature. The reaction solution was filtered through celite, and the filtrate was evaporated under reduced pressure to obtain the title compound (98.9 mg).

[2713] .sup.1H-NMR (CDCl.sub.3) δ: 7.74 (1H, s), 5.81-5.49 (2H, m), 4.34-4.09 (2H, m), 1.44 (9H, s), 1.27-1.21 (3H, m).

Reference Example 50-5: [(tert-butoxycarbonyl)amino](1H-1, 2, 3-triazol-4-yl) acetic acid

[2714] ##STR00798##

[2715] Lithium hydroxide monohydrate (14.1 mg, 0.336 mmol) was added to a THF/water (3:1) mixture solution (1.7 mL) of the compound of Reference Example 50-4 (45.4 mg, 0.168 mmol), and the reaction mixture was stirred for 3 hours at room temperature. Subsequently, 1M hydrochloric acid was added until the pH was 4, and the mixture was extracted with ethyl acetate, and then the aqueous layer was extracted again with chloroform. The organic phase was washed with saturated saline, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure. The resulting residue was washed and purified by decantation with diethyl ether to obtain the title compound (12.7 mg).

[2716] .sup.1H-NMR (CD.sub.3OD) δ: 7.93-7.65 (1H, m), 5.51-5.32 (1H, m), 1.45 (9H, s).

[2717] ##STR00799##

[2718] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 and the compound of Reference Example 50-5 as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound.

[2719] .sup.1H-NMR (CDCl.sub.3) δ: 7.71-7.62 (1H, m), 7.24-7.17 (1H, m), 6.39-6.32 (1H, m), 5.96-5.78 (1H, m), 5.52-5.37 (1H, m), 5.04-4.84 (1H, m), 4.62-3.93 (5H, m), 2.67-2.58 (2H, m), 2.51-2.27 (1H, m), 2.25-2.12 (1H, m), 2.04-1.99 (1H, m), 1.95-1.86 (1H, m), 1.83-1.74 (1H, m), 1.66-1.26 (33H, m), 1.14-1.08 (2H, m), 1.04-0.99 (1H, m), 0.83 (3H, s).

[2720] LCMS: [M+H].sup.+/Rt=796.42/2.30 min.sup.D

Reference Example 51: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-({1-[(4-nitro-1H-1,2,3-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2721] ##STR00800##

Reference Example 51-1: tert-butyl (4-nitro-1H-1,2,3-triazol-1-yl)acetate

[2722] ##STR00801##

[2723] 1-(dimethylamino)-2-nitroethylene (1.57 g, 13.5 mmol) was added to a 1,4-dioxane (8.2 mL) solution of tert-butyl 2-azidoacetate (1.29 g, 8.21 mmol), and the reaction mixture was stirred for 12 hours under microwave irradiation at 120° C. Subsequently, the reaction solution was evaporated under reduced pressure to obtain the title compound (226 mg).

[2724] .sup.1H-NMR (CDCl.sub.3) δ: 8.45 (1H, s), 5.13 (2H, s), 1.50 (9H, s).

[2725] LCMS: [M+H].sup.+/Rt=229.13/2.48 min.sup.D

Reference Example 51-2: (4-nitro-1H-1,2,3-triazol-1-yl)acetic acid

[2726] ##STR00802##

[2727] A 4 N hydrogen chloride-1,4-dioxane solution (14 mL) was added to the compound of Reference Example 51-1 (329 mg, 1.44 mmol), and the reaction mixture was stirred for 23 hours at room temperature. Subsequently, the reaction solution was evaporated under reduced pressure to obtain the title compound.

[2728] .sup.1H-NMR (CD.sub.3OD) δ: 8.94 (1H, s), 5.35-5.30 (2H, m).

[2729] ##STR00803##

[2730] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 and the compound of Reference Example 51-2 as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound.

[2731] .sup.1H-NMR (CDCl.sub.3) δ: 8.57 (1H, s), 6.43 (1H, d, J=8.6 Hz), 5.16-4.98 (3H, m), 4.65-4.57 (1H, m), 4.48-4.41 (1H, m), 4.36-4.29 (1H, m), 4.26-4.21 (1H, m), 4.20-4.13 (1H, m), 2.66-2.56 (2H, m), 2.33-2.28 (1H, m), 2.18-2.13 (1H, m), 2.05-1.97 (1H, m), 1.91-1.85 (1H, m), 1.82-1.75 (2H, m), 1.55 (9H, s), 1.52 (9H, s), 1.34 (3H, s), 1.26 (3H, 9), 1.12-1.07 (2H, m), 1.03-0.98 (1H, m), 0.82 (3H, s).

Reference Example 52: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[(1-D-serylazetidin-3-yl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2732] ##STR00804##

Reference Example 52-1: tert-butyl 6-[(1-(N-[(benzyloxy)carbonyl]-D-seryl)azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2733] ##STR00805##

[2734] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 (114.4 mug, 0.188 mmol) and N-carbobenzoxy-D-serine (91.8 mg, 0.384 mmol) as the starting materials by the same method described in Reference Example 3 to obtain the title compound (71.4 mg).

[2735] .sup.1H-NMR (CD.sub.3OD) b: 7.39-7.26 (6H, in), 6.67 (1H, d, J=8.5 Hz), 5.12-5.05 (3H, m), 4.39-4.33 (1H, in), 4.29 (2H, d, J=8.5 Hz), 4.00-3.94 (1H, m), 3.74-3.67 (2H, m), 3.34 (2H, s), 2.58 (2H, t, J=7.9 Hz), 2.39-2.32 (1H, m), 2.21-2.16 (1H, m), 1.99 (1H, t, J=5.5 Hz), 1.89-1.87 (1H, m), 1.79 (1H, d, J=15.3 Hz), 1.55 (9H, d, J=7.9 Hz), 1.52 (9H, s), 1.35 (3H, s), 1.29 (3H, s), 1.08 (2H, t, J=8.2 Hz), 0.99 (1H, d, J=10.4 Hz), 0.86 (3H, s).

[2736] LCMS: [M+H].sup.+/Rt=793.48/1.381 min.sup.A

Reference Example 52: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[(1-D-serylazetidin-3-yl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2737] ##STR00806##

[2738] Palladium on carbon (20 mg, Pd content: 10t, wetted with ca. 55% water) was added to a methanol solution (3.0 mL) of the compound of Reference Example 52-1 (200 mg, 0.252 mmol), and the reaction mixture was stirred for 30 minutes under a hydrogen atmosphere at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methylene chloride, and the combined filtrate was concentrated to obtain the title compound (198 mg).

[2739] .sup.1H-NMR (CDCl.sub.3) δ: 7.23 (1H, d, J=8.1 Hz), 6.44-6.40 (1H, m), 5.01-4.94 (1H, m), 4.71-4.06 (5H, m), 3.74-3.49 (3H, m), 2.64-2.58 (2H, m), 2.45-2.00 (6H, m), 1.93-1.77 (2H, m), 1.56 (9H, s), 1.54 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

[2740] LCMS: [M+H].sup.+/Rt=659.7/2.31 min$

Reference Example 53: tert-butyl 6-({1-[N.SUP.2.-(tert-butoxycarbonyl)-N-methyl-D-asparaginyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-(2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl)benzoate

[2741] ##STR00807##

Reference Example 53-1: tert-butyl 6-[(1-{(2R)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2742] ##STR00808##

[2743] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 and benzyl (R)-3-[(tert-butoxycarbonyl)amino]-4-oxobutanoate as the starting materials by the same method described in Reference Example 3 to obtain the title compound (1.84 g).

[2744] .sup.1H-NMR (CDCl.sub.3) δ: 7.40-7.31 (5H, m), 7.21 (1H, d, J=8.6 Hz), 6.40-6.30 (1H, m), 5.37-5.24 (1H, m), 5.16-5.07 (2H, m), 4.97-4.54 (3H, m), 4.42-4.27 (2H, m), 4.27-4.22 (1H, m), 4.08-4.00 (1H, m), 2.84-2.73 (2H, m), 2.65-2.57 (2H, m), 2.37-2.27 (1H, m), 2.24-2.13 (1H, m), 2.04-2.00 (1H, m), 1.93-1.87 (1H, m), 1.84-1.77 (1H, m), 1.56 (9H, s), 1.53 (9H, s), 1.44-1.40 (9H, m), 1.36 (3H, s), 1.28 (3H, s), 1.15-1.08 (2H, m), 1.06-1.01 (1H, m), 0.84 (3H, s).

[2745] LCMS: [M+H].sup.+/Rt=877.72/4.54 min.sup.D

Reference Example 53-2: (3R)-3-[(tert-butoxycarbonyl)amino]-4-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-4-oxobutanoic acid

[2746] ##STR00809##

[2747] A suspension of 10% palladium on carbon (150 mg) in ethyl acetate was added to an ethyl acetate (17 mL) solution of the compound of Example 53-1 (1.50 g, 1.71 mmol). Subsequently, under a hydrogen atmosphere, the reaction mixture was stirred for 3 hours at room temperature. The reaction solution was filtered through celite, and the filtrate was evaporated under reduced pressure to obtain the title compound (1.34 g).

[2748] .sup.1H-NMR (CD.sub.3OD) δ: 7.32 (1H, d, J=8.0 Hz), 6.69 (1H, d, J=8.6 Hz), 5.15-5.08 (1H, m), 4.63-4.59 (1H, m), 4.55-4.27 (4H, m), 3.99-3.92 (1H, m), 2.82-2.69 (1H, m), 2.61-2.51 (3H, m), 2.40-2.31 (1H, m), 2.23-2.14 (1H, m), 2.02-1.97 (2H, m), 1.92-1.86 (1H, m), 1.83-1.76 (1H, m), 1.57 (9H, s), 1.52 (9H, s), 1.47-1.40 (9H, m), 1.36 (3H, s), 1.30 (3H, s), 1.11-1.05 (2H, m), 1.02-0.96 (1H, m), 0.86 (3H, s).

[2749] LCMS: [M+H].sup.+/Rt=787.62/4.14 min.sup.D

Reference Example 53: tert-butyl 6-({1-[N.SUP.2.-(tert-butoxycarbonyl)-N-methyl-D-asparaginyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2750] ##STR00810##

[2751] A reaction, work-up, and purification were performed using the compound of Reference Example 53-2 and methylamine hydrochloride as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound (270 mg).

[2752] .sup.1H-NMR (CD.sub.3OD) δ: 7.32 (1H, d, J=8.6 Hz), 6.68 (1H, d, J=8.6 Hz), 5.14-5.07 (1H, m), 4.61-4.27 (5H, m), 4.00-3.91 (1H, m), 2.74-2.54 (6H, m), 2.49-2.41 (1H, m), 2.41-2.32 (1H, m), 2.23-2.14 (1H, m), 2.01-1.97 (1H, m), 1.92-1.86 (1H, m), 1.83-1.76 (1H, m), 1.57 (9H, s), 1.52 (9H, s), 1.46-1.40 (9H, m), 1.36 (3H, s), 1.30 (3H, s), 1.11-1.04 (2H, m), 1.01-0.95 (1H, m), 0.86 (3H, s).

[2753] LCMS: [M+H].sup.+/Rt=800.73/4.09 min.sup.D

Reference Example 54: tert-butyl 6-({1-[N.SUP.2.-(tert-butoxycarbonyl)-N,N-dimethyl-D-asparaginyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2754] ##STR00811##

[2755] A reaction, work-up, and purification were performed using the compound of Reference Example 53-2 and dimethylamine hydrochloride as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound (251 mg).

[2756] .sup.1H-NMR (CDCl.sub.3) δ: 7.18 (1H, d, J=8.6 Hz), 6.36 (1H, d, J=8.6 Hz), 5.82-5.50 (1H, m), 4.94-4.86 (1H, m), 4.85-4.72 (1H, m), 4.64-4.53 (1H, m), 4.43-4.31 (2H, m), 4.26-4.19 (1H, m), 4.08-3.99 (1H, m), 2.99-2.84 (8H, m), 2.62-2.54 (2H, m), 2.34-2.25 (1H, m), 2.18-2.12 (1H, m), 2.02-1.98 (1H, m), 1.90-1.85 (1H, m), 1.83-1.75 (1H, m), 1.54 (9H, s), 1.51 (9H, s), 1.40 (9H, s), 1.33 (3H, s), 1.26 (3H, s), 1.12-1.06 (2H, m), 1.03-0.99 (1H, m), 0.81 (3H, s).

[2757] LCMS: [M+H].sup.+/Rt=814.69/4.15 min.sup.D

Reference Example 55: tert-butyl 6-{[(3R)-1-{[(tert-butoxycarbonyl)amino](1H-imidazol-4-yl)acetyl}pyrrolidin-3-yl]oxy}-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2758] ##STR00812##

Reference Example 55-1: benzyl (3R)-3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]pyrrolidine-1-carboxylate

[2759] ##STR00813##

[2760] Cyanomethylenetri-n-butylphosphorane (0.762 mL, 2.90 mmol) was added dropwise to a toluene solution (5 mL) of the compound of Reference Example 1-6 (500 mg, 0.968 mmol) and (S)-1-Cbz-3-pyrrolidinol (321 mg). The reaction solution was warmed up to 100° C., and stirred for 3 hours. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=90/10 to 65/35) to obtain the title compound (681 mg).

[2761] .sup.1H-NMR (CDCl.sub.3) δ: 7.29-7.25 (5H, m), 7.14 (1H, dd, J=8.5, 3.0 Hz), 6.60 (1H, dd, J=12.2, 8.5 Hz), 5.08-5.03 (2H, m), 4.82 (1H, s), 4.18-4.16 (1H, m), 3.69-3.45 (4H, m), 2.55-2.53 (2H, m), 2.26-2.23 (1H, m), 2.14-2.10 (2H, m), 1.96-1.94 (2H, m), 1.84-1.81 (1H, m), 1.76-1.72 (1H, m), 1.45-1.44 (18H, m), 1.29 (3H, s), 1.21 (3H, s), 1.05-1.03 (2H, m), 0.97 (1H, d, J=10.4 Hz), 0.76 (3H, s).

Reference Example 55-2: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-{[(3R)-pyrrolidin-3-yl]oxy}-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2762] ##STR00814##

[2763] 10% palladium on carbon (340 mg) was added to a methanol (5 mL) solution of the compound of Reference Example 55-1 (681 mg, 0.945 mmol), and the reaction mixture was stirred for 5 hours under a hydrogen atmosphere at room temperature. The reaction solution was filtered through celite, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5 to 80/20) to obtain the title compound (333 mg).

[2764] LCMS: [M+H].sup.+/Rt=586/0.990 min.sup.A

[2765] ##STR00815##

[2766] A reaction, work-up, and purification were performed using the compound of Reference Example 55-2 (86 mg, 0.138 mmol) as the starting material by the same method described in Reference Example 36-4 to obtain the title compound (90.7 mg).

[2767] LCMS: [M+H].sup.+/Rt=809.53/0.874 min.sup.E

Reference Example 56: tert-butyl 4-(1-[(tert-butoxycarbonyl)amino]-2-{(3S)-3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]pyrrolidin-1-yl}-2-oxoethyl)-1H-imidazole-1-carboxylate

[2768] ##STR00816##

Reference Example 56-1: benzyl (3S)-3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl)}phenoxy]pyrrolidine-1-carboxylate

[2769] ##STR00817##

[2770] A reaction, work-up, and purification were performed using the compound of Reference Example 1-6 and (R)-1-Cbz-3-pyrrolidinol as the starting materials by the same method described in Reference Example 55-1 to obtain the title compound.

[2771] .sup.1H-NMR (CDCl.sub.3) δ: 7.30-7.21 (5H, in), 7.17-7.11 (1H, m), 6.60 (1H, dd, J=12.8, 8.5 Hz), 5.10-5.01 (2H, m), 4.83-4.80 (1H, m), 4.18-4.16 (1H, in), 3.69-3.45 (4H, m), 2.55-2.53 (2H, in), 2.28-2.21 (1H, m), 2.14-2.10 (2H, m), 1.95 (2H, t, J=5.5 Hz), 1.83-1.80 (1H, m), 1.76-1.72 (1H, m), 1.45-1.44 (18H, m), 1.29 (3H, s), 1.21 (3H, s), 1.05-1.03 (2H, m), 0.97 (1H, d, J=11.0 Hz), 0.76 (3H, s).

Reference Example 56-2: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-{[(3S)-pyrrolidin-3-yl]oxy}-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2772] ##STR00818##

[2773] A reaction, work-up, and purification were performed using the compound of Reference Example 56-1 as the starting material by the same method described in Reference Example 55-2 to obtain the title compound.

[2774] LCMS: [M+H].sup.+/Rt=586/0.993 min.sup.A

Reference Example 56: tert-butyl 4-(1-[(tert-butoxycarbonyl)amino]-2-{(3S)-3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-(2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]pyrrolidin-1-yl)-2-oxoethyl)-1H-imidazole-1-carboxylate

[2775] ##STR00819##

[2776] A reaction, work-up, and purification were performed using the compound of Reference Example 56-2 (54 mg, 0.093 mmol) and [(tert-butoxycarbonyl)amino][1-(tert-butoxycarbonyl)-1H-imidazol-4-yl]acetic acid (38 mg, 0.11 mmol) as the starting materials by the same method described in Reference Example 55 to obtain the title compound (47 mg).

[2777] LCMS: [M+H].sup.+/Rt=909.53/1.356 min.sup.E

[2778] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 and carboxylic acid corresponding to each of the following Reference Examples as the starting materials by the same method described in Reference Example 36-4 to obtain each of Reference Example compounds 57 to 62 shown in Tables 2-7 and 2-8.

TABLE-US-00003 TABLE 2-7 Reference Example Structural formula NMR and/or LCMS 57 [00820] embedded image LCMS: [M + H].sup.+/Rt = 809.49/0.973 min.sup.C 58 [00821] LCMS: [M + H].sup.+/Rt = 707.43/1.187 min.sup.A 59 [00822] LCMS: [M + H].sup.+/Rt = 681.60/3.75 min.sup.D .sup.1H-NMR (CDCl.sub.3) δ: 7.66 (1H, s), 7.20 (1H, d, J = 8.0 Hz), 6.38 (1H, d, J = 8.6 Hz), 4.99-4.87 (1H, m), 4.55-4.49 (1H, m), 4.40- 4.34 (1H, m), 4.28-4.20 (1H, m), 4.12-4.06 (1H, m), 3.62-3.58 (2H, m), 2.63-2.54 (2H, m), 2.33-2.24 (1H, m), 2.21-2.10 (1H, m), 2.03-1.96 (1H, m), 1.90-1.84 (1H, m), 1.81- 1.74 (1H, m), 1.53-1.51 (18H, m), 1.34 (3H, s), 1.26 (3H, s), 1.11-1.07 (2H, m), 1.02- 0.98 (1H, m), 0.81 (3H, s). 60 [00823] embedded image .sup.1H-NMR (CDCl.sub.3) δ: 7.20 (2H, d, J = 8.5 Hz), 6.39 (1H, d, J = 8.5 Hz), 4.93-4.90 (1H, m), 4.42-4.31 (2H, m), 4.22 (1H, dd, J = 9.2, 1.8 Hz), 4.13-4.02 (2H, m), 3.59-3.55 (1H, m), 3.44-3.38 (1H, m), 3.29-3.25 (1H, m), 2.92-2.87 (1H, m), 2.59 (3H, t, J = 8.2 Hz), 2.35-2.23 (1H, m), 2.19-2.12 (3H, m), 2.09-2.02 (2H, m), 1.88-1.85 (1H, m), 1.78 (1H, d, J = 14.6 Hz), 1.54 (9H, s), 1.52 (18H, s), 1.43 (3H, s), 1.34 (3H, s), 1.09 (2H, t, J = 8.5 Hz), 1.01 (1H, d, J = 11.0 Hz), 0.82 (3H, s).

TABLE-US-00004 TABLE 2-8 61 [00824] embedded image .sup.1H-NMR (CDCl.sub.3) δ: 7.21 (1H, d, J = 8.5 Hz), 6.40 (1H, d, J = 8.5 Hz), 4.94-4.90 (1H, m), 4.70-4.30 (4H, m), 4.25 (1H, dd, J = 8.9, 2.1 Hz), 4.13-3.80 (6H, m), 3.01-2.75 (3H, m), 2.61 (2H, t, J = 8.2 Hz), 2.35- 2.28 (1H, m), 2.20-2.14 (1H, m), 2.04-2.00 (1H, m), 1.92-1.87 (1H, m), 1.83-1.78 (1H, m), 1.56 (9H, s), 1.53 (9H, s), 1.47 (18H, s), 1.36 (3H, s), 1.27 (3H, s), 1.13 (2H, dt, J = 17.5, 6.3 Hz), 1.03 (1H, d, J = 11.0 Hz), 0.84 (3H, s) 62 [00825] embedded image LCMS: [M + H].sup.+/Rt = 801.41/1.463 min.sup.C .sup.1H-NMR (CD.sub.3OD) δ: 7.31 (1H, d, J = 8.5 Hz), 6.69 (1H, dd, J = 8.5, 2.4 Hz), 5.30 (1H, s), 5.17 (1H, s), 5.08 (1H, s), 4.61 (1H, t, J = 7.6 Hz), 4.37 (1H, dd, J = 11.3, 6.4 Hz), 4.31-4.26 (3H, m), 4.18-4.14 (1H, m), 3.94 (1H, d, J = 11.6 Hz), 3.63 (1H, s), 3.55 (1H, s), 2.58 (2H, t, J = 7.9 Hz), 2.38-2.31 (2H, m), 2.20- 2.15 (2H, m), 1.98 (1H, t, J = 5.5 Hz), 1.89-1.85 (1H, m), 1.78 (1H, d, J = 14.6 Hz), 1.58 (9H, s), 1.52 (9H, s), 1.47 (9H, s), 1.35 (3H, s), 1.29 (3H, s), 1.07 (2H, t, J = 8.2 Hz), 0.97 (1H, dd, J = 11.0, 1.8 Hz), 0.85 (3H, s).

[2779] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 as the starting material by the same method described in Reference Example 3 to obtain each of Reference Example compounds 63 to 105 shown in Tables 2-9 to 2-16.

TABLE-US-00005 TABLE 2-9 Refe- rence Exam- ple Structural formula NMR and/or LCMS 63 [00826] embedded image LCMS: [M + H].sup.+/Rt = 807.2/2.91 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 8.63-8.57 (2H, m), 7.73-7.66 (1H, m), 7.34-7.29 (1H, m), 7.20 (1H, dd, J = 8.1 Hz, 5.4 Hz), 6.34 (1H, t, J = 8.1 Hz), 6.00-5.83 (1H, m), 5.24-5.17 (1H, m), 4.98-4.78 (1H, m), 4.64-4.42 (1H, m), 4.33-4.06 (3H, m), 4.04-3.82 (1H, m), 2.64- 2.56 (2H, m), 2.36-2.27 (1H, m), 2.21-2.12 (1H, m), 2.05-2.00 (1H, m), 1.91-1.77 (2H, m), 1.56-1.40 (27H, m), 1.36 (3H, s), 1.26 (3H, s), 1.13-1.00 (3H, m), 0.83 (3H, s). 64 [00827] embedded image LCMS: [M + H].sup.+/Rt = 810.0/2.93 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.46-7.36 (2H, m), 7.22-7.18 (1H, m), 6.36-6.33 (1H, m), 5.67-5.50 (1H, m), 5.19- 5.15 (1H, m), 5.05-4.93 (1H, m), 4.85-4.63 (1H, m), 4.48-4.22 (3H, m), 4.16-3.95 (1H, m), 3.88-3.66 (3H, m), 2.63-2.57 (2H, m), 2.36-2.27 (1H, m), 2.19- 2.14 (1H, m), 2.05-2.00 (1H, m), 1.93-1.76 (2H, m), 1.56-1.41 (27H, m), 1.35 (3H, s), 1.28 (3H, s), 1.13- 1.00 (3H, m), 0.83 (3H, s). 65 [00828] embedded image LCMS: [M + H].sup.+/Rt = 813.0/2.97 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 8.15 (1H, br), 7.21 (1H, d, J = 8.1 Hz), 6.71 (1H, s), 6.41 (1H, d, J = 8.1 Hz), 5.00- 4.88 (1H, m), 4.54-4.49 (1H, m), 4.42-4.35 (1H, m), 4.31-4.23 (2H, m), 4.14-4.08 (1H, m), 3.49 (2H, s), 2.65-2.56 (2H, m), 2.36-2.26 (1H, m), 2.19-2.12 (1H, m), 2.06-2.00 (1H, m), 1.92-1.77 (2H, m), 1.61- 1.44 (27H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.00 (3H, m), 0.83 (3H, s) 66 [00829] embedded image LCMS: [M + H].sup.+/Rt = 798.8/3.05 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.82 (1H, br), 7.72 (1H, s), 7.23 (1H, d, J = 8.1 Hz), 6.45 (1H, d, J = 8.1 Hz), 4.97- 4.84 (2H, m), 4.56-4.52 (2H, m), 4.26-4.19 (2H, m), 2.65-2.59 (2H, m), 2.36-2.28 (1H, m), 2.22-2.14 (1H, m), 2.04-2.00 (1H, m), 1.91-1.76 (2H, m), 1.60- 1.49 (27H, m), 1.36 (3H, s), 1.28 (3H, s), 1.15-1.01 (3H, m), 0.84 (3H, s). 67 [00830] embedded image LCMS: [M + H].sup.+/Rt = 1017.7/3.24 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.47-7.18 (11H, m), 6.92-6.87 (3H, m), 6.36-6.26 (1H, m), 5.86-5.69 (1H, m), 5.19- 3.76 (11H, m), 2.63-2.57 (2H, m), 2.36-2.27 (1H, m), 2.18-2.13 (1H, m), 2.05-2.00 (1H, m), 1.89-1.77 (2H, m), 1.57-1.39 (27H, m), 1.35 (3H, s), 1.26 (3H, s), 1.14-1.00 (3H, m), 0.83 (3H, s).

TABLE-US-00006 TABLE 2-10 68 [00831] embedded image LCMS: [M + H]′/Rt = 1017.9/3.36 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.41-7.15 (12H, m), 6.61-6.53 (2H, m), 6.24-6.11 (1H, m), 5.66-5.49 (2H, m), 5.11-5.00 (4H, m), 4.81-3.72 (5H, m), 2.64-2.54 (2H, m), 2.36-2.28 (1H, m), 2.20-2.16 (1H, m), 2.09-2.00 (1H, m), 1.89-1.78 (2H, m), 1.68-1.23 (33H, m), 1.14-1.02 (3H, m), 0.83 (3H, s). 69 [00832] embedded image LCMS: [M + H].sup.+/Rt = 681.39/3.96 min.sup.D .sup.1H-NMR (CDCl.sub.3) δ: 7.78 (1H, d, J = 1.1 Hz), 7.73 (1H, d, J = 1.1 Hz), 7.23-7.18 (1H, m), 6.37 (1H, d, J = 8.6 Hz), 5.09 (1H, d, J = 16.0 Hz), 5.01-4.91 (2H, m), 4.53-4.45 (1H, m), 4.45-4.37 (1H, m), 4.26-4.21 (1H, m), 4.19-4.07 (2H, m), 2.63-2.56 (2H, m), 2.34-2.25 (1H, m), 2.20-2.12 (1H, m), 2.03-1.98 (1H, m), 1.92-1.85 (1H, m), 1.83-1.75 (1H, m), 1.54 (9H, s), 1.52 (9H, s), 1.34 (3H, s), 1.26 (3H, s), 1.12-1.07 (2H, m), 1.01 (1H, d, J = 11.5 Hz), 0.82 (3H, s). 70 [00833] embedded image LCMS: [M + H].sup.+/Rt = 824.0/2.51 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.39 (1H, s), 7.22 (1H, d, J = 8.1 Hz), 6.90 (1H, s), 6.41 (1H, d, J = 8.1 Hz), 4.93-4.61 (3H, m), 4.41-4.35 (1H, m), 4.27-4.23 (2H, m), 4.06-4.00 (2H, m), 3.52-3.37 (4H, m), 2.64-2.56 (2H, m), 2.36-2.27 (1H, m), 2.19-2.13 (1H, m), 2.05-2.00 (1H, m), 1.93-1.66 (2H, m), 1.56 (9H, s), 1.53 (9H, s), 1.44 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.00 (3H, m), 0.86 (3H, s). 71 [00834] embedded image LCMS: [M + H].sup.+/Rt = 812.9/2.93 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 8.77-8.76 (1H, m), 7.36-7.33 (1H, m), 7.22 (1H, d, J = 8.1 Hz), 6.39 (1H, d, J = 8.1 Hz), 5.98-5.92 (1H, m), 5.54-5.48 (1H, m), 5.01-4.87 (1H, m), 4.74-4.68 (1H, m), 4.48-4.03 (4H, m), 2.64-2.58 (2H, m), 2.36-2.27 (2H, m), 2.04-2.00 (1H, m), 1.92- 1.76 (2H, m), 1.57-1.52 (18H, m), 1.44 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.13-1.01 (3H, m), 0.83 (3H, s). 72 [00835] embedded image LCMS: [M + H].sup.+/Rt = 865.61/1.332 min.sup.E

TABLE-US-00007 TABLE 2-11 73 [00836] embedded image .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.39-7.37 (6H, m), 7.27-7.12 (10H, m), 6.49 (1H, d, J = 8.5 Hz), 5.16-5.13 (1H, m), 4.92-4.90 (1H, m), 4.83-4.79 (2H, m), 4.24-4.20 (3H, m), 4.13-4.07 (1H, m), 2.64-2.56 (4H, m), 2.35-2.26 (1H, m), 2.19-2.13 (1H, m), 2.02-1.99 (1H, m), 1.90-1.86 (1H, m), 1.81-1.77 (1H, m), 1.54 (9H, s), 1.51 (9H, s), 1.41 (9H, s), 1.34 (3H, s), 1.26 (3H, s), 1.11-1.00 (2H, m), 0.82 (3H, s). 74 [00837] embedded image LCMS: [M + H].sup.+/Rt = 1045/1.347 min.sup.C 75 [00838] LCMS: [M + H].sup.+/Rt = 759.20/4.09 min.sup.D .sup.1H-NMR (CDCl.sub.3) δ: 7.22-7.17 (1H, m), 6.40-6.36 (1H, m), 5.58-5.41 (1H, m), 4.98-4.89 (1H, m), 4.76-4.53 (1H, m), 4.44-4.19 (3H, m), 4.13-4.02 (1H, m), 3.91- 3.80 (1H, m), 3.73-3.64 (1H, m), 2.62-2.55 (2H, m), 2.35-2.25 (1H, m), 2.19-2.11 (1H, m), 2.03-1.97 (1H, m), 1.92-1.84 (1H, m), 1.82-1.75 (1H, m), 1.54 (9H, s), 1.51 (9H, s), 1.44-1.40 (9H, m), 1.34 (3H, s), 1.26 (3H, s), 1.12-1.06 (2H, m), 1.03-0.99 (1H, m), 0.81 (3H, s). 76 [00839] embedded image LCMS: [M + H].sup.+/Rt = 843.8/3.14 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J = 8.1 Hz), 6.40 (1H, d, J = 8.1 Hz), 4.93 (1H, br), 4.79-4.67 (1H, m), 4.61- 4.48 (1H, m), 4.40-4.31 (2H, m), 4.25 (1H, dd, J = 8.1 Hz, 2.7 Hz), 4.14-4.05 (1H, m), 2.67-2.58 (4H, m), 2.36-2.27 (1H, m), 2.22-2.13 (1H, m), 2.04-2.00 (1H, m), 1.93-1.77 (2H, m), 1.56 (9H, s), 1.54 (9H, s), 1.46- 1.42 (18H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 77 [00840] embedded image LCMS: [M + H].sup.+/Rt = 814.7/2.89 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.23 (1H, d, J = 8.1 Hz), 6.77 (1H, br), 6.41 (1H, d, J = 8.1 Hz), 5.70-4.90 (2H, m), 4.75-4.04 (7H, m), 2.65-2.59 (2H, m), 2.36-2.28 (1H, m), 2.20-2.14 (1H, m), 2.04-2.00 (1H, m), 1.91-1.78 (2H, m), 1.56 (9H, s), 1.54 (9H, s), 1.45 (9H, s), 1.36-1.23 (12H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

TABLE-US-00008 TABLE 2-12 78 [00841] embedded image LCMS: [M + H].sup.+/Rt = 843.7/3.21 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J = 8.1 Hz), 6.40 (1H, d, J = 8.1 Hz), 5.32-5.29 (1H, m), 5.00-4.84 (1H, m), 4.79-4.64 (1H, m), 4.59-4.48 (1H, m), 4.40-4.30 (2H, m), 4.27-4.23 (1H, m), 4.14-4.05 (1H, m), 2.67-2.56 (4H, m), 2.36-2.26 (1H, m), 2.22-2.13 (1H, m), 2.05- 2.00 (1H, m), 1.92-1.77 (2H, m), 1.56 (9H, s), 1.54 (9H, s), 1.45-1.40 (18H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 79 [00842] embedded image LCMS: [M + H].sup.+/Rt = 785.7/1.40 min.sup.C 80 [00843] LCMS: [M − Boc + H].sup.+/Rt = 737.5/1.47 min.sup.C 81 [00844] LCMS: [M + H].sup.+/Rt = 787.7/1.40 min.sup.C 82 [00845] LCMS: [M + H].sup.+/Rt = 805.7/3.07 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.23 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 5.01-4.43 (3H, m), 4.37-4.30 (1H, m), 4.27-4.00 (3H, m), 3.85-3.75 (2H, m), 2.65-2.48 (4H, m), 2.36-2.27 (1H, m), 2.20-2.14 (1H, m), 2.05-2.00 (1H, m), 1.92-1.77 (2H, m), 1.59-1.45 (27H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

TABLE-US-00009 TABLE 2-13 83 [00846] embedded image LCMS: [M + H]′/Rt = 797.3/3.07 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J = 8.1 Hz), 6.42 (1H, d, J = 8.1 Hz), 4.97-4.89 (1H, m), 4.45-4.32 (2H, m), 4.27-4.23 (1H, m), 4.16-4.05 (2H, m), 2.96-2.71 (4H, m), 2.65-2.56 (2H, m), 2.36-2.27 (1H, m), 2.22-2.13 (1H, m), 2.05-2.01 (5H, m), 1.92-1.67 (5H, m), 1.56 (9H, s), 1.54 (9H, s), 1.45 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 84 [00847] embedded image LCMS: [M + H].sup.+/Rt = 769.8/3.03 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.23 (1H, d, J = 8.1 Hz), 6.43 (1H, d, J = 8.1 Hz), 4.99-4.93 (1H, m), 4.45-4.46 (1H, m), 4.40-4.34 (1H, m), 4.27-4.05 (3H, m), 3.60-3.26 (4H, m), 2.95-2.80 (1H, m), 2.65-2.59 (2H, m), 2.36-2.26 (1H, m), 2.22-2.13 (1H, m), 2.05-2.00 (3H, m), 1.90- 1.76 (2H, m), 1.57 (9H, s), 1.54 (9H, s), 1.45 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 85 [00848] embedded image LCMS: [M + H].sup.+/Rt = 797.8/3.18 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 5.00-4.82 (1H, m), 4.48-4.08 (7H, m), 3.40-3.12 (1H, m), 2.64-2.58 (2H, m), 2.36-2.27 (1H, m), 2.22-2.13 (1H, m), 2.05-1.76 (5H, m), 1.60-1.56 (15H, m), 1.54 (9H, s), 1.45 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 86 [00849] embedded image LCMS: [M + H].sup.+/Rt = 783.9/3.09 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J = 8.1 Hz), 6.42 (1H, d, J = 8.1 Hz), 4.96-4.86 (1H, m), 4.37-4.00 (6H, m), 3.37-3.26 (2H, m), 2.80-2.58 (4H, m), 2.36-2.26 (1H, m), 2.20-2.13 (1H, m), 2.09-1.77 (7H, m), 1.56 (9H, s), 1.54 (9H, s), 1.46 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.83 (3H, s). 87 [00850] embedded image LCMS: [M + H].sup.+/Rt = 783.8/3.22 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.21 (1H, d, J = 8.1 Hz), 6.39-6.33 (1H, m), 4.94-4.68 (2H, m), 4.55-3.89 (7H, m), 2.64- 2.56 (2H, m), 2.36-2.27 (1H, m), 2.27-2.13 (1H, m), 2.05-2.00 (1H, m), 1.93-1.77 (2H, m), 1.70-1.23 (39H, m), 1.13-1.01 (3H, m), 0.83 (3H, s). 88 [00851] embedded image LCMS: [M + H].sup.+/RT = 783.9/3.11 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.23 (1H, d, J = 8.1 Hz), 6.43 (1H, d, J = 8.1 Hz), 5.00-4.92 (1H, m), 4.51-4.04 (8H, m), 2.85-2.56 (3H, m), 2.36-2.14 (3H, m), 2.05-2.00 (1H, m), 1.93-1.77 (3H, m), 1.74-1.44 (30H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

TABLE-US-00010 TABLE 2-14 89 [00852] embedded image LCMS: [M + H]′/Rt = 783.6/3.05 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J = 8.1 Hz), 6.43 (1H, d, J = 8.1 Hz), 4.99-4.92 (1H, m), 4.51-4.45 (1H, m), 4.39-4.32 (1H, m), 4.27-4.04 (5H, m), 2.80-2.53 (3H, m), 2.36-2.25 (2H, m), 2.20-2.13 (1H, m), 2.05-2.00 (1H, m), 1.92-1.77 (2H, m), 1.71-1.51 (23H, m), 1.45 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 90 [00853] embedded image LCMS: [M + H].sup.+/Rt = 670.7/2.88 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 4.97-4.90 (1H, m), 4.76-4.63 (1H, m), 4.47-4.22 (4H, m), 4.14-4.05 (1H, m), 3.92-3.81 (2H, m), 2.64-2.58 (2H, m), 2.36-2.27 (1H, m), 2.21-2.11 (3H, m), 2.05-2.00 (1H, m), 1.95-1.79 (4H, m), 1.62- 1.54 (18H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 91 [00854] embedded image LCMS: [M + H].sup.+/Rt = 845.8/3.14 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.32-7.20 (6H, m), 6.42 (1H, d, J = 8.1 Hz), 5.05-4.86 (1H, m), 4.64-3.91 (7H, m), 3.49- 3.26 (2H, m), 2.64-2.58 (2H, m), 2.36-2.27 (1H, m), 2.22-2.13 (2H, m), 2.08-2.00 (2H, m), 1.96-1.78 (2H, m), 1.56-1.45 (27H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.83 (3H, s). 92 [00855] embedded image LCMS: [M + H].sup.+/Rt = 781.7/3.07 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.21 (1H, d, J = 8.1 Hz), 6.39 (1H, d, J = 8.1 Hz), 4.97-4.86 (1H, m), 4.78-4.33 (3H, m), 4.26-3.98 (3H, m), 3.50-3.42 (1H, m), 2.64-2.58 (2H, m), 2.41-2.27 (1H, m), 2.22-2.13 (1H, m), 2.05-2.00(2H, m), 1.96-1.77 (2H, m), 1.56-1.41 (29H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (4H, m), 0.96-0.69(4H, m). 93 [00856] embedded image LCMS: [M + H].sup.+/Rt = 684.0/2.18 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.23 (1H, d, J = 8.1 Hz), 6.42 (1H, d, J = 8.1 Hz), 5.00-4.92 (1H, m), 4.67-4.57 (1H, m), 4.47-4.36 (1H, m), 4.27-4.23 (2H, m), 4.15-4.05 (1H, m), 3.25-2.94 (1H, m), 2.64-2.58 (2H, m), 2.47-2.27 (5H, m), 2.21-2.14 (2H, m), 2.05-2.00 (1H, m), 1.97-1.66 (6H, m), 1.56 (9H, s), 1.54 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 94 [00857] embedded image LCMS: [M + H].sup.+/Rt = 797.9/3.23 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.21 (1H, d, J = 8.1 Hz), 6.42 (1H, d, J = 8.1 Hz), 4.97-4.89 (1H, m), 4.47-4.33 (2H, m), 4.26-4.23 (1H, m), 4.16-4.03 (4H, m), 3.87-3.77 (2H, m), 2.65-2.58 (2H, m), 2.36-2.28 (1H, m), 2.21-2.12 (1H, m), 2.08-1.78 (10H, m), 1.60-1.44 (27H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

TABLE-US-00011 TABLE 2-15 95 [00858] embedded image LCMS: [M + H].sup.+/Rt = 799.9/3.01 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 4.95-4.88 (1H, m), 4.56-4.32 (2H, m), 4.26-3.81 (6H, m), 3.57-3.48 (1H, m), 2.93-2.80 (1H, m), 2.71-2.58 (3H, m), 2.36-2.26 (2H, m), 2.22-2.10 (2H, m), 2.04-2.00 (2H, m), 1.93-1.77 (2H, m), 1.56 (9H, s), 1.54 (9H, s), 1.46 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.83 (3H, s). 96 [00859] embedded image LCMS: [M + H].sup.+/Rt = 769.9/2.98 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.23 (1H, d, J = 8.1 Hz), 6.42 (1H, d, J = 8.1 Hz), 4.98-4.91 (1H, m), 4.47-4.41 (1H, m), 4.37-4.31 (1H, m), 4.27-4.23 (1H, m), 4.18-4.02 (4H, m), 3.61-3.55 (2H, m), 2.98-2.85 (1H, m), 2.65-2.59 (2H, m), 2.42 (2H, d, J = 8.1 Hz), 2.22-2.13 (1H, m), 2.05-2.00 (1H, m), 1.92-1.76 (2H, m), 1.57 (9H, s), 1.54 (9H, s), 1.43 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 97 [00860] embedded image LCMS: [M + H].sup.+/Rt = 898.9/3.14 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.23 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 5.24-5.07 (1H, m), 5.02-4.90 (1H, m), 4.55-4.00 (6H, m), 3.62-2.92 (5H, m), 2.65-2.59 (2H, m), 2.49-2.23 (2H, m), 2.22-2.12 (1H, m), 2.05-2.00 (1H, m), 1.95-1.78 (3H, m), 1.58-1.42 (36H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 98 [00861] embedded image LCMS: [M + H].sup.+/Rt = 798.0/3.10 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 4.96-4.89 (1H, m), 4.49-4.32 (2H, m), 4.27-4.23 (1H, m), 4.16-4.02 (3H, m), 3.89-3.75 (1H, m), 3.33-3.26 (1H, m), 2.65-2.58 (2H, m), 2.36-2.28 (1H, m), 2.22-2.07 (3H, m), 2.05-2.00 (2H, m), 1.97-1.78 (7H, m), 1.56 (9H, s), 1.54 (9H, s), 1.45 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 99 [00862] embedded image LCMS: [M + H].sup.+/Rt = 912.7/3.1 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.23 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 5.13-5.09 (1H, m), 5.00-4.91 (1H, m), 4.75-4.69 (1H, m), 4.54-3.99 (8H, m), 2.70-2.59 (4H, m), 2.36-2.28 (1H, m), 2.23-2.13 (1H, m), 2.05-2.00 (1H, m), 1.94-1.87 (1H, m), 1.84-1.62 (4H, m), 1.60- 1.53 (18H, m), 1.45-1.42 (18H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 100 [00863] embedded image LCMS: [M + H].sup.+/Rt = 783.7/2.99 min.sup.B

TABLE-US-00012 TABLE 2-16 101 [00864] embedded image LCMS: [M + H].sup.+/Rt = 783.6/3.01 min.sup.B 102 [00865] LCMS: [M + H].sup.+/Rt = 783.9/3.08 min.sup.B 103 [00866] LCMS: [M + H].sup.+/Rt = 783.8/3.08 min.sup.B 104 [00867] LCMS: [M + H].sup.+/Rt = 797.9/3.17 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J = 8.1 Hz), 6.42 (1H, d, J = 8.1 Hz), 4.97-4.89 (1H, m), 4.68-4.40 (2H, m), 4.36-3.94 (5H, m), 2.87-2.69 (1H, m), 2.63-2.53 (2H, m), 2.47-2.13 (4H, m), 2.04-2.00 (1H, m), 1.93-1.77 (2H, m), 1.68-1.54 (24H, m), 1.46-1.45 (9H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 105 [00868] embedded image LCMS: [M + H].sup.+/Rt = 794.6/2.90 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 5.00-4.85 (1H, m), 4.61-3.92 (7H, m), 3.67-3.56 (1H, m), 3.50-2.98 (1H, m), 2.64-2.46 (3H, m), 2.41-2.13 (3H, m), 2.05-2.00 (1H, m), 1.92-1.77 (2H, m), 1.59-1.54 (18H, m), 1.45 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

[2780] A reaction, work-up, and purification were performed using the compound of Reference Example 1-7 as the starting material by the same method described in Reference Example 41 to obtain each of Reference Example compounds 106 to 108 shown in Table 2-17.

TABLE-US-00013 TABLE 2-17 Reference Example Structural formula NMR and/or LCMS 106 [00869] embedded image LCMS: [M + H].sup.+/Rt = 702.8/2.72 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 10.51 (1H, br), 7.62 (1H, s), 7.56 (1H, s), 7.18 (1H, d, J = 8.1 Hz), 6.30 (1H, d, J = 8.1 Hz), 4.76- 4.71 (1H, m), 4.33-4.22 (3H, m), 4.01- 3.96 (2H, m), 2.62-2.56 (2H, m), 2.36- 2.27 (1H, m), 2.19-2.13 (1H, m), 2.04- 2.00 (1H, m), 1.92-1.76 (2H, m), 1.53 (9H, s), 1.52 (9H, s), 1.35 (3H, s), 1.26 (3H, s), 1.11-1.00 (3H, m), 0.83 (3H, s). 107 [00870] embedded image LCMS: [M + H].sup.+/Rt = 714.0/2.96 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 9.07 (1H, d, J = 2.7 Hz), 8.88 (1H, dd, J = 5.4 Hz, 2.7 Hz), 8.15-8.11 (1H, m), 7.53 (1H, dd, J = 8.1 Hz, 5.4 Hz), 7.18 (1H, d, J = 8.1 Hz), 6.37 (1H, d, J = 8.1 Hz), 4.86-4.82 (1H, m), 4.27-4.21 (3H, m), 3.87-3.82 (2H, m), 2.62-2.56 (2H, m), 2.35-2.27 (1H, m), 2.19-2.12 (1H, m), 2.03-1.99 (1H, m), 1.91-1.76 (2H, m), 1.52 (9H, s), 1.49 (9H, s), 1.35 (3H, s), 1.26 (3H, s), 1.11- 0.99 (3H, m), 0.83 (3H, s). 108 [00871] embedded image LCMS: [M + H].sup.+/Rt = 729.8/2.84 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 8.23 (1H, d, J = 8.1 Hz), 7.99 (1H, dd, J = 8.1 Hz, 2.7 Hz), 7.46-7.31 (2H, m), 7.20 (1H, d, J = 8.1 Hz), 6.40 (1H, d, J = 8.1 Hz), 4.99-4.90 (1H, m), 4.60-4.54 (2H, m), 4.42-4.36 (2H, m), 4.24 (1H, dd, J = 8.1 Hz, 2.7 Hz), 2.64-2.56 (2H, m), 2.36-2.27 (1H, m), 2.22-2.13 (1H, m), 2.05-2.00 (1H, m), 1.92-1.76 (2H, m), 1.56 (9H, s), 1.53 (9H, s), 1.35 (3H, s), 1.28 (3H, s), 1.13- 1.00 (3H, m), 0.83 (3H, s).

[2781] A reaction, work-up, and purification were performed using the compound of Reference Example 1-7 as the starting material by the same method described in Reference Example 42 to obtain each of Reference Example compounds 109 to 113 shown in Table 2-18.

TABLE-US-00014 TABLE 2-18 Reference Example Structural formula NMR and/or LCMS 109 [00872] embedded image LCMS: [M + H].sup.+/Rt = 786.9/2.77 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J = 8.1 Hz), 6.41-6.37 (1H, m), 6.02 (1H, br), 5.71- 5.61 (1H, m), 5.48-5.39 (1H, m), 4.95-4.89 (1H, m), 4.75-4.50 (2H, m), 4.42-4.32 (2H, m), 4.27-4.23 (1H, m), 4.10-4.03 (1H, m), 2.73-2.54 (4H, m), 2.36-2.27 (1H, m), 2.20-2.13 (1H, m), 2.04-2.00 (1H, m), 1.92- 1.77 (2H, m), 1.57 (9H, s), 1.53 (9H, s), 1.43 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.83 (3H, s). 110 [00873] embedded image LCMS: [M + H].sup.+/Rt = 671.6/2.59 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.32 (1H, d, J = 8.1 Hz), 6.70 (1H, d, J = 8.2 Hz), 5.12-5.06 (1H, m), 4.68-4.62 (1H, m), 4.40-4.17 (3H, m), 3.96-3.90 (1H, m), 2.60-2.49 (4H, m), 2.45-2.31 (3H, m), 2.23-2.11 (1H, m), 2.01-1.97 (1H, m), 1.90-1.66 (2H, m), 1.56 (9H, s), 1.52 (9H, s), 1.35 (3H, s), 1.29 (3H, s), 1.20-0.96 (3H, m), 0.86 (3H, s). 111 [00874] embedded image LCMS: [M + H].sup.+/Rt = 800.8/2.72 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.23 (1H, d, J = 8.1 Hz), 6.43-6.39 (1H, m), 5.01-4.91 (1H, m), 4.69-4.02 (6H, m), 2.64-2.58 (2H, m), 2.36-1.76 (9H, m), 1.61-1.53 (18H, m), 1.43-1.42 (9H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 112 [00875] embedded image LCMS: [M + H].sup.+/Rt = 800.7/2.81 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.23 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 6.23-6.16 (1H, m), 5.56-5.40 (1H, m), 5.00-4.92 (1H, m), 4.75-4.65 (1H, m), 4.56-4.23 (4H, m), 4.12-4.03 (1H, m), 3.67-3.27 (2H, m), 2.64- 2.58 (2H, m), 2.37-2.27 (1H, m), 2.22-2.12 (1H, m), 2.04-1.98 (4H, m), 1.93-1.77 (2H, m), 1.60-1.54 (18H, m), 1.44 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 113 [00876] embedded image LCMS: [M + H].sup.+/Rt = 801.7/2.70 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.26-7.21 (1H, m), 6.43 (1H, d, J = 8.1 Hz), 6.25 (1H, br), 5.30-4.95 (2H, m), 4.75-4.52 (3H, m), 4.44-4.05 (5H, m), 3.74-3.15 (2H, m), 2.63-2.57 (2H, m), 2.37-2.28 (1H, m), 2.23-2.13 (1H, m), 2.05-2.01 (1H, m), 1.93-1.77 (2H, m), 1.57 (9H, s), 1.52 (9H, s), 1.44 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.13-1.01 (3H, m), 0.84 (3H, s).

[2782] A reaction, work-up, and purification were performed using the compound of Reference Example 43-2 as the starting material by the same method described in Reference Example 43 to obtain each of Reference Example compounds 114 to 116 shown in Table 2-19.

TABLE-US-00015 TABLE 2-19 Refe- ence Exam- ple Structural formula NMR and/or LCMS 114 [00877] embedded image LCMS: [M + H].sup.+/Rt = 824.58/4.36 min.sup.D .sup.1H-NMR (CDCl.sub.3) δ: 7.76-7.65 (1H, m), 7.24 (1H, d, J = 8.6 Hz), 6.41 (1H, d, J = 8.6 Hz), 5.11-5.04 (1H, m), 5.02-4.96 (1H, m), 4.95-4.89 (1H, m), 4.60-4.48 (3H, m), 4.47- 4.40 (1H, m), 4.31-4.20 (2H, m), 4.19-4.11 (1H, m), 2.92 (3H, s), 2.63 (2H, t, J = 8.3 Hz), 2.38-2.29 (1H, m), 2.23-2.14 (1H, m), 2.07- 2.01 (1H, m), 1.94-1.88 (1H, m), 1.86-1.78 (1H, m), 1.58 (9H, s), 1.55 (9H, s), 1.48 (9H, s), 1.37 (3H, s), 1.30 (3H, s), 1.13 (2H, t, J = 8.3 Hz), 1.04 (1H, d, J = 10.9 Hz), 0.85 (3H, s). 115 [00878] embedded image LCMS: [M + H].sup.+/Rt = 879.59/3.24 min.sup.D .sup.1H-NMR (CDCl.sub.3) δ: 7.72 (1H, s), 7.40-7.17 (1H, m), 6.48-6.36 (1H, m), 5.12-4.87 (3H, m), 4.62-4.51 (1H, m), 4.49-4.36 (1H, m), 4.30- 4.21 (2H, m), 4.19-4.09 (1H, m), 3.74-3.65 (2H, m), 3.51-3.37 (4H, m), 2.67-2.56 (2H, m), 2.54-2.41 (4H, m), 2.36-2.26 (1H, m), 2.21- 2.12 (1H, m), 2.06-1.99 (1H, m), 1.94-1.75 (2H, m), 1.62-1.42 (27H, m), 1.38-1.35 (3H, m), 1.30-1.27 (3H, m), 1.14-1.08 (2H, m), 1.06-1.00 (1H, m), 0.86-0.82 (3H, m). 116 [00879] embedded image LCMS: [M + H].sup.+/Rt = 725.50/3.77 min.sup.D .sup.1H-NMR (CDCl.sub.3) δ: 7.62 (1H, s), 7.22 (1H, d, J = 8.6 Hz), 6.38 (1H, d, J = 8.6 Hz), 5.10-4.90 (3H, m), 4.53-4.39 (2H, m), 4.28-4.22 (1H, m), 4.16-4.04 (2H, m), 3.98-3.82 (2H, m), 2.96 (2H, t, J = 5.7 Hz), 2.65-2.56 (3H, m), 2.37-2.26 (1H, m), 2.21-2.12 (1H, m), 2.04-2.00 (1H, m), 1.94-1.88 (1H, m), 1.86- 1.74 (1H, m), 1.57 (9H, s), 1.54 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.13-1.08 (2H, m), 1.03 (1H, d, J = 10.9 Hz), 0.84 (3H, s).

Reference Example 117: tert-butyl (4R)-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S, 7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidine-1-carbonyl}-4-hydroxypyrrolidine-1-carboxylate

[2783] ##STR00880##

[2784] Palladium on carbon (20 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (3 mL) of the compound of Reference Example 1-7 (200 mg, 0.283 mmol), and the reaction mixture was stirred for 30 minutes under a hydrogen atmosphere at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methanol, and the combined filtrate was concentrated. The resulting residue was dissolved in DMF (2 mL)(this is referred to as “solution A”). Meanwhile, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (94.1 mg, 0.340 mmol) was added to a DMF-methanol (2:1) mixture solution (3 mL) of trans-N-(tert-butoxycarbonyl)-4-hydroxy-L-proline (98.3 mg, 0.425 mmol), and the reaction mixture was stirred for 20 minutes at room temperature. The aforementioned solution A was then added, and the reaction mixture was stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol) to obtain the title compound (222 mg).

[2785] .sup.1H-NMR. (CDCl.sub.3) δ: 7.22 (1H, d, J=8.1 Hz), 6.41 (1H, d, J=8.1 Hz), 4.99-4.89 (1H, m), 4.58-3.99 (7H, m), 3.69-3.42 (2H, m), 2.65-2.58 (2H, m), 2.36-2.26 (1H, m), 2.22-2.07 (3H, m), 2.05-2.00 (1H, m), 1.93-1.73 (2H, m), 1.56 (9H, s), 1.54 (9H, s), 1.45-1.44 (9H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

[2786] LCMS: [M+H].sup.+/Rt=785.8/2.79 min.sup.B

[2787] A reaction, work-up, and purification were performed using the compound of Reference Example 1-7 as the starting material by the same method described in Reference Example 117 to obtain each of Reference Example compounds 118 to 119 shown in Table 2-20.

TABLE-US-00016 TABLE 2-20 Reference Example Structural formula NMR and/or LCMS 118 [00881] embedded image LCMS: [M + H].sup.+/Rt = 785.8/2.94 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.23 (1H, d, J = 8.1 Hz), 6.43 (1H, d, J = 8.1 Hz), 5.14- 4.94 (2H, m), 4.57-4.03 (6H, m), 3.65- 3.42 (2H, m), 2.65-2.59 (2H, m), 2.36- 2.14 (3H, m), 2.04-1.76 (4H, m), 1.61- 1.42 (27H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 119 [00882] embedded image LCMS: [M + H].sup.+/Rt = 785.8/2.87 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 8.65 (1H, br), 7.22 (1H, d, J = 8.1 Hz), 6.43 (1H, d, J = 8.1 Hz), 5.00-4.88 (1H, m), 4.59- 4.05 (7H, m), 3.62-3.43 (2H, m), 2.64- 2.56 (2H, m), 2.36-2.26 (1H, m). 2.19- 2.00 (4H, m), 1.92-1.77 (2H, m), 1.56 (9H, s), 1.53 (9H, s), 1.45 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

Reference Example 120: tert-butyl (2S,4S)-4-amino-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S, 7aR)-3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidine-1-carbonyl}pyrrolidine-1-carboxylate

[2788] ##STR00883##

Reference Example 120-1: tert-butyl (2S,4S)-4-azido-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidine-1-carbonyl}pyrrolidine-1-carboxylate

[2789] ##STR00884##

[2790] Palladium on carbon (40 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (6 mL) of the compound of Reference Example 1-7 (400 mug, 0.567 mmol), and the reaction mixture was stirred for 30 minutes under a hydrogen atmosphere at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methylene chloride, and the combined filtrate was concentrated. The resulting residue was dissolved in DMF (6 mL). cis-4-azido-(tert-butoxycarbonyl)-L-proline (160 mg, 0.624 mmol), HATU (259 mg, 0.680 mmol), and triethylamine (236 μL, 1.70 mmol) were added, and the reaction mixture was stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (392 mg) as a colorless amorphous compound.

[2791] .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J=8.1 Hz), 6.40 (1H, d, J=8.1 Hz), 5.00-4.89 (1H, m), 4.82-4.01 (7H, m), 3.86-3.76 (1H, m), 3.39-3.32 (1H, m), 2.64-2.58 (2H, m), 2.48-2.28 (2H, m), 2.22-2.14 (1H, m), 2.04-2.00 (1H, m), 1.93-1.77 (3H, m), 1.56 (9H, s), 1.54 (9H, s), 1.45 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

[2792] LCMS: [M+H].sup.+/Rt=810.8/3.02 min.sup.B

Reference Example 120: tert-butyl (2S,4S)-4-amino-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-(2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidine-1-carbonyl)pyrrolidine-1-carboxylate

[2793] ##STR00885##

[2794] Palladium on carbon (40 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (5 mL) of the compound of Reference Example 120-1 (392 mg, 0.484 mmol), and the reaction mixture was stirred for 3 hours under a hydrogen atmosphere at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methanol, and the combined filtrate was concentrated. The residue was dissolved in acetonitrile (10 mL) and further filtered through cellulose. The filtered substance was washed with acetonitrile and the combined filtrate was concentrated to obtain the title compound (355 mg) as a brown solid.

[2795] .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J=8.1 Hz), 6.41 (1H, d, J=8.1 Hz), 5.00-4.89 (2H, m), 4.52-4.02 (5H, m), 3.68-3.49 (2H, m), 3.33-3.29 (1H, m), 2.64-2.61 (2H, m), 2.36-2.26 (2H, m), 2.20-2.14 (1H, m), 2.04-2.01 (1H, m), 1.93-1.73 (3H, m), 1.61 (9H, s), 1.54 (9H, s), 1.45 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

[2796] LCMS: [M+H].sup.+/Rt=785.0/2.28 min.sup.B

Reference Example 121: tert-butyl (2S,4S)-4-acetamido-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidine-1-carbonyl}pyrrolidine-1-carboxylate

[2797] ##STR00886##

[2798] Triethylamine (101 μL, 0.727 mmol) and acetyl chloride (19 μL, 0.267 mmol) were added to a THE solution (2.4 mL) of the compound of Reference Example 120 (190 mg, 0.242 mmol), and the reaction mixture was stirred for 30 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol) to obtain the title compound (204 mg) as a colorless amorphous compound.

[2799] .sup.1H-NMR (CDCl.sub.3) δ: 8.38-8.23 (1H, m), 7.23 (1H, d, J=8.1 Hz), 6.43 (1H, d, J=8.1 Hz), 5.12-4.93 (2H, m), 4.72-4.63 (1H, m), 4.53-4.46 (1H, m), 4.32-4.02 (4H, m), 3.61-3.45 (2H, m), 2.65-2.59 (2H, m), 2.37-2.27 (2H, m), 2.21-2.14 (1H, m), 2.04-2.00 (1H, m), 1.98-1.78 (6H, m), 1.57 (9H, s), 1.54 (9H, s), 1.46-1.43 (9H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

[2800] LCMS: [M+H].sup.+/Rt=827.0/2.86 min$

Reference Example 122: tert-butyl (2S,4R)-4-amino-2-{3-(2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl)ethyl}phenoxy]azetidine-1-carbonyl}pyrrolidine-1-carboxylate

[2801] ##STR00887##

Reference Example 122-1: tert-butyl (2S,4R)-4-azido-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidine-1-carbonyl}pyrrolidine-1-carboxylate

[2802] ##STR00888##

[2803] Palladium on carbon (40 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (6 mL) of the compound of Reference Example 1-7 (400 mug, 0.567 mmol), and the reaction mixture was stirred for 30 minutes under a hydrogen atmosphere at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methylene chloride, and the combined filtrate was concentrated. The resulting residue was dissolved in DMF (6 mL). (2S,4R)-4-azido-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (189 mg, 0.737 mmol), HATU (259 mg, 0.680 mmol), and triethylamine (236 μL, 1.70 mmol) were added, and the reaction mixture was stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (397 mg) as a colorless amorphous compound.

[2804] .sup.1H-NMR (CDCl.sub.3) δ: 7.23 (1H, d, J=8.1 Hz), 6.41 (1H, d, J=8.1 Hz), 5.00-4.00 (8H, m), 3.75-3.45 (2H, m), 2.74-2.58 (2H, m), 2.36-2.12 (4H, m), 2.05-2.00 (1H, m), 1.92-1.77 (2H, m), 1.60-1.54 (18H, m), 1.46-1.44 (9H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

[2805] LCMS: [M+H].sup.+/Rt=810.7/3.05 min.sup.B

Reference Example 122: tert-butyl (2S,4R)-4-amino-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidine-1-carbonyl}pyrrolidine-1-carboxylate

[2806] ##STR00889##

[2807] A reaction, work-up, and purification were performed using the compound of Reference Example 122-1 (397 mg, 0.490 mmol) as the starting material by the same method described in Reference Example 120 to obtain the title compound (368 mg) as a colorless amorphous compound.

[2808] .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J=8.1 Hz), 6.40 (1H, d, J=8.1 Hz), 5.50-3.50 (9H, m), 3.26-3.07 (1H, m), 2.74-2.58 (2H, m), 2.36-2.28 (1H, m), 2.22-2.00 (3H, m), 1.92-1.77 (3H, m), 1.60-1.54 (18H, m), 1.45 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.17-1.01 (3H, m), 0.84 (3H, s).

[2809] LCMS: [M+H].sup.+/Rt=784.8/2.27 min.sup.B

Reference Example 123: tert-butyl (2S,4R)-4-acetamido-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidine-1-carbonyl}pyrrolidine-1-carboxylate

[2810] ##STR00890##

[2811] A reaction, work-up, and purification were performed using the compound of Reference Example 122 (181 mg, 0.232 mmol) as the starting material by the same method described in Reference Example 121 to obtain the title compound (162 mg) as a colorless amorphous compound.

[2812] .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J=8.1 Hz), 6.42 (1H, d, J=8.1 Hz), 5.63-5.49 (1H, m), 5.00-3.94 (8H, m), 3.81-3.70 (1N, m), 3.48-3.32 (1H, m), 2.64-2.58 (2H, m), 2.36-2.14 (4H, m), 2.05-2.00 (1H, m), 1.98 (3H, s), 1.93-1.77 (2H, m), 1.56 (9H, s), 1.54 (9H, s), 1.47-1.43 (9H, m), 1.36 (3H, S), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

[2813] LCMS: [M+H].sup.+/Rt=826.7/2.81 min.sup.B

Reference Example 124: tert-butyl (2S,4R)-4-(2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-2-(dimethylcarbamoyl) pyrrolidine-1-carboxylate

[2814] ##STR00891##

Reference Example 124-1: benzyl (2S)-2-(dimethylcarbamoyl)-4-oxopyrrolidine-1-carboxylate

[2815] ##STR00892##

[2816] Triethylamine (0.48 mL, 3.44 mmol), HATU (873 mg, 2.30 mmol), and aqueous dimethylamine solution (about 9.5 mol/L, 0.24 mL, 2.3 mmol) were added to a THP solution (5.7 mL) of (2S)-1-benzyloxycarbonyl-4-oxopyrrolidine-2-carboxylic acid (302 mg, 1.15 mmol) while cooling with ice, and the reaction mixture was stirred for 8 hours at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (285 mg) as a colorless oily compound.

[2817] LCMS: [M+H].sup.+/Rt=291.14/0.582 min.sup.A

Reference Example 124-2: benzyl (2S)-2-(dimethylcarbamoyl)-4-(2-ethoxy-2-oxoethylidene) pyrrolidine-1-carboxylate

[2818] ##STR00893##

[2819] An n-butyl lithium/hexane solution (1.57 mol/L, 1.38 mL, 2.16 mmol) was slowly added to a THF solution (4.9 mL) of ethyl dimethylphosphonoacetate (423 mg, 2.16 mmol) at 78° C., and the reaction mixture was stirred for 30 minutes. A THF solution (4 ml) of the compound of Reference Example 124-1 (285 mg, 0.983 mmol) was added to the reaction solution at −78° C., and the reaction mixture was stirred for 5 hours at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (190 mg) as a colorless oil.

[2820] LCMS: [M+H].sup.+/Rt=361.19/0.757 min.sup.A, 361.19/0.795 min.sup.A (E/Z isomer mixture)

Reference Example 124-3: ethyl[(3R,5S)—S-(dimethylcarbamoyl)pyrrolidin-3-yl]acetate

[2821] ##STR00894##

[2822] A palladium on carbon-ethylenediamine complex (180 mg, Pd content: 10%, wetted with ca. 55t water) was added to a methanol solution (3.8 mL) of the compound of Reference Example 124-2 (190 mg, 0.526 mmol), and the reaction mixture was stirred for 7.5 hours under a hydrogen atmosphere. The reaction solution was filtered through celite. The filtered substance was washed with methanol, and the combined filtrate was concentrated to obtain the title compound (116.3 mg) as a colorless oil.

[2823] .sup.1H-NMR (CDCl.sub.3) δ: 4.05 (2H, q, J=7.1 Hz), 3.89 (1H, t, J=7.9 Hz), 3.02 (1H, dd, J=10.4, 6.7 Hz), 2.94 (3H, s), 2.91 (3H, s), 2.76 (1H, dd, J=10.4, 7.3 Hz), 2.57-2.48 (1H, m), 2.38-2.30 (3H, m), 2.23 (1H, dd, J=15.9, 7.9 Hz), 1.18 (3H, t, J=7.0 Hz).

[2824] LCMS: [M+H].sup.+/Rt=229.12/0.244 min.sup.A

Reference Example 124-4: tert-butyl (2S,4R)-2-(dimethylcarbamoyl)-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate

[2825] ##STR00895##

[2826] Sodium hydrogen carbonate (128 mg, 1.53 mmol) and di-tert-butyl dicarbonate (0.237 mL, 1.02 mmol) were added to a THF-water (1:1) mixture solution (3 mL) of the compound of Reference Example 124-3 (116 mg, 0.509 mmol), and the reaction mixture was stirred for 14 hours at room temperature. The reaction solution was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (125 mg) as a colorless oil.

[2827] .sup.1H-NMR (CDCl.sub.1) δ: 5.25 (1H, s), 4.00-3.94 (1H, m), 3.78-3.72 (1H, m), 3.76 (3H, s), 3.17 (1H, s), 1.46 (3H, s), 1.43 (9H, S).

Reference Example 124-5: [(3R,5S)-1-(tert-butoxycarbonyl)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]acetic acid

[2828] ##STR00896##

[2829] An aqueous 2 N sodium hydroxide solution (0.38 mL, 0.76 mmol) was added to a THF-water (2:1) mixture solution (1.8 mL) of the compound of Reference Example 124-4 (125 mg, 0.380 mmol) while cooling with ice, and the reaction mixture was stirred for 16 hours at room temperature. 1 N hydrochloric acid was added to the reaction solution, which was extracted with chloroform. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated to obtain the title compound (114 mg) as a white solid.

[2830] .sup.1H-NMR (CDCl.sub.3) δ: 4.54 (1H, dt, J=38.8, 7.9 Hz), 3.82-3.73 (1H, m), 3.11 (1H, td, J=9.6, 4.9 Hz), 3.04-2.97 (3H, m), 2.91 (3H, s), 2.54-2.35 (3H, m), 1.60-1.50 (2H, m), 1.35 (9H, d, J=23.3 Hz).

[2831] ##STR00897##

[2832] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 (145 mg, 0.253 mmol) and the compound of Reference Example 124-5 (114 mg, 0.380 mmol) as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound (167 mg) as a colorless amorphous compound.

[2833] LCMS: [M+H].sup.+/RT=854.45/1.398 min.sup.C

Reference Example 125: tert-butyl (2R,4S)-4-(2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate

[2834] ##STR00898##

Reference Example 125-1. tert-butyl (2R)-2-(dimethylcarbamoyl)-4-(2-ethoxy-2-oxoethylidene)pyrrolidine-1-carboxylate

[2835] ##STR00899##

[2836] A reaction, work-up, and purification were performed using tert-butyl (R)-2-(dimethylcarbamoyl)-4-oxopyrrolidine-1-carboxylate (325 mg, 1.27 mmol) as the starting material by the same method described in Reference Example 124-2 to obtain the title compound (167 mg) as a colorless oil.

[2837] LCMS: [M+H].sup.+/Rt=327.24/0.704 min.sup.A, 327.24/0.748 min.sup.A (two peaks detected due to being an E/Z isomer mixture)

Reference Example 125-2: tert-butyl (2R,4S)-2-(dimethylcarbamoyl)-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate

[2838] ##STR00900##

[2839] A reaction and work-up were performed using the compound of Reference Example 125-1 (167 mg, 0.511 mmol) was used as the starting material by the same method described in Reference Example 124-3 to obtain the title compound (128 mg) as a colorless oil.

[2840] LCMS: [M+H].sup.+/Rt=329.18/0.681 min.sup.A

Reference Example 125-3: [(3S,5R)-1-(tert-butoxycarbonyl)-5-(dimethylcarbamoyl) pyrrolidin-3-yl]acetic

[2841] ##STR00901##

[2842] A reaction and work-up were performed using the compound of Reference Example 125-2 (128 mg, 0.388 mmol) as the starting materials by the same method described in Reference Example 124-4 to obtain the title compound (117 mg) as a white solid.

[2843] .sup.1H-NMR (CDCl.sub.3) δ: 4.55 (1H, dt, J=39.1, 7.9 Hz), 3.82-3.73 (1H, m), 3.10 (1H, dd, J m 11.3, 7.6 Hz), 3.02 (3H, d, J=16.4 Hz), 2.91 (3H, d, J=1.2 Hz), 2.52-2.39 (3H, m), 1.60-1.50 (2H, m), 1.35 (9H, d, J=23.2 Hz).

[2844] ##STR00902##

[2845] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 (149 mg, 0.260 mmol) and the compound of Reference Example 125-3 (116 mg, 0.386 mmol) as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound (153 mg) as a colorless amorphous compound.

[2846] LCMS: [M+H].sup.+/RT=854.47/1.398 min.sup.C

Reference Example 126: tert-butyl 2-(2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-1,1-dioxo-1λ.SUP.6.-thiomorpholine-4-carboxylate

[2847] ##STR00903##

Reference Example 126-1: [4-(tert-butoxycarbonyl)-1,1-dioxo-1λ.SUP.6.-thiomorpholin-2-yl]acetic acid

[2848] ##STR00904##

[2849] An aqueous 2 N sodium hydroxide solution (1.15 mL, 2.31 mmol) was added to a methanol solution (7 mL) of tert-butyl 2-(2-ethoxy-2-oxoethyl)thiomorpholine-4-carboxylate 1,1-dioxide (247 mg, 0.769 mmol) while cooling with ice, and the reaction mixture was stirred for 4.5 hours at room temperature. An aqueous 2 N sodium hydroxide solution (1.15 mL, 2.31 mmol) was further added, and the reaction mixture was stirred for 2 hours. 1 N hydrochloric acid was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated to obtain the title compound (225 mg) as a light yellow oily compound.

[2850] LCMS: [M+H].sup.+/RT=292.13/0.521 min.sup.C

[2851] ##STR00905##

[2852] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 (0.30 g, 0.493 mmol) and the compound of Reference Example 126-1 (159 mg, 0.543 mmol) as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound (225 mg) as a light yellow oil.

[2853] .sup.1H-NMR (CDCl.sub.1) 5: 7.22 (1H, d, J=8.7 Hz), 6.40 (1H, d, J=8.7 Hz), 4.97-4.91 (1H, m), 4.56-4.35 (3H, m), 4.31-4.16 (5H, m), 4.09-3.98 (2H, m), 3.05-3.00 (2H, m), 2.79 (1H, d, J=16.0 Hz), 2.62 (2H, t, J=8.2 Hz), 2.35-2.28 (1H, m), 2.22-2.15 (1H, m), 2.04-2.00 (1H, m), 1.95-1.85 (2H, m), 1.81 (1H, d, J=14.6 Hz), 1.56 (9H, s), 1.54 (9H, s), 1.47 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.11 (2H, t, J=8.2 Hz), 1.03 (1H, d, J=11.0 Hz), 0.83 (3H, s).

Reference Example 127: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-{([1-(1H-imidazole-2-carbonyl)azetidin-3-yl]oxy)-3-(2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2854] ##STR00906##

[2855] A reaction, work-up, and purification were performed using the compound of Reference Example 1-7 (200 mg, 0.283 mmol) as the starting material by the same method described in Reference Example 40 to obtain the title compound (119 mg).

[2856] .sup.1H-NMR (CDCl.sub.3) δ: 10.76 (1H, br), 7.23 (1H, d, J=8.1 Hz), 7.19 (1H, s), 7.13 (1H, s), 6.46 (1H, d, J=8.1 Hz), 5.15-4.99 (2H, m), 4.76-4.70 (1H, m), 4.60-4.54 (1H, m), 4.29-4.23 (2H, m), 2.65-2.59 (2H, m), 2.36-2.26 (1H, m), 2.23-2.14 (1H, m), 2.05-2.01 (1H, m), 1.93-1.78 (2H, m), 1.56 (9H, s), 1.53 (9H, s), 1.36 (3H, s), 1.29 (3H, s), 1.15-1.01 (3H, m), 0.84 (3H, s).

[2857] LCMS: [M+H].sup.+/Rt=666.9/2.83 min.sup.B

Reference Example 128: N.SUP.2.-(tert-butoxycarbonyl)-N-[(2R)-1-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-serinamide

[2858] ##STR00907##

Reference Example 128-1: benzyl N-(tert-butoxycarbonyl)-D-seryl-D-alaninate

[2859] ##STR00908##

[2860] 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (809 mg, 2.92 mmol), triethylamine (0.355 mL, 2.56 mmol), and D-alanine benzyl p-toluenesulfonate (899 mg, 2.56 mmol) were added to a methanol (24 mL) solution of N-(tert-butoxycarbonyl)-D-serine (500 mg, 2.44 mmol), and the reaction mixture was stirred for 13 hours at room temperature. Water was added to the reaction solution, which was extracted with methylene chloride and then washed with 1 N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution. The resultant was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (955 mg).

[2861] .sup.1H-NMR (CDCl.sub.3) δ: 7.42-7.31 (5H, m), 7.03-7.00 (1H, m), 5.53-5.50 (1H, m), 5.23-5.13 (2H, m), 4.70-4.55 (1H, m), 4.23-4.15 (1H, (n), 4.09-3.94 (1H, m), 3.68-3.59 (1H, m), 3.11-3.03 (1H, m), 1.45-1.42 (12H, m).

[2862] LCMS: [M+H].sup.+/Rt=367.2/1.77 min.sup.B

Reference Example 128-2: N-(tert-butoxycarbonyl)-D-seryl-D-alanine

[2863] ##STR00909##

[2864] 10% palladium on carbon (48 mg) was added to a methanol (18 mL) solution of the compound of Reference Example 128-1 (955 mg, 2.61 mmol). The reaction mixture was subjected to hydrogen substitution and was stirred for 2 hours at room temperature. After the reaction solution was filtered, the filtrate was concentrated to obtain the title compound (735 mg).

[2865] .sup.1H-NMR (CDCl.sub.3) δ: 7.50-7.42 (1H, m), 5.75-5.72 (1H, m), 4.62-4.51 (1H, m), 4.30 (1H, br), 4.03-3.66 (3H, m), 1.47-1.44 (12H, m).

[2866] LCMS: [M+H].sup.+/Rt=277.1/1.04 min.sup.B

[2867] ##STR00910##

[2868] A reaction, work-up, and purification were performed using the compound of Reference Example 1-7 (200 mg, 0.283 mmol) and the compound of Reference Example 128-2 (86.1 mg, 0.312 mmol) as the starting materials by the same method described in Reference Example 117 to obtain the title compound (203 mg).

[2869] .sup.1H-NMR (CDCl.sub.3) δ: 7.24 (1H, d, J=8.1 Hz), 6.92-6.82 (1H, m), 6.41 (1H, d, J=8.1 Hz), 5.46-5.37 (1H, m), 5.02-4.95 (1H, m), 4.72-4.66 (1H, m), 4.51-3.94 (7H, m), 3.65-3.32 (2H, m), 2.65-2.49 (2H, m), 2.36-2.28 (1H, m), 2.22-2.13 (1H, m), 2.05-2.00 (1H, m), 1.93-1.77 (2H, m), 1.57 (9H, s), 1.54 (9H, s), 1.45 (9H, s), 1.36-1.23 (9H, m), 1.14-1.01 (3H, m), 0.84 (3H, s).

[2870] LCMS: [M+H].sup.+/Rt=830.4/2.80 min.sup.B

[2871] A reaction, work-up, and purification were performed using N.sup.α-(tert-butoxycarbonyl)-D-asparagine and tert-butyl N.sup.α-(tert-butoxycarbonyl)-D-aspartate as the starting materials by the same method described in Reference Example 128-1 and Reference Example 128-2 to obtain each of Reference Example compounds 129 and 130 shown in Table 2-21.

TABLE-US-00017 TABLE 2-21 Reference Example Starting material Structural formula NMR and/or LCMS 129 N.sup.α-(tert- butoxycarbonyl)- D-asparagine [00911] embedded image LCMS: [M + H].sup.+/Rt = 304.1/1.03 min.sup.B .sup.1H-NMR (DMSO-d.sub.6) δ: 12.6 (1H, br), 8.01 (1H, d, J = 8.1 Hz), 7.24 (1H, br), 6.91-6.88 (1H, m), 4.30-4.15 (2H, m), 3.42-3.35 (1H, m), 2.52-2.28 (2H, m), 1.37 (9H, s), 1.26 (3H, d, J = 8.1 Hz). 130 tert-Butyl N.sup.α-(tert- butoxycarbonyl)- D-aspartate [00912] embedded image LCMS: [M + H].sup.+/Rt = 361.2/1.71 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.19 (1H, d, J = 5.4 Hz), 6.75 (1H, d, J = 8.1 Hz), 4.64-4.46 (2H, m), 2.89-2.57 (2H, m), 1.47-1.45 (21H, m).

[2872] A reaction, work-up, and purification were performed using the compound of Reference Example 1-7 and a corresponding commercially available carboxylic acid or the compound of Reference Example 129 as the starting materials by the same method described in Reference Example 42 to obtain each of Reference Example compounds 131 to 134 shown in Table 2-22.

TABLE-US-00018 TABLE 2-22 Refe- rence Exam- ple Structural formula NMR and/or LCMS 131 [00913] embedded image LCMS: [M + H].sup.+/Rt = 814.9/2.79 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.23 (1H, d, J = 8.1 Hz), 6.64- 6.39 (2H, m), 5.50-5.39 (1H, m), 5.01-4.91 (1H, m), 4.63- 4.00 (6H, m), 3.79-3.56 (1H, m), 3.07-2.83 (1H, m), 2.64- 2.58 (2H, m), 2.37-2.26 (1H, m), 2.23-2.13 (1H, m), 2.05- 1.77 (8H, m), 1.59-1.54 (18H, m), 1.44 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 132 [00914] embedded image LCMS: [M + H].sup.+/Rt = 786.8/2.77 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.24- 7.20 (1H, m), 7.00-6.86 (1H, m), 6.41 (1H, d, J = 8.1 Hz), 6.34-6.07 (1H, m), 5.43-5.35 (1H, m), 4.98-4.89 (1H, m), 4.63-4.31 (3H, m), 4.26-4.22 (1H, m), 4.17-4.00 (2H, m), 2.96-2.83 (1H, m), 2.64-2.58 (2H, m), 2.44-2.27 (2H, m), 2.21-2.13 (1H, m), 2.05-2.00 (1H, m, 1.93-1.76 (2H, m), 1.59-1.53 (18H, m), 1.45 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.00 (3H, m), 0.83 (3H, s). 133 [00915] embedded image LCMS: [M + H].sup.+/Rt = 814.8/2.88 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.24 (1H, d, J = 8.1 Hz), 6.80-6.70 (1H, m), 6.41 (1H, d, J = 8.1 Hz), 5.05-4.90 (2H, m), 4.71- 4.03 (7H, m), 2.65-2.59 (2H, m), 2.37-2.27 (1H, m), 2.22- 2.13 (1H, m), 2.05-2.00 (1H, m), 1.93-1.76 (2H, m), 1.59- 1.54 (18H, m), 1.45-1.44 (9H, m), 1.36-1.26 (12H, m), 1.14-1.01 (3H, m), 0.84 (3H, s). 134 [00916] embedded image LCMS: [M + H].sup.+/Rt = 857.8/2.71 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.40- 7.31 (1H, m), 7.23 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 6.09-5.95 (1H, m), 5.90-5.79 (1H, m), 5.51-5.41 (1H, m), 5.01-4.92 (1H, m), 4.70-4.00 (7H, m), 2.97-2.88 (1H, m), 2.64-2.48 (3H, m), 2.37-2.27 (1H, m), 2.22-2.13 (1H, m), 2.05-2.00 (1H, m), 1.93-1.77 (2H, m), 1.56 (9H, s), 1.53 (9H, s), 1.46-1.45 (9H, m), 1.36 (3H, s), 1.32- 1.23 (6H, m), 1.14-1.01 (3H, m), 0.84 (3H, s).

[2873] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 and a corresponding commercially available carboxylic acid or the compound of Reference Example 130 as the starting materials by the same method described in Reference Example 3 to obtain each of Reference Example compounds 135 to 137 shown in Table 2-23.

TABLE-US-00019 TABLE 2-23 Refe- rence Exam- ple Structural formula NMR and/or LCMS 135 [00917] embedded image LCMS: [M + H].sup.+/Rt = 800.7/2.83 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.26-7.21 (1H, m), 6.77-6.68 (1H, m), 6.41 (1H, d, J = 8.1 Hz), 5.10-4.92 (2H, m), 4.72- 4.03 (6H, m), 3.85-3.76 (2H, m), 2.65-2.59 (2H, m), 2.36-2.28 (1H, m), 2.22-2.12 (1H, m), 2.04-2.00 (1H, m), 1.93-1.76 (2H, m), 1.56- 1.54 (18H, m), 1.46 (9H, s), 1.36- 1.28 (9H, m), 1.14-1.01 (3H, m), 0.84 (3H, s). 136 [00918] embedded image LCMS: [M + H].sup.+/Rt = 914.7/3.07 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.24-7.03 (1H, m), 6.42-6.38 (1H, m), 5.66-5.53 (1H, m), 4.99-4.91 (1H, m), 4.69- 4.04 (8H, m), 2.94-2.82 (1H, m), 2.64-2.55 (3H, m), 2.36-2.27 (1H, m), 2.20-2.12 (1H, m), 2.05-2.00 (1H, m), 1.93-1.77 (2H, m), 1.59- 1.53 (18H, m), 1.46-1.43 (18H, m), 1.36 (3H, s), 1.32-1.23 (6H, m), 1.14-1.01 (3H, m), 0.84 (3H, s). 137 [00919] embedded image LCMS: [M + H].sup.+/Rt = 843.6/3.14 min.sup.B .sup.1H-NMR (CDCl.sub.3) δ: 7.22 (1H, d, J = 8.1 Hz), 6.40 (1H, d, J = 8.1 Hz), 5.75-5.67 (1H, m), 4.94-4.89 (1H, m), 4.48-4.32 (3H, m), 4.26-4.22 (1H, m), 4.19-4.11 (1H, m), 4.07- 4.02 (1H, m), 2.86-2.71 (1H, m), 2.64-2.48 (3H, m), 2.37-2.26 (1H, m), 2.23-2.13 (1H, m), 2.05-2.00 (1H, m), 1.92-1.77 (2H, m), 1.56 (9H, s), 1.53 (9H, s), 1.46-1.43 (18H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.00 (3H, m), 0.83 (3H, s).

Reference Example 138: tert-butyl 4-[2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy)azetidin-1-yl}-1-(methylamino)-2-oxoethyl]-1H-imidazole-1-carboxylate

[2874] ##STR00920## ##STR00921##

Reference Example 138-1: {[(benzyloxy)cabonyl]amino}(1H-imidazol-4-yl)acetic acid

[2875] ##STR00922##

[2876] Sodium hydrogen carbonate (5.78 g, 68.8 mmol) and benzyl chloroformate (5.87 g, 34.4 mmol) were added to an ethanol/water (1:1) mixture solution (57 mL) of the compound of Reference Example 36-2 (3.68 g, 17.2 mmol) while cooling with ice. After stirring for 15 minutes, the reaction solution was warmed up to room temperature, and stirred for another 12 hours. Saturated ammonium chloride water was added to the reaction solution, which was extracted with ethanol (40 mL) and dichloromethane (40 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by chromatography (dichloromethane/methanol-10/1) to obtain the title compound (1.7 g).

[2877] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ: 8.86-8.82 (1H, m), 7.51-7.47 (1H, m), 7.37-7.24 (5H, m), 5.57 (1H, s), 5.10 (2H, s).

Reference Example 138-2: tert-butyl 6-({1-[{[(benzyloxy)carbonyl]amino}(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2878] ##STR00923##

[2879] Triethylamine (5 mL, 18 mmol), ethylcarbodiimide (1.16 g, 6 mmol), and 1-hydroxybenzotriazole (1.64 g, 12 mmol) were added to a DMF (24 mL) solution of the compound of Reference Example 138-1 (1.7 g, 6.1 mmol) and the compound of Reference Example 1-8 (1.7 g, 3.0 mmol), and the reaction mixture was stirred for 12 hours at room temperature. A saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the reaction solution, which was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated saline (30 mL), then dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (dichloromethane/methanol=50/1) to obtain the title compound (956 mg).

[2880] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ: 9.30 (1H, brs), 7.59 (1H, s), 7.40-7.22 (5H, m), 7.21-7.05 (2H, m), 6.03 (1H, brs), 5.48-5.32 (2H, m), 5.15-5.08 (4H, m), 4.43-4.06 (2H, m), 3.79-3.67 (3H, m), 2.63-1.79 (3H, m), 1.54 (9H, s), 1.53 (9H, s), 1.36-1.16 (6H, m), 1.13-1.01 (2H, m), 0.89-0.80 (4H, m).

Reference Example 138-3: tert-butyl 4-(1-{[(benzyloxy)carbonyl]amino}-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-1H-imidazole-1-carboxylate

[2881] ##STR00924##

[2882] Triethylamine (0.641 mL, 4.6 mmol) and di-tert-butyl dicarbonate (503 mg, 2.3 mmol) were added to a dichloromethane (5.75 mL) solution of the compound of Reference Example 138-2 (956 mg, 1.15 mmol), and the reaction mixture was stirred overnight at room temperature. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution, which was extracted with dichloromethane (10 mL). The organic phase was dried over sodium sulfate, then filtered and concentrated. The resulting residue was purified by column chromatography (dichloromethane/methanol-50/1) to obtain the title compound (228 mg).

[2883] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ: 8.02-7.98 (1H, m), 7.38-7.12 (7H, m), 6.39-6.07 (1H, m), 5.32-4.05 (5H, m), 3.50-3.49 (1H, m), 2.63-1.78 (7H, m), 1.62 (9H, s), 1.56 (9H, s), 1.52 (9H, s), 1.38-1.23 (8H, m), 1.15-1.08 (2H, m), 1.05-0.83 (5H, m).

Reference Example 138-4: tert-butyl 4-(1-amino-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-1H-imidazole-1-carboxylate

[2884] ##STR00925##

[2885] Palladium hydroxide (22 mg) was added to a methanol solution (4 mL) of the compound of Reference Example 138-3 (228 mg, 0.245 mmol), and the reaction mixture was stirred under a hydrogen atmosphere at room temperature. After 12 hours, the reaction solution was filtered through celite, and the filtrate was concentrated. The resulting residue was purified by column chromatography (dichloromethane/methanol 50/1) to obtain the title compound (123 mg).

[2886] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ: 8.02-8.00 (1H, m), 7.35-7.20 (2H, m), 6.40-6.37 (1H, m), 4.96-4.90 (1H, brs), 4.45-4.39 (m, 1H), 4.25-4.20 (1H, m), 4.13-4.11 (1H, m), 2.63-2.60 (2H, m), 2.35-2.28 (1H, m), 2.17-2.14 (1H, m), 2.03-2.01 (1H, m), 1.61 (9H, s), 1.56 (9H, s), 1.52 (9H, s), 1.28-1.26 (6H, m), 1.13-1.10 (1H, m), 0.83 (6H, s).

Reference Example 138: tert-butyl 4-[2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-1-(methylamino)-2-oxoethyl]-1H-imidazole-1-carboxylate

[2887] ##STR00926##

[2888] A formalin solution (30% methanol solution, 2.32 μL, 0.231 mmol) was added to a diethyl ether solution (3 mL) of the compound of Reference Example 138-4 (123 mg, 0.154 mmol), and the reaction mixture was stirred for 1.5 hours at room temperature. Dichloromethane (10 mL) was added to the reaction solution. The organic layer was washed three times with water (10 mL), dried over sodium sulfate, then filtered and concentrated. Sodium triacetoxyborohydride (65 mg, 0.308 mmol) was added to a dichloromethane/acetic acid (1:1) mixture solution (3 mL) of the resulting residue, and the reaction mixture was stirred for 1.5 hours at room temperature. The reaction solution was added to a saturated aqueous sodium hydrogen carbonate solution (10 mL) and extracted with dichloromethane (10 mL). The retrieved organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by preparative thin-layer chromatography (dichloromethane/methanol=10/1) to obtain the compound of Reference Example 138 (26 mg) and the compound of Reference Example 139 (42 mg).

[2889] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ: 8.00 (1H, d, J=6.3 Hz), 7.35 (1H, d, J=8.6 Hz), 7.24-7.15 (1H, m), 6.38 (1H, dd, J=8.6, 8.3 Hz), 4.95-4.72 (1H, m), 4.66-4.05 (4H, m), 2.63-2.58 (2H, m), 2.41 (3H, s), 2.35-1.78 (5H, m), 1.47 (9H, s), 1.52 (9H, s), 1.52 (9H, s), 1.35 (3H, s), 1.28 (3H, s), 1.28-1.23 (2H, m), 1.24-1.08 (2H, m), 1.04-1.02 (1H, m), 0.83 (3H, s).

Reference Example 139: tert-butyl 4-[2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-1-(dimethylamino)-2-oxoethyl]-1H-imidazole-1-carboxylate

[2890] ##STR00927##

[2891] .sup.1H-NMR (500 MHz, CDCl.sub.3) δ: 8.04-8.03 (1H, m), 7.52-7.49 (1H, m), 7.21-7.19 (1H, m), 6.39-6.37 (1H, m), 4.91-3.98 (6H, m), 2.63-2.58 (2H, m), 2.35-1.78 (11H, m), 1.56 (9H, s), 1.53 (9H, s), 1.52 (9H, s), 1.35-1.23 (5H, m), 1.14-1.03 (3H, m), 0.83 (4H, s).

[2892] A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 as the starting material by the same method described in Reference Example 3 to obtain each of Reference Example compounds 140 to 147 shown in Tables 2-24 and 2-25. Further, a reaction, work-up, and purification were performed using the compound of Reference Example 1-8 as the starting material by the same method described in Reference Example 36-4 to obtain Reference Example compounds 148 and 149 shown in Table 2-26.

TABLE-US-00020 TABLE 2-24 Reference Example Structural formula NMR and/or LCMS 140 [00928] embedded image LCMS: [M + H].sup.+/Rt = 773.00/1.394 min.sup.A1 H-NMR (CD.sub.3OD) δ: 7.39-7.26 (6H, m), 6.67 (1H, d, J = 8.5 Hz), 5.12-5.05 (3H, m), 4.39-4.33 (1H, m), 4.29 (2H, d, J = 8.5 Hz), 4.00-3.94 (1H, m), 3.74-3.67 (2H, m), 3.34 (2H, s), 2.58 (2H, t, J = 7.9 Hz), 2.39-2.32 (1H, m), 2.21-2.16 (1H, m), 1.99 (1H, t, J = 5.5 Hz), 1.89-1.87 (1H, m), 1.79 (1H, d, J = 15.3 Hz), 1.55 (9H, d, J = 7.9 Hz), 1.52 (9H, s), 1.35 (3H, s), 1.29 (3H, s), 1.08 (2H, t, J = 8.2 Hz), 0.99 (1H, d, J = 10.4 Hz), 0.86 (3H, s). 141 [00929] embedded image LCMS: [M + H].sup.+/Rt = 773/2.275 min.sup.H

TABLE-US-00021 TABLE 2-25 142 [00930] embedded image LCMS: [M + H].sup.+/Rt = 905/2.433 min.sup.H 143 [00931] LCMS: [M + H].sup.+/Rt = 812/2.217 min.sup.H 144 [00932] LCMS: [M + H].sup.+/Rt = 877/2.150 min.sup.H 145 [00933] LCMS: [M + H].sup.+/Rt = 892/1.411 min.sup.E 146 [00934] LCMS: [M + H].sup.+/Rt = 857.7/3.17 min.sup.B 147 [00935] embedded image LCMS: [M + H].sup.+/Rt = 800.7/2.81 min.sup.B

TABLE-US-00022 TABLE 2-26 148 [00936] embedded image LCMS: [M + H].sup.+/Rt = 773.54/3.960 min.sup.I 149 [00937] LCMS: [M + H].sup.+/Rt = 773.54/3.940 min.sup.I

Reference Example 150: (4S)-4-[(tert-butoxycarbonyl)amino]-6-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-6-oxohexanoic acid

[2893] ##STR00938##

[2894] 10% palladium on carbon (113 mg) was added to a methanol (7 mL) solution of the compound of Reference Example 142 (334 mg, 0.369 mmol). The reaction mixture was subjected to hydrogen substitution and was stirred for 2 hours at room temperature. After filtering the reaction solution, the filtrate was concentrated to obtain the title compound (329 mg).

[2895] LCMS: [M+H].sup.+/Rt=815.5/2.211 min.sup.H

[2896] A reaction, work-up, and purification were performed using the compounds of Reference Examples 144 and 145 as the starting materials by the same method described in Reference Example 151 to obtain Reference Example compounds 151 and 152 shown in Table 2-27, respectively.

TABLE-US-00023 TABLE 2-27 Reference Starting Example material Structural formula NMR and/or LCMS 151 Reference Example 144 [00939] embedded image LCMS: [M + H].sup.+/Rt = 787/2.247 min.sup.H 152 Reference Example 145 [00940] LCMS: [M + H].sup.+/Rt = 801/2.231 min.sup.H

Reference Example 153: tert-butyl 6-[(1-{(3S)-6-amino-3-[(tert-butoxycarbonyl)amino]-6-oxohexanoyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[2897] ##STR00941##

[2898] N,N-diisopropylethylamine (0.131 mL, 0.750 mmol) and HATU (107 mg, 0.281 mmol) were added to a DMF (1 mL) solution of the compound of Reference Example 150 (153 mg, 0.188 mmol), and the reaction mixture was stirred for 30 minutes at room temperature. Ammonium chloride (16.1 mg, 0,300 mmol) was added, and the reaction mixture was stirred for 2 hours at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and then saturated saline, dried over sodium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (45.7 mg).

[2899] LCMS: [M+H].sup.+/Rt=814.5/2.204 min.sup.H

[2900] A reaction, work-up, and purification were performed using the compounds of Reference Examples 151 and 152 as the starting materials by the same method described in Reference Example 153 to obtain Reference Example compounds 154 and 155 shown in Table 2-28, respectively. text missing or illegible when filed

Example 1: 7-[(1-acetylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

[2901] ##STR00942##

[2902] The compound of Reference Example 1 (105 mug) and phenylboronic acid (19 mg) were added to CPME (0.9 mL). 3 mol/L hydrochloric acid (1.14 mL) was added thereto, and the reaction mixture was stirred overnight at room temperature. The aqueous layer was concentrated and purified by reversed phase column chromatography (eluent: acetonitrile/water 1/99 to 95/5) to obtain the title compound (9.2 mag).

[2903] .sup.1H-NMR (CD.sub.3OD) 5: 7.16-7.08 (1H, m), 6.35-6.25 (1H, m), 5.06-4.97 (1H, m), 4.58-4.52 (1H, m), 4.37-4.30 (1H, m), 4.22-4.17 (1H, m), 3.96-3.89 (1H, m), 2.70-2.62 (2H, m), 1.86 (3H, s), 1.05-1.01 (2H, m).

Example 2: 2-hydroxy-7-({1-[(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride

[2904] ##STR00943##

[2905] Triethylsilane (0.2 mL) and, additionally, TFA (0.9 mL) was added to the compound of Reference Example 3 (96 mg) and phenylboronic acid (14 mg), and the reaction mixture was stirred for 3 hours at room temperature. After concentrating the reaction mixture, the residue was washed with a mixture solvent of diethyl ether/hexane (1:1). The resulting solid was dissolved in methanol and purified by reversed phase chromatography and concentrated. After adding 0.2 mL of aqueous 1 N hydrochloric acid solution to the residue, the mixture was concentrated to obtain the compound of interest (21.6 mg).

[2906] LCMS: [M+H].sup.+/Rt=372/0.44 min.sup.C

Example 3: 2-hydroxy-7-{[1-(methanesulfonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

[2907] ##STR00944##

[2908] Triethylsilane (0.2 mL) and, additionally, TFA (0.9 mL) was added to the compound of Reference Example 2 (96 mg) and phenylboronic acid (14 mg), and the reaction mixture was stirred for 3 hours at room temperature. After concentrating the reaction mixture, the residue was washed with a mixture solvent of diethyl ether/hexane (1:1). The resulting solid was dissolved in methanol and purified by reversed phase chromatography and concentrated to obtain the compound of interest (28 mg).

[2909] .sup.1H-NMR (CD.sub.3OD) δ: 7.16-7.00 (1H, m), 6.37-6.20 (1H, m), 5.06-4.97 (1H, m), 4.31-4.25 (2H, m), 3.98-3.94 (2H, m), 2.96 (3H, s), 2.68-2.65 (2H, m), 1.05-1.01 (2H, m)

Example 4: 8-({1-[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

[2910] ##STR00945##

[2911] The compound of Reference Example 17 (119 mg), phenylboronic acid (16.2 mg), acetonitrile (2.0 mL), hexane (2.0 mL), and 4 N hydrochloric acid/dioxane solution (1.0 mL) were added, and the reaction mixture was stirred for 19 hours at room temperature. After allowing it to stand, the supernatant (top layer) of the reaction solution separated into two layers was removed, and the remaining bottom layer was washed 5 times with hexane and twice with diethyl ether (the washing process removes the supernatant after standing). The solid produced in the solution at the bottom layer was washed with acetonitrile (5.0 mL). The residue of the solid obtained by removing the solvent was dried under reduced pressure. The resulting dried residue was dissolved in water. An aqueous 2 N sodium hydroxide solution (0.5 mL) was added. The mixture was purified by reversed phase column chromatography to obtain the title compound (41.7 mg) as a colorless solid.

[2912] .sup.1H-NMR (D.sub.2O) 5: 7.20-7.13 (2H, m), 6.83-6.75 (3H, m), 5.98-5.90 (1H, m), 5.00-4.91 (1H, m), 4.63-3.90 (5H, m), 2.59-2.50 (2H, m), 0.39-0.29 (2H, m).

[2913] A reaction, work-up, and purification were performed using Reference Example compounds 4 to 16 and 18 to 33 shown in Table 2 as the starting materials by the same method described in Example 4 to obtain each of Example compounds to 33. However, if a free form is the final product (Examples 5 and 34), the free form was obtained without sodium hydroxide treatment. If a hydrochloride (hydrochloride salt) is the final product (Example 6), the hydrochloride was obtained by purifying the compound by using reversed phase chromatography and then adding hydrochloric acid and concentrating. A reaction, work-up, and purification were performed using Reference Example compound 34 as the starting material by the same method described in Example 3 to obtain Example compound 34.

TABLE-US-00024 TABLE 3 Starting Example material Structural formula NMR and/or LCMS 5 Reference Example 4 [00946] embedded image LCMS: [M +H].sup.+/Rt = 447/0.626min.sup.C 6 Reference Example 5 [00947] .sup.1H-NMR (CD.sub.3OD) δ: 8.67-8.64 (1H, m), 8.06-8.01 (2H, m), 7.59-7.56 (1H, m), 7.18-7.15 (1H, m), 6.38-6.35 (1H, m), 5.13-5.10 (2H, m), 4.72-4.69 (1H, m), 4.63-4.60 (1H, m), 4.22-4.19 (1H, m), 2.70 (2H, t, J = 7.3 Hz), 1.05 (2H, t, J = 7.3 Hz). 7 Reference Example 6 [00948] embedded image .sup.1H-NMR(D.sub.2O) as a mixture of keto and enol forms δ: 6.87-6.82 (1H, m), 6.04-6.02 (1H, m), 5.02-4.97 (1H, m). 4.65-3.64 (4H, m), 3.20-3.13 (2H, m), 2.57-2.54 (2H, m), 2.11 and 2.07 (3H, s) and 0.36-0.33 (2H, m). 8 Reference Example 7 [00949] .sup.1H-NMR(D.sub.2O) δ: 8.32-8.31 (1H, m), 6.94-6.92 (1H, m), 6-94-6.92 (1H, m), 5.13-5.11 (1H, m), 4.99-4.94 (1H, m), 4.65-4.59 (2H, m), 4.28-4.25 (1H, m), 2.63-2.60 (2H, m), and 0.45-0.42 (2H, m). 9 Reference Example 8 [00950] embedded image .sup.1H-NMR (D.sub.2O) δ: 8.41 (1H, d, J = 6.4 Hz), 7.83 (1H, t, J = 7.8 Hz), 7.76 (1H, dd J = 7.8, 1.8 Hz), 7.73-7.69 (1H, m), 6.91 (1H, d, 3= 7.8 Hz), 6.07 (1H, d, J = 7.8 Hz), 5.15-5.10 (1H, m), 4.69-4.63 (1H, m), 4.47 (1H, dd, 3 = 9.6, 7.3 Hz), 4.32 (1H, dd, J = 13.3, 4.1 Hz), 4.20 (1H, dd, J = 9.6, 3.2 H2), 2.61 (2H, t, J = 7.1 H2), 0.44 (2H, s). 10 Reference Example 9 [00951] embedded image .sup.1H-NMR (D.sub.2O) as a mixture of isomers δ: 7.46-7:38 (5H, m), 6.89-6.80 (1H, m), 6.01-5.91. (1H, m), 5.04-4.93 (0.5H, m), 4.71-4.59 (1.5H, m), 4.49- 4.38 (0.5H, m), 4.22-4.07 (1H, m), 4.01-3.91 (1H, m), 2.63-2.50 (2H, m), 0.45-0.30 (2H, m). 11 Reference Example 10 [00952] .sup.1H-NMR (D.sub.2O) δ: 7.65-7.49 (5H, m), 6.88 (1H, d, J = 8.2 Hz), 6.04 (1H, d, J = 8.2 Hz), 5.04 (1H, td, J = 7.0, 3.7 Hz), 4.65 (1H, dd, J = 10.1, 6.4 Hz), 4.57 (1H, dd, J = 11.4, 6.9 Hz), 4.45 (1H, dd, J = 10.5, 2.7 Hz), 4.23 (1H, dd, J = 10.8, 3.4 Hz), 2.58 (2H, t, J = 6.9 Hz), 0.38 (2H, t, J = 7.1 Hz). 12 Reference Example 11 [00953] embedded image .sup.1H-NMR (D.sub.2O) δ: 8.72 (1H, d, J = 1.4 Hz), 8.63 (1H, dd, J = 5.0, 1.4 Hz), 8.05 (1H, dt, J = 7.8, 1.8 Hz), 7.53 (1H, dd, J = 7.8, 5.0 Hz), 6.85 (1H, d, J = 8.2 Hz), 6.01 (1H, d, J = 8.2 Hz), 5.04 (1H, td, J = 7.9, 4.7 Hz), 4.66 (1H, t, J = 8.5 Hz), 4.56 (1H, dd, J = 11.2, 6.6 Hz), 4.44 (1H, dd, J = 10.1, 3.7 Hz), 4.23 (1H, dd, J = 11.2, 3.9 Hz), 2.55 (2H, t, J = 7.1 Hz), 0.34 (2H, t, J = 6.9 Hz). 13 Reference Example 12 [00954] embedded image .sup.1H-NMR (CD.sub.3OD) δ: 8.85-8.78 (1H, m), 8.62-8.52 (1H, m), 8.06-7.95 (2H, m), 7.18 (1H, d, J = 8.2 Hz), 6.36 (1H, d, J = 7.9 Hz), 5.19-5.06 (1H, m), 4.83-4.70 (2H, m), 4.49-4.38 (2H, m), 4.14-4.02 (2H, m), 2.71 (2H, t, J = 7.7 Hz), 1.07 (2H, t, J = 7.7 Hz). 14 Reference Example 13 [00955] embedded image .sup.1H-NMR (CD.sub.3OD)) δ: 8.87-8.74 (2H, m), 8.62-8.53 (1H, m), 8.12-8.03 (1H, m), 7.18 (1H, d, J = 8.2 Hz), 6.36 (1H, d, J = 8.2 Hz), 5.18-5.09 (1H,m), 4.82-4.70 (2H, m), 4.49- 4.36 (2H, m), 4.07-3.99 (2H, m), 2.71 (2H, t, J = 7.7 Hz), 1.07 (2H, t, J = 7.7 Hz). 15 Reference Example 14 [00956] embedded image .sup.1H-NMR (D.sub.2O) as a mixture of isomers δ: 7.43-7.29 (5H, m), 6.84-6.76 (1H, m), 6.01-5.89 (1H, m), 4.95-4.83 (1H, m), 4.65-4.53 (1H, m), 4.41-3.50 (4H, m) 2.52 (2H, t, J = 6.6 Hz), 0.31 (2H, q, J = 6.4 Hz). 16 Reference Example 15 [00957] .sup.1H-NMR (D.sub.2O) δ: 8.32 (2H, d, J = 6.0 Hz), 7.19 (2H, d, J = 6.0 Hz), 6.74 (1H, d, J = 8.2 Hz), 5.91 (1H, d, J = 8.2 Hz), 4.91-4.80 (1H,m), 4.52-4.49 (1H, m), 4.29-4.20 (2H, m), 3.96-3.91 (1H, m), 3.52 (2H, s), 2.44 (2H, t, J = 7.1 Hz), 0.23 (2H, t, J = 7.1 Hz). 17 Reference Example 16 [00958] embedded image .sup.1H-NMR (D.sub.2O) δ: 7.03 (2H, d, J = 8.2 Hz), 6.86 (1H, d, J = 8.2 Hz), 6.67 (2H, d, J = 8.2 Hz), 6.01 (1H, d, J = 8.2 Hz), 4.99-4.93 (1H, m), 4.62-4.55 (1H, m), 4.29-4.38 (2H, m), 4.05-3.99 (1H, m), 3.46-3.36 (2H, m), 2.56 (2H, t, J = 7.1 Hz), 0.35 (2H, t, J = 7.1 Hz). 18 Reference Example 18 [00959] embedded image .sup.1H-NMR (D.sub.2O) δ: 8.51 (1H, s), 8.12 (1H, s), 6.94 (1H, d, J = 8.2 Hz), 6.11 (1H, d, J = 8.2 Hz), 5.20-5.05 (3H, m), 4.72-4..64 (1H, m), 4.52-4.45 (1H, m), 4.42-4.37 (1H, m), 4.20-4.13 (1H, m), 2.62 (2H, t, J = 6.9 Hz), 0.46 (2H, t, J = 6.9 Hz). 19 Reference Example 19 [00960] embedded image .sup.1H-NMR (D.sub.2O)) δ: 7.75-7.65 (1H, m), 7.42-7.35 and 7.70-7.09 (1H, m), 6.90- 6.82 (1H, m), 6.02-5.96 (1H, m), 5.05- 4.85 and 4.70-3.91 (6H, m), 2.62-2.50 (2H, m), 0.43-0.31 (2H, m). 20 Reference Example 20 [00961] .sup.1H-NMR (D.sub.2O)) δ: 7.41-7.24 (5H, m), 6.36 (1H, d, J = 8.2 Hz), 6.02 (1H, d, J = 8.2 Hz), 5.01-4.96 (1H, m), 4.63-4.58 (1H, m), 4.40-4.32 (2H, m), 4.08-4.01 (1H, m), 3.58 (2H, s), 2.56 (2H, t, J = 7.1 Hz), 0.35 (2H, t, J = 6.9 Hz). 21 Reference Example 21 [00962] embedded image .sup.1H-NMR (D.sub.2O) δ: 7.39-7.28 (2H, m), 7.30-7.22 (3H, m), 6.84 (1H, d, J = 7.8 Hz), 5.92 (1H, d, J = 7.8 Hz), 4.28-4.20 (1H, m), 4.17-4.09 (1H, m), 3.98-3.88 (2H, m), 2.94-2.80 (2H, m), 2.60-2.50 (2H, m), 2.50-2.43 (2H, m), 0.40-0.31 (2H, m). 22 Reference Example 22 [00963] .sup.1H-NMR (D.sub.2O) δ: 7.80-7.62 (1H, m), 7.22-7.0 (2H, m), 6.96-6.85 (1H, m), 6.13-5.99 (1H, m), 5.10-5.05 (1H, m), 4.64-4.53 (1H, m), 4.47-4.38 (1H, m), 4.36-4.27 (1H, m), 4.20-4.05 (1H, m), 2.67 (2H, m), 0.50-0.38 (2H,m). 23 Reference Example 23 [00964] embedded image .sup.1H-NMR (CD.sub.3OD) δ: 9.18 (1H, s), 7.21- 7.14 (1H, m), 6.44-6.12 (1H, m), 5.38 (2H, s), 5.22-5.08 (1H, m), 4.80-4.69 (1H, m), 4.51-4.38 (2H, m), 4.15-4.03 (1H, m), 2.78-2.65 (2H, m), 1.14-0.98 (2H, m). 24 Reference Example 24 [00965] .sup.1H-NMR (D.sub.2O) δ: 6.89 (1H, d, J = 8.2 Hz), 6.05 (1H, d, J = 8.2 Hz), 5.03-4.97 (1H, m), 4.54 (1H, dd, J = 9.6, 6.9 Hz), 4.40 (1H, dd, J = 11.0, 6.9 Hz), 4.29 (1H, dd, J = 9.6, 3.7 Hz), 4.08 (1H, dd, J = 11.0, 3.7 Hz), 3.85 (1H, d, J = 16.3 Hz), 3.75 (1H, d, J= 16.3 Hz), 2.58 (2H, t, J = 6.9 Hz), 0.41 (2H, t, J = 7.1 Hz). 25 Reference Example 25 [00966] embedded image .sup.1H-NMR (D.sub.2O) δ: 7.41-7.21 (5H, m), 6.97-6.78 (1H, m), 5.93-5.80 (1H, m), 4.59-4.52, 4.33-4.25, 4.33-4.25, 4.18- 4.10, 4.05-3.99, 3.91-3.82, 3.74-3.65, 3.53-3.48, 3.38-3.30 (6H, m), 2.99-2.90 (1H, m), 2.88-2.72 (1H, m), 2.60-2.50 (2H, m), 0.43-0.27 (2H, m). 26 Reference Example 26 [00967] embedded image .sup.1H-NMR (D.sub.2O) δ: 7.14-7.01 (2H, m), 6.88-6.76 (3H, m), 5.86-5.70 (1H, m), 4.61-4.56, 4.30-4.12, 4.00-3.82, 3.63- 3.44, 2.95-2.80, 2.72-2.48 (10H, m), 0.44-0.26 (2H, m). 27 Reference Example 27 [00968] .sup.1H-NMR (D.sub.2O) δ: 7.69, 7.52 (1H, s), 6.93-6.83 (2H, m), 5.99-5.78 (1H, m), 4.42-4.07, 4.01-3.79, 3.70-3.50, 3.05- 2.91 (5H, m), 2.91-2.66 (1H, m), 2.61- 2.48 (2H, m), 0.42-0.28 (2H, m). 28 Reference Example 28 [00969] embedded image .sup.1H-NMR (D.sub.2O) δ: 6.87 (1H, d, J = 8.2. Hz), 6.03 (1H, d, J = 8.2 Hz), 5.04-4.96 (1H, m), 4.68-4.58 (1H, m), 4.43-4.28 (2H, m), 4.08-4.00 (1H, m), 3.19-3.13 (1H, m), 2.56 (2H, t, J = 6.9 Hz), 1.81- 1.73 (1H, m), 1.00-0.81 (6H, m), 0.35 (2H, t, J = 7.1 Hz). 29 Reference Example 29 [00970] embedded image .sup.1H-NMR (D.sub.2O) δ: 7.73, 7.54 (1H, s), 6.98-6.80 (2H, m), 5.96-5.80 (1H, m), 4.42-4.11, 4.04-3.83, 3.74-3.66, 3.65- 3.57, 3.08-2.96 (5H, m), 2.90-2.74 (2H, m), 2.64-2.50 (2H, m), 0.48-0.31 (2H, m). 30 Reference Example 30 [00971] .sup.1H-NMR (D.sub.2O) δ: 7.50-7.31 (5H, m), 6.89-6.84 (1H, m), 6.03-5.95 (1H, m), 5.33-5.27 (1H, m), 5.15-4.97 (1H, m), 4.50-4.28 (2H, m), 4.20-3.95 (2H, m), 3.33 (6H, dt, J = 28.1, 9.6 Hz), 2.63- 2.48 (2H, m), 1.16-1.02 (3H, m), 0.50- 0.30 (2H, m). 31 Reference Example 31 [00972] embedded image .sup.1H-NMR (D.sub.2O) δ: 6.87 (1H, d, J = 7.9 Hz), 6.04 (1H, d, J = 7.9 Hz), 5.09-4.96 (1H, m), 4.90-4.84 (1H, m), 4.66-4.52 (1H, m), 4.43-4.30 (2H, m), 4.10-4.00 (1H, m), 3.93-3.80 (1H, m), 3.08-2.90 (2H, m), 2.57 (2H, t, J = 6.9 Hz), 2.28- 2.02 (1H, m), 1.93-1.68 (3H, m), 0.36 (2H, t, J = 6.9 Hz). 32 Reference Example 32 [00973] embedded image LCMS: [M + H].sup.+/Rt = 361/0.87min.sup.B 33 Reference Example 33 [00974] .sup.1H-NMR (D.sub.2O) δ: 7.56 (1H, s), 6.93 (1H, s), 6.83 (1H, d, J = 8.2 Hz), 5.99 (1H, d, J = 8.2 Hz), 5.04-4.93 (1H, m), 4.57-4.48 (1H, m), 4.42-4.33 (1H, m), 4.23-4.17 (1H, m), 4.09-3.98 (1H, m), 3.14 (2H, t, J = 6.6 Hz), 2.82 (2H, t, J = 6.6 Hz), 2.52 (2H, t, J = 6.9 Hz), 0.31 (2H, t, J = 6.9 Hz) 34 Reference Example 34 [00975] embedded image .sup.1H-NMR (CD.sub.3OD) δ: 6.96 (1H, d, J = 7.9. Hz), 6.90-6.87 (1H, m), 6.80-6.78 (2H, m), 6.58 (1H, d, J = 7.9 Hz), 4.99-4.97 (2H, m), 4.68-4.65 (1H, m), 4.48-4.45 (1H, m), 4.18-4.16 (1H, m), 2.57 (2H, t, J = 7.3 Hz), 0.51 (2H, t, J = 7.3 Hz).

[2914] The names of the compounds of Examples 5 to 34 are described below. [2915] 7-({1-[(2-amino-1,3-thiazol-4-yl)(methoxyimino)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid (Example 5) [2916] 2-hydroxy-7-{[1-(pyridine-2-carbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 6) [2917] 4,4-dihydroxy-8-({1-[(methylsulfanyl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 7) [2918] 4,4-dihydroxy-8-{[1-(1H-1,2,4-triazole-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 8) [2919] 4,4-dihydroxy-8-{[1-(1-oxido-2-pyridinylcarbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 9) [2920] 8-({1-[(2R)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 10) [2921] 8-[(1-benzoylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 11) [2922] 4,4-dihydroxy-8-{[1-(pyridine-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 12) [2923] 4,4-dihydroxy-8-({1-[(pyridin-2-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 13) [2924] 4,4-dihydroxy-8-({1-[(pyridin-3-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 14) [2925] 8-({1-[(2S)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 15) [2926] 4,4-dihydroxy-8-({1-[(pyridin-4-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 16) [2927] 4,4-dihydroxy-8-({1-[(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 17) [2928] 4,4-dihydroxy-8-({1-[(1H-1,2,4-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 18) [2929] 8-({1-[amino(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 19) [2930] 4,4-dihydroxy-8-{[1-(phenylacetyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 20) [2931] 4,4-dihydroxy-8-{[1-(3-phenylpropanoyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 21) [2932] 4,4-dihydroxy-8-({1-[(1H-imidazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 22) [2933] 4,4-dihydroxy-8-({1-[(1H-tetrazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 23) [2934] 4,4-dihydroxy-8-({1-[(2H-tetrazol-5-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 24) [2935] 4,4-dihydroxy-8-[(1-D-phenylalanylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 25) [2936] 4,4-dihydroxy-8-[(1-D-tyrosylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 26) [2937] 8-[(1-D-histidylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 27) [2938] 4,4-dihydroxy-8-[(1-D-valylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 28) [2939] 8-[(1-L-histidylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 29) [2940] 8-[(1-{(2R)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 30) [2941] 4,4-dihydroxy-8-[(1-D-prolylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 31) [2942] 4,4-dihydroxy-8-[(1-L-prolylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 32) [2943] 8-[(1-{[4-(2-aminoethyl)-1H-imidazol-1-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 33) [2944] 7-{[1-(3,4-dihydroxybenzoyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid (Example 34)

Example 35: 2-hydroxy-7-{[1-(hydroxycarbamoyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

[2945] ##STR00976##

[2946] Phenylboronic acid (10.3 mg), 4 N hydrocholic acid/ethyl acetate solution, and hexane (3.6 mL) were added to an acetonitrile (0.73 mL) solution of the compound of Reference Example 35. The reaction mixture was stirred for 7 hours at room temperature and allowed to stand overnight. The acetonitrile phase was washed with hexane and concentrated. The residue was washed with acetonitrile to obtain the title compound (0.4 mg).

[2947] LCMS: [M+H].sup.+/Rt=323/0.489 min.sup.C

Example 36: 7-({1-[(2R)-2-amino-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

[2948] ##STR00977##

[2949] Phenylboronic acid (0.146 g) and 1 N hydrochloric acid/acetic acid solution (25.2 mL) were added to Reference Example (R)-36 (1.0 g). The reaction mixture was stirred for 1 hour at room temperature and then concentrated. The residue was dissolved in methanol (3 mL) and washed twice with heptane (6 mL)(the washing process removes the supernatant (top layer) after standing). The bottom layer was concentrated under reduced pressure, and the resulting residue was purified by reversed phase column chromatography to obtain the title compound (200 mg).

[2950] .sup.1H-NMR (600 MHz, D.sub.2O) δ: 7.56 (1H, m), 6.99 (1H, m), 6.73 (1H, d, J=8.4 Hz), 5.86 (1H, d, J=8.4 Hz), 4.86-4.65 (2H, m), 4.51-4.46 (0.5H, m), 4.30-4.14 (2H, m), 3.96-3.82 (1.5H, m), 2.45-2.43 (2H, m), 0.24-0.21 (2H, m).

[2951] LCMS: [M+H].sup.+/Rt=387.05/0.421 min.sup.C

Example 37: 8-({1-[(2S)-2-amino-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

[2952] ##STR00978##

[2953] Phenylboronic acid (2.46 mg), hexane (0.337 mL), and 4 N hydrochloric acid/cyclopentyl methyl ether solution (0.151 mL) were added to an acetonitrile (0.337 mL) solution of the compound of Reference Example (S)-36 (18.1 mg), and the reaction mixture was stirred for 16 hours at room temperature. After allowing it to stand, the supernatant (top layer) of the reaction solution separated into two layers was removed, and the remaining bottom layer was washed with hexane (the washing process removes the supernatant after standing). The solid produced in the solution at the bottom layer was washed with diethyl ether. The residue of the solid obtained by removing the solvent was dried under reduced pressure. The resulting dried residue was dissolved in water. An aqueous 2 N sodium hydroxide solution (0.1 mL) was added. The mixture was purified by reversed phase column chromatography to obtain the title compound (7.8 mg) as a white solid.

[2954] LCMS: [M+H].sup.+/Rt=387.00/0.428 min.sup.C

[2955] The column retention times of the compound of Example 36 and the compound of Example 37 in chiral chromatography were the following.

[2956] Column: CROWNPAK CR-I(−)(0.30 cm I.D.×15 cm L)(Daicel Corporation)

[2957] Mobile phase: aqueous perchloric acid solution (pH 1.0)/acetonitrile (60% perchloric acid: 1.7%)

[2958] Flow rate: 0.5 mL/min

[2959] Temperature: 25° C.

[2960] Rt of compound of Example 36: 6.001 min

[2961] Rt of compound of Example 37: 3.968 min

[2962] Optical purity of Example 36 (computed by HPLC area percentage value): 98.5% ee

[2963] Optical purity of Example 37 (computed by HPLC area percentage value): 98.3% ee

[2964] The stereostructure of the compound of Example 36 was estimated to be an R form by Mosher's method (reference document for Mosher's method include: The Journal of Organic Chemistry, 2016, 81, 7373).

Example 38: 8-({1-[amino(1-methyl-1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

[2965] ##STR00979##

[2966] Phenylboronic acid (18.6 mg) and 4 N hydrochloric acid/cyclopentyl methyl ether solution (1.21 mL) were added to an acetic acid (1.61 mL) solution of the compound of Reference Example 37 (130 mg) while cooling with ice, and the reaction mixture was stirred for 3 hours at room temperature. The solvent was removed under reduced pressure. The resulting dried residue was dissolved in water. An aqueous 2 N sodium hydroxide solution (0.402 mL) was added, and the mixture was purified by reversed phase column chromatography to obtain the title compound (5 mg) as a white solid.

[2967] LCMS: [M+H].sup.+/Rt=401.31/0.473 min.sup.C

Example 39: 2-hydroxy-7-{[1-(4H-1,2,4-triazole-3-sulfonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid trifluoroacetate

[2968] ##STR00980##

[2969] Phenylboronic acid (35.6 mg), hexane (2.9 mL), and TFA (2.23 mL) were added to an acetonitrile (2.9 mL) solution of the compound of Reference Example 41 (205 mg), and the reaction mixture was stirred for 5 hours at room temperature. After allowing it to stand, the supernatant (top layer) of the reaction solution separated into two layers was removed, and the remaining bottom layer was washed with hexane (the washing process removes the supernatant after standing). The solid produced in the solution at the bottom layer was washed with diethyl ether. The residue of the solid obtained by removing the solvent was dried under reduced pressure. The resulting dried residue was purified by reversed phase column chromatography to obtain the title compound (39.8 mg) as a colorless solid.

[2970] .sup.1H-NMR (CD.sub.3OD) δ: 8.69 (1H, s), 7.11 (1H, d, J=8.1 Hz), 6.21 (1H, d, J=8.1 Hz), 4.95-4.85 (1H, m), 4.44-4.35 (2H, m), 4.04-3.99 (2H, m), 2.65 (2H, t, J=8.1 Hz), 1.04 (2H, t, J=8.1 Hz).

[2971] LCMS: [M+H].sup.+/Rt=395.1/1.24 min.sup.B

Example 40: 7-({1-[2-amino-2-(1H-imidazol-4-yl)(2H) ethanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid dihydrochloride

[2972] ##STR00981##

[2973] Acetic acid-d1 (3 mL) was added to the compound of Reference Example 36-4 (0.3 g, 0.377 mmol), and the reaction mixture was stirred for 4 days at room temperature. Phenylboronic acid (46 mg, 0.377 mmol) and 4 N hydrochloric acid cyclopentyl methyl ether solution (2 mL, 8.0 mmol) were then added, and the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was dried and solidified under reduced pressure. The resulting dried residue was dissolved in methanol (1 mL), and isopropanol (10 mL) was added. The precipitated solid was filtered out, dried and solidified under reduced pressure. The resulting solid was purified by reversed phase column chromatography, and the resulting dried residue was washed with acetonitrile, dried and solidified under reduced pressure to obtain the title compound (71 mg) as a white solid.

[2974] .sup.1H-NMR (0.1M Na.sub.2CO.sub.3 in D.sub.2O) 5: 7.84-7.76 (1H, m), 7.30-7.20 (1H, m), 6.91-6.89 (1H, m), 6.12-6.01 (1H, m), 5.02-4.89 (1H, m), 4.58-3.76 (4H, m), 2.59 (2H, m), 0.55 (2H, m).

[2975] LCMS: [M+H].sup.+/Rt=388.12/0.410 min.sup.C

Example 41; 7-({1-[2-amino-2-(1H-imidazol-4-yl)propanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

[2976] ##STR00982##

[2977] A reaction, work-up, and purification were performed using the compound of Reference Example 39 (153 mg, 0.189 mmol) as the starting material by the same method described in Example 36 to obtain the title compound (42 mg) as a white solid.

[2978] .sup.1H-NMR (0.1 M Na.sub.2CO.sub.3 in D.sub.2O) δ: 7.77 (1H, m), 7.18 (1H, m), 6.83 (1H, m), 5.91 (1H, m), 4.35 (1H, m), 3.95-4.20 (2H, m), 3.30-3.51 (2H, m), 2.57 (2H, m), 1.63 (3H, s), 0.36 (2H, m).

[2979] LCMS: [M+H].sup.+/Rt=401.12/0.422 min.sup.C

[2980] A reaction, work-up, and purification were performed using the compounds of Reference Examples 56 and 58 as the starting materials by the same method described in Example 37 to obtain Example compounds 42 and 43, respectively. However, if hydrochloride is the final product (Example 43), the hydrochloride was obtained from purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE-US-00025 TABLE 3-5 Starting Example material Structural formula NMR and/or LCMS 42 Reference Example 56 [00983] embedded image LCMS: [M + H].sup.+/Rt = 401.10/0.451 min.sup.C 43 Reference Example 58 [00984] LCMS: [M + H].sup.+/Rt = 399.10/0.493 min.sup.C .sup.1H-NMR (CD.sub.3OD) δ: 8.61 (1H, s), 7.21 (1H, s), 7.17 (1H, d, J = 7.9 Hz), 6.34 (1H, d, J = 7.9 Hz). 5.18- 5.15 (1H, m), 4.70-4.67 (2H, m), 4.34- 4.21 (2H, m), 2.70 (2H, t, J = 7.6 Hz), 2.67 (3H, s), 1.05 (2H, t, J = 7.6 Hz).

[2981] The names of the compounds of Examples 42 and 43 are described below. [2982] 8-({(3S)-1-[amino(1H-imidazol-4-yl)acetyl]pyrrolidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 42) [2983] 2-hydroxy-7-([1-(4-hydroxy-6-methylpyridine-3-carbonyl)azetidin-3-yl]oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 43)

[2984] A reaction, work-up, and purification were performed using the compounds of Reference Examples 38, 48, 49, 55, 57, 63, 64, and 71 as the starting materials by the same method described in Example 38 to obtain each of the following Example compounds 44 to 51. However, if hydrochloride is the final product (Examples 46 and 51), the hydrochloride was obtained from purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE-US-00026 TABLE 3-6 Starting Example material Structural formula NMR and/or LCMS 44 Reference Example 57 [00985] embedded image LCMS: [M + H].sup.+/Rt = 401.20/0.393 min.sup.C 45 Reference Example 48 [00986] LCMS: [M + H ].sup.+/Rt = 445.2/0.82 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.57 (1H, s), 7.08 (1H, s), 6.70 (1H, d, J = 8.1 Hz), 5.90 (1H, d, J = 8.1 Hz), 4.98-4.90 (1H, m), 4.62-3.93 (7H, m), 2.55 (2H, t, J = 5.4 Hz), 0.44 (2H, t, J = 5.4 Hz). 46 Reference Example 49 [00987] embedded image LCMS: [ M + H ].sup.+/Rt = 444.3/0.52 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 9.01 (1H, s), 7.88 (1H, s), 7.15 (1H, d, J = 8.1 Hz), 6.35- 6.28 (1H, m), 5.55 (1H, d, J = 16.2 Hz), 5.20-4.97 (3H, m), 4.77-3.72 (4H, m), 2.69 (2H, t, J = 8.1 Hz), 1.05 (2H, t, J = 8.1 Hz). 47 Reference Example 63 [00988] embedded image LCMS: [M + H].sup.+/Rt = 398.3/0.82 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 8.59 (1H, s), 8.50-8.47 (1H, m), 7.90-7.84 (1H, m), 7.47-7.41 (1H, m), 6.67 (1H, d, J = 8.1 Hz), 5.89-5.85 (1H, m), 5.01-4.94 (1H, m), 4.73-3.73 (5H, m), 2.54 (2H, t, J = 5.4 Hz), 0.41 (2H, t, J = 5.4 Hz).

TABLE-US-00027 TABLE 3-7 48 Reference Example 64 [00989] embedded image LCMS: [M + H].sup.+/Rt = 401.3/0.92 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.61-7.59 (1H, m), 7.47 (1H, s), 6.68 (1H, d, J = 8.1 Hz), 5.90-5.86 (1H, s), 5.00-4.94 (1H, m), 4.64-3.96 (5H, m), 3.86 (3H, s), 2.55 (2H, t, J = 8.1 Hz), 0.41 (2H, t, J = 8.1 Hz). 49 Reference Example 55 [00990] embedded image LCMS: [M + H].sup.+/Rt = 401.05/0.442 min.sup.C 50 Reference Example 38 [00991] LCMS: [M + H].sup.+/RT = 401.16/0.387 min.sup.C .sup.1H-NMR (D.sub.2O) δ: 6.62 (1H, d, J = 12.8 Hz), 6.48 (1H, d, J = 7.9 Hz), 5.61 (1H, d, J = 7.9 Hz), 4.61-4.49 (2H, m), 4.30-4.26 (1H, m), 4.05-3.94 (1H, m), 3.90-3.81 (1H, m), 3.70-3.63 (1H, m), 2.18 (2H, t, J = 6.4 Hz), 1.94 (3H, d, J = 4.3 Hz), 0.00 (2H, t, J = 6.1 Hz). 51 Reference Example 71 [00992] embedded image LCMS: [M + H].sup.+/Rt = 404.2/0.95 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 9.13-9.10 (1H, m), 7.92-7.91 (1H, m), 7.13 (1H, d, J = 8.2 Hz), 6.27 (1H, d, J = 8.2 Hz), 5.50- 5.49 (1H, m), 5.12-5.03 (1H, m), 4.73- 3.62 (4H, m), 2.68 (2H, t, J = 8.1 Hz), 1.05 (2H, t, J = 8.1 Hz).

[2985] The names of the compounds of Examples 44 to 51 are described below. [2986] 8-({1-[amino(1-methyl-1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo(4.4.0)deca-1(6,7,9-triene-7-carboxylic acid disodium salt (Example 44) [2987] 8-[(1-{amino[1-(carboxymethyl)-1H-imidazol-4-yl)acetyl)azetidin-3-yl)oxy]-4,4-dihydroxy-S-oxa-4-boranuidabicyclo(4.4.0)deca-1(6),7,9-triene-7-carboxylic acid trisodium salt (Example 45) [2988] 7-[(1-{amino[1-(2-amino-2-oxoethyl)-1H-imidazol-4-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 46) [2989] 8-({1-[amino(pyridin-3-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 47) [2990] 8-({1-[amino(1-methyl-1H-pyrazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 48) [2991] 8-({(3R)-1-[amino(1H-imidazol-4-yl)acetyl]pyrrolidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 49) [2992] 8-({1-[amino(2-methyl-1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 50) [2993] 7-({1-[amino(1,3-thiazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 51)

[2994] A reaction, work-up, and purification were performed using the compounds of Reference Examples 106 to 108 as the starting materials by the same method described in Example 38 to obtain the following Example compounds 52 to 54, respectively.

TABLE-US-00028 TABLE 3-8 Starting Example material Structural formula NMR and/or LCMS 52 Reference Example 106 [00993] embedded image LCMS: [M + H].sup.+/Rt = 394.4/1.20 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 8.07 (1H, s), 7.87 (1H, s), 7.12 (1H, d, J = 8.1 Hz), 6.23 (1H, d, J = 8.1 Hz), 4.93-4.87 (1H, m), 4.34-4.26 (2H, m), 3.91-3.88 (2H, m), 2.66 (2H, t, J = 8.1 Hz), 1.04 (2H, t, J = 8.1 Hz). 53 Reference Example 107 [00994] embedded image LCMS: [M + H].sup.+/Rt = 405.3/1.41 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 9.00 (1H, s), 8.87 (1H, d, J = 5.4 Hz), 8.31 (1H, d, J = 8.1 Hz), 7.74-7.00 (1H, m), 7.10 (1H, d, J = 8.1 Hz), 6.22 (1H, d, J = 8.1 Hz), 4.97-4.65 (1H, m), 4.33-4.27 (2H, m), 3.83-3.77 (2H, m), 2.65 (2H, t, J = 8.1 Hz), 1.02 (2H, t, J = 8.1 Hz). 54 Reference Example 108 [00995] embedded image LCMS: [M + H].sup.+/Rt = 421.3/1.30 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 8.46-8.36 (1H, m), 8.06 (1H, dd, J = 5.4 Hz, 2.7 Hz), 7.70-7.57 (2H, m), 7.12 (1H, d, J = 8.1 Hz), 6.28 (1H, d, J = 8.1 Hz), 5.08- 5.00 (1H, m), 4.61-4.55 (2H, m), 4.33- 4.26 (2H, m), 2.65 (2H, t, J = 8.1 Hz), 1.05 (2H, t, J = 8.1 Hz).

[2995] The names of the compounds of Examples 52 to 54 are described below. [2996] 2-hydroxy-7-{[1-(1H-imidazole-4-sulfonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid trifluoroacetate (Example 52) [2997] 2-hydroxy-7-{[1-(pyridine-3-sulfonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid trifluoroacetate (Example 53) [2998] 2-hydroxy-7-{[1-(1-oxo-1λ.sup.5-pyridine-2-sulfonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid trifluoroacetate (Example 54)

[2999] A reaction, work-up, and purification were performed using the compounds of Reference Examples 40, 43 to 47, 50, 51, 59, 65, 66, 69, 70, 114 to 116, and 127 as the starting materials by the same method described in Example 4 to obtain the following Example compounds 55 to 71 (corresponding starting materials are not in order). However, if a free form is the final product (Examples 57, 61, 64, 65: 67, and 71), the free form was obtained from purifying the compound without sodium hydroxide treatment. If hydrochloride is the final product (Examples 58, 62, and 63), the hydrochloride was obtained from purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE-US-00029 TABLE 3-9 Starting Example material Structural formula NMR and/or LCMS 55 Reference Example 65 [00996] embedded image LCMS: [M + H].sup.+/Rt = 404.4/1.03 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.69 (1H, d, J = 8.2 Hz), 6.31 (1H, s), 5.90 (1H, d, J = 8.2 Hz), 5.00-4.86 (1H, m), 4.63-4.47 (1H, m), 4.39-4.21 (2H, m), 4.08-3.96 (1H, m), 3.41-3.35 (2H, m), 2.63-2.49 (2H, m), 0.48-0.35 (2H, m). 56 Reference Example 66 [00997] embedded image LCMS: [M + H]+/Rt = 390.2/1.16 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.24 (1H, s), 6.72 (1H, d, J = 8.1 Hz), 5.94 (1H, d, J = 8.1 Hz), 4.95-4.90 (2H, m), 4.62-4.56 (1H, m), 4.47-4.41 (1H, m), 4.16-4.12 (1H, m), 2.59-2.54 (2H, m), 0.47-0.42 (2H, m). 57 Reference Example 69 [00998] LCMS: [M + H].sup.+/Rt = 373.22/1.62 min.sup.D .sup.1H-NMR (CD.sub.3OD) δ: 8.11 (1H, d, J = 1.1 Hz), 7.91 (1H, s), 7.22-7.13 (1H, m), 6.40-6.28 (1H, m), 5.32 (2H, s), 5.16-5.10 (1H, m), 4.74-4.66 (1H, m), 4.50-4.42 (1H, m), 4.37-4.31 (1H, m), 4.10-4.02 (1H, m), 2.77-2.62 (2H, m), 1.10-1.01 (2H, m).

TABLE-US-00030 TABLE 3-10 58 Reference Example 70 [00999] embedded image LCMS: [M + H].sup.+/Rt = 415.2/0.52 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 9.04 (1H, s), 7.63 (1H, s), 7.18 (1H, d, J = 8.1 Hz), 6.37 (1H, d, J = 8.1 Hz), 5.15-5.12 (1H, m), 4.79-4.73 (1H, m), 4.60 (2H, t, J = 5.4 Hz), 4.54-4.33 (2H, m), 4.18-4.02 (1H, m), 3.79 (2H, s), 3.53 (2H, t, J = 5.4 Hz), 2.71-2.65 (2H, m), 1.10-1.04 (2H, m). 59 Reference Example 40 [01000] embedded image LCMS: [M + H].sup.+/Rt = 358.2/0.90 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.81 (1H, s), 7.67 (1H, s), 6.93 (1H, d, J = 8.1 Hz), 6.11 (1H, d, J = 8.1 Hz), 5.14-5.03 (1H, m), 4.92-4.73 (1H, m), 4.59-4.52 (2H, m), 4.24-4.19 (1H, m), 2.60 (2H, t, J = 8.1 Hz), 0.40 (2H, t, J = 8.1 Hz). 60 Reference Example 127 [01001] embedded image LCMS: [M + H].sup.+/Rt = 358.1/1.17 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.28 (2H, s), 6.93 (1H, d, J = 8.1 Hz), 6.11 (1H, d, J = 8.1 Hz), 5.16-5.09 (1H, m), 5.04-4.71 (1H, m), 4.67-4.55 (2H, m), 4.27-4.21 (1H, m), 2.61 (2H, t, J = 8.1 Hz), 0.41 (2H, t, J = 8.1 Hz). 61 Reference Example 43 [01002] embedded image LCMS: [M + H].sup.+/Rt = 403.17/1.58 min.sup.D .sup.1H-NMR (CD.sub.3OD) δ: 8.06 (1H, s), 7.21-7.12 (1H, m), 6.41-6.27 (1H, m), 5.31 (2H, s), 5.16-5.10 (1H, m), 4.77-4.67 (3H, m), 4.50-4.42 (1H, m), 4.38-4.31 (1H, m), 4.10-4.02 (1H, m), 2.74-2.63 (2H, m), 1.06 (2H, t, J = 7.7 Hz). 62 Reference Example 114 [01003] embedded image LCMS: [M + H].sup.+/Rt = 416.30/1.25 min.sup.D .sup.1H-NMR (CD.sub.3OD) δ: 8.12 (1H, s), 7.23-7.10 (1H, m), 6.41-6.29 (1H, m), 5.30 (2H, s), 5.18-5.10 (1H, m), 4.78-4.71 (1H, m), 4.50-4.43 (1H, m), 4.40-4.28 (3H, m), 4.11-4.03 (1H, m), 2.79-2.65 (5H, m), 1.10-1.02 (2H, m). 63 Reference Example 115 [01004] embedded image LCMS: [M + H].sup.+/Rt = 471.27/1.15 min.sup.D .sup.1H-NMR (CD.sub.3OD) δ: 8.29 (1H, s), 7.21-7.13 (1H, m), 6.40-6.30 (1H, m), 5.34 (2H, s), 5.19-5.13 (1H, m), 4.79-4.73 (1H, m), 4.64 (2H, s), 4.50-4.45 (1H, m), 4.41-4.36 (1H, m), 4.11-4.04 (1H, m), 3.71-3.54 (8H, m), 2.74-2.66 (2H, m), 1.10-1.03 (2H, m).

TABLE-US-00031 TABLE 3-11 64 Reference Example 116 [01005] embedded image LCMS: [M + H].sup.+/Rt = 417.26/1.56 min.sup.D .sup.1H-NMR (CD.sub.3OD) δ: 8.10 (1H, s), 7.23-7.13 (1H, m), 6.43-6.28 (1H, m), 5.36 (2H, s), 5.19-5.12 (1H, m), 4.76-4.68 (1H, m), 4.52-4.44 (1H, m), 4.38-4.32 (1H, m), 4.13-4.06 (1H, m), 3.90-3.78 (2H, m), 3.04-2.95 (2H, m), 2.78-2.65 (2H, m), 1.12-1.00 (2H, m). 65 Reference Example 44 [01006] embedded image LCMS: [M + H].sup.+/Rt = 403.35/1.44 min.sup.D .sup.1H-NMR (CD.sub.3OD) δ: 7.77 (1H, s), 7.23-7.12 (1H, m), 6.44-6.25 (1H, m), 5.35-5.31 (2H, m), 5.16-5.12 (1H, m), 4.76-4.70 (3H, m), 4.51-4.44 (1H, m), 4.40-4.32 (1H, m), 4.11-4.04 (1H, m), 2.77-2.65 (2H, m), 1.10-1.03 (2H, m). 66 Reference Example 45 [01007] embedded image LCMS: [M + H].sup.+/Rt = 416.34/1.12 min.sup.D .sup.1H-NMR (D.sub.2O) δ: 7.76 (1H, s), 6.89 (1H, d, J = 8.0 Hz), 6.06 (1H, d, J = 8.0 Hz), 5.33-5.22 (2H, m), 5.12-5.06 (1H, m), 4.74-4.67 (1H, m), 4.49-4.36 (2H, m), 4.16-4.10 (1H, m), 3.79 (2H, s), 2.62-2.54 (2H, m), 2.34 (3H, s), 0.41-0.33 (2H, m). 67 Reference Example 59 [01008] embedded image LCMS: [M + H].sup.+/Rt = 373.35/1.59 min.sup.D .sup.1H-NMR (CD.sub.3OD) δ: 8.19 (1H, s), 7.21-7.07 (1H, m), 6.42-6.21 (1H, m), 5.09-5.05 (1H, m), 4.72-4.65 (1H, m), 4.43-4.36 (1H, m), 4.35-4.28 (1H, m), 4.03-3.95 (1H, m), 3.84 (2H, s), 2.71-2.61 (2H, m), 1.06-0.97 (2H, m). 68 Reference Example 46 [01009] embedded image LCMS: [M + H].sup.+/Rt = 431.12/1.71 min.sup.D .sup.1H-NMR (D.sub.2O) δ: 7.84 (1H, d, J = 6.9 Hz), 6.92 (1H, d, J = 8.0 Hz), 6.09 (1H, d, J = 8.0 Hz), 5.33-5.22 (2H, m), 5.12-5.05 (1H, m), 4.72-4.66 (1H, m), 4.50-4.43 (1H, m), 4.43-4.37 (1H, m), 4.16-4.10 (1H, m), 3.64 (2H, s), 2.64-2.56 (2H, m), 0.51-0.42 (2H, m). 69 Reference Example 47 [01010] embedded image LCMS: [M + H].sup.+/Rt = 431.16/1.44 min.sup.D .sup.1H-NMR (D.sub.2O) δ: 7.86 (1H, s), 6.89 (1H, d, J = 8.0 Hz), 6.06 (1H, d, J = 8.0 Hz), 5.06-5.00 (3H, m), 4.70-4.65 (1H, m), 4.44-4.35 (2H, m), 4.11-4.05 (1H, m), 3.80-3.67 (2H, m), 2.62-2.55 (2H, m), 0.41-0.34 (2H, m). 70 Reference Example 50 [01011] embedded image LCMS: [M + H].sup.+/R = 388.35/0.93 min.sup.D .sup.1H-NMR (D.sub.2O) δ: 7.77-7.72 (1H, m), 6.92-6.34 (1H, m), 6.05-5.93 (1H, m), 5.03-4.85 (2H, m), 4.64-3.91 (4H, m), 2.62-2.49 (2H, m), 0.49-0.37 (2H, m).

TABLE-US-00032 TABLE 3-12 71 Reference Example 51 [01012] embedded image LCMS: [M + H].sup.+/R = 418.13/2.03 min.sup.D .sup.1H-NMR (CD.sub.3OD) δ: 8.92 (1H, s), 7.22-7.13 (1H, m), 6.40-6.12 (1H, m), 5.41-5.34 (2H, m), 5.19-5.12 (1H, m), 4.78-4.71 (1H, m), 4.52-4.45 (1H, m), 4.44-4.37 (1H, m), 4.13-4.06 (1H, m), 2.76-2.66 (2H, m), 1.11-1.02 (2H, m).

[3000] The names of the compounds of Examples 55 to 71 are described below. [3001] 8-({1-[(2-amino-1,3-thiazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 55) [3002] 8-{[1-(2-amino-1,3-thiazole-4-carbonyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 56) [3003] 2-hydroxy-7-({1-[(1H-1,2,3-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid (Example 57) [3004] 7-[(1-{[1-(2-aminoethyl)-1H-imidazol-4-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 58) [3005] 4,4-dihydroxy-8-{[1-(1H-imidazole-4-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 59) [3006] 4,4-dihydroxy-8-{[1-(1H-imidazole-2-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 60) [3007] 2-hydroxy-7-[(1-{[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid (Example 61) [3008] 2-hydroxy-7-{[1-({4-[(methylamino)methyl]-1H-1,2,3-triazol-1-yl}acetyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 62) [3009] 2-hydroxy-7-{[1-({4-[(piperazin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}acetyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid dihydrochloride (Example 63) [3010] 2-hydroxy-7-[(1-{[4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid (Example 64) [3011] 2-hydroxy-7-[(1-{[5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid (Example 65) [3012] 4,4-dihydroxy-8-{[1-({5-[(methylamino)methyl]-1H-1,2,3-triazol-1-yl}acetyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 66) [3013] 2-hydroxy-7-({1-[(1H-1,2,3-triazol-4-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid (Example 67) [3014] 8-[(1-{([4-(carboxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo(4.4.0)deca-1(6),7,9-triene-7-carboxylic acid trisodium salt (Example 68) [3015] 8-[(1-{[1-(carboxymethyl)-1H-1,2,3-triazol-4-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid trisodium salt (Example 69) [3016] 8-({1-[amino(1H-1,2,3-triazol-4-yl)acetyl]azetidin-3-yl}oxy-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 70) [3017] 2-hydroxy-7-({1-[(4-nitro-1H-1,2,3-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid (Example 71)

Example 72; 7-({1-(amino(3,4-dihydroxyphenyl)acetyl)azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride

[3018] ##STR01013##

Example 72-1: tert-butyl 6-[(1-{[(tert-butoxycarbonyl)amino](3,4-dihydroxyphenyl)acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

[3019] ##STR01014##

[3020] Palladium on carbon (19 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (2 mL) of the compound of Reference Example 67 (190 mg, 0.187 mmol), and the reaction mixture was stirred for 2.5 hours under a hydrogen atmosphere at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methanol, and the combined filtrate was concentrated to obtain the title compound (143 mg) as a colorless amorphous compound.

[3021] .sup.1H-NMR (CDCl.sub.3) δ: 7.19 (1H, d, J=8.1 Hz), 6.93 (1H, d, J=16.2 Hz), 6.82-6.71 (2H, m), 6.32 (1H, d, J=8.1 Hz), 5.99 (1H, br), 5.77-5.65 (1H, m), 5.08-3.80 (7H, m), 2.63-2.56 (2H, m), 2.36-2.27 (1H, m), 2.19-2.12 (1H, m), 2.04-1.99 (1H, m), 1.89-1.77 (2H, m), 1.63-1.39 (27H, m), 1.35 (3H, s), 1.28 (3H, s), 1.12-1.00 (3H, m), 0.83 (3H, s).

[3022] LCMS: [M+H].sup.+/Rt=837.7/2.83 min.sup.B

Example 72: 7-({1-[amino(3,4-dihydroxyphenyl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride

[3023] ##STR01015##

[3024] Phenylboronic acid (18.7 mg, 0.153 mmol), hexane (1.5 mL), and 4 N hydrochloric acid/dioxane solution (0.76 mL) were added to an acetonitrile solution (1.5 mL) of the compound of Example 72-1 (128 mg, 0.153 mmol), and the reaction mixture was stirred for 17 hours at room temperature. The reaction solution was allowed to stand. The supernatant (top layer) was removed, and hexane (5 mL) was added to the remaining bottom layer. After stirring and then allowing it to stand, the supernatant was removed. This was repeated 5 times. Diethyl ether (5 mL) was added to the bottom layer. After stirring and then allowing it to stand, the supernatant (top layer) was removed. This was repeated 3 times. The resulting residue was dried under reduced pressure. Since an intermediate (Boc-undeprotected form of the title compound) was also found in the resulting residue, a 4 N hydrochloric acid/dioxane solution (3.0 mL) was further added. The reaction mixture was stirred for 21 hours at room temperature, and the reaction solution was concentrated. The resulting residue was dissolved in methanol (1.5 mL) and purified by reversed phase column chromatography to obtain the title compound (19.3 mg) as a light yellow solid.

[3025] .sup.1H-NMR (CD.sub.3OD) δ: 7.25-7.05 (1H, m), 6.91-6.79 (3H, m), 6.25-6.00 (1H, m), 5.09-4.94 (1H, m), 4.63-3.98 (3H, m), 3.76-3.53 (2H, m), 2.81-2.39 (2H, m), 1.16-0.51 (2H, m).

[3026] LCMS: [M+H].sup.+/Rt=429.2/0.96 min.sup.B

Example 73: 7-({1-[amino(2,4-dihydroxyphenyl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride

[3027] ##STR01016##

Example 73-1:7-[(1-{amino[2,4-bis(benzyloxy)phenyl]acetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

[3028] ##STR01017##

[3029] A reaction, work-up, and purification were performed using the compound of Reference Example 68 (195 mg, 0.192 mmol) as the starting material by the same method described in Example 72 to obtain the title compound (78 mg) as a colorless solid.

[3030] .sup.1H-NMR (CD.sub.3OD) δ: 7.45-7.26 (11H, m), 7.14-7.11 (1H, m), 6.87-6.79 (1H, m), 6.74-6.65 (1H, m), 6.16 (1H, brs), 5.25-5.04 (5H, m), 5.03-4.91 (1H, m), 4.48-3.90 (31H, m), 3.77-3.60 (1H, m), 2.73-2.64 (2H, m), 1.09-1.02 (2H, m).

[3031] LCMS: [M+H].sup.+/Rt=609.6/1.80 min.sup.B

Example 73: 7-({1-([amino(2,4-dihydroxyphenyl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride

[3032] ##STR01018##

[3033] Palladium on carbon (13 mg, Pd content: 10%, wetted with ca. 55% water) was added to a THF solution (25 mL) of the compound of Example 73-1 (65.1 mg, 0.101 mmol), and the reaction mixture was stirred for 2.5 hours under a hydrogen atmosphere at room temperature. Subsequently, methanol (0.25 mL) was added, and the reaction mixture was stirred for 4 days at room temperature. Subsequently, palladium on carbon (13 mg) was added, and the reaction mixture was stirred for 1 day at room temperature. Palladium on carbon (13 mg) was further added, and the reaction mixture was stirred for 5 days at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methanol, and the combined filtrate was concentrated. The resulting residue was dissolved in methanol (2 mL) and purified by reversed phase column chromatography to obtain the title compound (9.0 mg) as a colorless solid.

[3034] .sup.1H-NMR (CD.sub.3OD) δ: 7.13-5.98 (5H, m), 5.23-5.19 (1H, m), 5.04-4.79 (1H, m), 4.51-3.47 (4H, m), 2.85-1.93 (2H, m), 1.16-0.65 (2H, m).

[3035] LCMS: [M+H].sup.+/Rt=429.2/0.94 min.sup.B

Example 74: 7-{[1-(S-benzyl-D-cysteinyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine 8-carboxylic acid trifluoroacetate

[3036] ##STR01019##

[3037] Trifluoroacetic acid (3.3 mL) was added to the compound of Reference Example 72 (106 mg), and the reaction mixture was stirred for 8 hours at room temperature. The reaction mixture was dried and solidified under reduced pressure. The resulting dried residue was purified by reversed phase column chromatography. The resulting dried residue was washed with acetonitrile, dried and solidified under reduced pressure to obtain the title compound (24.6 mg) as a white solid.

[3038] LCMS: [M+H].sup.+/Rt=865.61/1.332 min.sup.A

[3039] A reaction, work-up, and purification were performed using the compounds of Reference Examples 73 and 74 as the starting materials by the same method described in Reference Example 74 to obtain the following Example compounds 75 and 76, respectively. text missing or illegible when filed

[3040] The names of the compounds of Examples 75 and 76 are described below. [3041] 7-[(1-D-cysteinylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid trifluoroacetate (Example 75) [3042] 2-hydroxy-7-{[1-(3-sulfanyl-D-valyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid trifluoroacetate (Example 76)

[3043] A reaction, work-up, and purification were performed using the compounds of Reference Examples 42, 52, 76 to 78, and 109 to 113 as the starting materials by the same method described in Example 38 to obtain the following Example compounds 77 to 86 (corresponding starting materials are not in order). However, if a free form is the final product (Example 83), the free form was obtained from purifying the compound without sodium hydroxide treatment. If hydrochloride is the final product (Examples 79, 80, 82, and 84 to 86), the hydrochloride was obtained from purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE-US-00033 TABLE 3-14 Starting Example material Structural formula NMR and/or LCMS 77 Reference Example 76 [01020] embedded image LCMS: [M + H].sup.+/Rt = 379.1/0.76 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.71 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 5.00-4.93 (1H, m), 4.73-4.61 (1H, m), 4.37-4.27 (2H, m), 4.05-4.01 (1H, m), 3.79-3.71 (1H, m), 2.59-2.47 (3H, m), 2.38-2.25 (1H, m), 0.41 (2H, t, J = 8.1 Hz). 78 Reference Example 77 [01021] embedded image LCMS: [M + H].sup.+/Rt = 406.3/1.00 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.73 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 5 05-4-95 (1H, m), 4-75-4.53 (1H, m), 4.48-4.28 (3H, m), 4.08-3.98 (1H, m), 3.66-3.42 (1H, m), 2.57 (2H, d, J = 8.1 Hz), 1.32-1.25 (6H, m), 0.45 (2H, t, J = 8.1 Hz). 79 Reference Example 42 [01022] embedded image LCMS: [M + H].sup.+/Rt = 378.2/0.81 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.21-7.11 (1H, m), 6.38-6.10 (1H, m), 5.16-4.98 (1H, m), 4.78-4.64 (1H, m), 4.54-4.26 (3H, m), 4.12-4.02 (1H, m), 2.90-2.54 (4H, m), 1.10-0.64 (2H, m). 80 Reference Example 109 [01023] LCMS: [M + H].sup.+/Rt = 378.2/0.58 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.18 (1H, d, J = 8.1 Hz), 6.35 (1H, d, J = 8.1 Hz), 5.17-5.07 (1H, m), 4.79-4.72 (1H, m), 4.55-4.27 (3H, m), 4.12-4.01 (1H, m), 2.92-2.64 (4H, m), 1.07 (2H, t, J = 8.1 Hz). 81 Reference Example 78 [01024] embedded image LCMS: [M + H].sup.+/Rt = 379.1/0.56 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.72 (1H, d, J = 8.1 Hz), 5.94 (1H, d, J = 8.1 Hz), 5.00-4.92 (1H, m), 4.73-4.61 (1H, m), 4.37-4.27 (2H, m), 4.06-4.00 (1H, m), 3.80-3.72 (1H, m), 2.59-2.47 (3H, m), 2.39-2.26 (1H, m), 0.44 (2H, t, J = 8.1 Hz). 82 Reference Example 52 [01025] embedded image LCMS: [M + H].sup.+/Rt = 351.0/0.48 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.17 (1H, d, J = 8.2 Hz), 6.35 (1H, d, J = 8.1 Hz), 5.18-5.09 (1H, m), 4.79-4.70 (1H, m), 4.55-4.33 (2H, m), 4.12-4.02 (2H, m), 3.92-3.84 (1H, m), 3.80-3.73 (1H, m), 2.70 (2H, t, J = 8.1 Hz), 1.06 (2H, t, J = 8.1 Hz).

TABLE-US-00034 TABLE 3-15 83 Reference Example 110 [01026] embedded image LCMS: [M + H].sup.+/Rt = 363.0/0.97 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.18-7.09 (1H, m), 6.33-6.09 (1H, m), 5.10-5.02 (1H, m), 4.67-4.62 (1H, m), 4.40-4.34 (1H, m), 4.28-4.23 (1H, m), 3.99-3.94 (1H, m), 2.72-2.38 (6H, m), 1.09-0.91 (2H, m). 84 Reference Example 111 [01027] LCMS: [M + H].sup.+/Rt = 392.1/0.79 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.17 (1H, d, J = 8.2 Hz), 6.40-6.30 (1H, m), 5.17-5.08 (1H, m), 4.77-4.71 (1H, m), 4.54-4.31 (2H, m), 4.14-4.02 (2H, m), 2.70 (2H, t, J = 8.1 Hz), 2.48-2.42 (2H, m), 2.15-2.00 (2H, m), 1.06 (2H, t, J = 8.1 Hz). 85 Reference Example 113 [01028] embedded image LCMS: [M + H].sup.+/Rt = 393.1/0.47 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.17 (1H, d, J = 8.2 Hz), 6.35 (1H, d, J = 8.2 Hz), 5.17-5.08 (1H, m), 4.81-4.72 (1H, m), 4.55-4.30 (2H, m), 4.17-4.03 (2H, m), 3.60-3.40 (2H, m), 2.70 (2H, t, J = 8.1 Hz), 1.06 (2H, t, J = 8.1 Hz). 86 Reference Example 112 [01029] embedded image LCMS: [M + H].sup.+/Rt = 392.1/0.86 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.18 (1H, d, J = 8.2 Hz), 6.39-6.30 (1H, m), 5.18-5.09 (1H, m), 4.80-4.72 (1H, m), 4.55-4.32 (2H, m), 4.21-4.03 (2H, m), 3.60-3.42 (2H, m), 2.70 (2H, t, J = 8.1 Hz), 2.01-1.98 (3H, m), 1.06 (2H, t, J = 8.1 Hz).

[3044] The names of the compounds of Examples 77 to 86 are described below. [3045] 8-({1-[(2S)-2-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid trisodium salt (Example 77) [3046] 8-{[1-(D-alanyl-D-alanyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 78) [3047] 7-[(1-L-asparaginylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 79) [3048] 7-[(1-D-asparaginylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 80) [3049] 8-({1-[(2R)-2-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid trisodium salt (Example 81) [3050] 2-hydroxy-7-[(1-D-serylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 82) [3051] 7-{[1-(4-amino-4-oxobutanoyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid (Example 83) [3052] 7-[(1-D-glutaminylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 84) [3053] 7-({1-[3-(carbamoylamino)-D-alanyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 85) [3054] 1-(3-acetamido-D-alanyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 86)

[3055] The following Example compounds 87 to 89 (corresponding starting materials are not in order) were obtained by performing a reaction and work-up using the compounds of Reference Examples 53, 54, and 75 as the starting materials by the same method described in Example 4, and purifying the compounds by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE-US-00035 TABLE 3-16 Starting Example material Structural formula NMR and/or LCMS 87 Reference Example 54 [01030] embedded image LCMS: [M + H]+/Rt = 406.36/1.38 min.sup.D .sup.1H-NMR (CD.sub.3OD) δ: 7.22-7.12 (1H, m), 6.41-6.28 (1H, m), 5.17-5.07 (1H, m), 4.83-4.68 (1H, m), 4.54-4.24 (3H, m), 4.13-4.00 (1H, m), 3.11-2.77 (8H, m), 2.75-2.64 (21-I, m), 1.10-1.00 (2H, m). 88 Reference Example 53 [01031] LCMS: [M + H]+/Rt = 392.19/1.43 min.sup.D .sup.1H-NMR (CD.sub.3OD) δ: 7-24-7.10 (1H, m), 6.46-6.23 (1H, m), 5.18-5.09 (1H, m), 4.79-4.68 (1H, m), 4.57-4.27 (3H, m), 4.22-3.98 (1H, m), 2.85-2.61 (7H, m), 1.10-1.03 (2H, m). 89 Reference Example 75 [01032] embedded image LCMS: [M + H]+/Rt = 351.21/0.97 min.sup.D .sup.1H-NMR (CD.sub.3OD) δ: 7.20-7.14 (1H, m), 6.40-6.28 (1H, m), 5.17-5.09 (1H, m), 4.78-4.70 (1H, m), 4.56-4.41 (1H, m), 4.39-4.32 (1H, m), 4.14-4.02 (2H, m), 3.92-3.85 (1H, m), 3.81-3.74 (1H, m), 2.75-2.65 (2H, m), 1.12-1.03 (2H, m).

[3056] The names of the compounds of Examples 87 to 89 are described below. [3057] 7-{[1-(N,N-dimethyl-D-asparaginyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 87) [3058] 2-hydroxy-7-{[1-(N-methyl-D-asparaginyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 88) [3059] 2-hydroxy-7-[(1-L-serylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborine-8-carboxylic acid hydrochloride (Example 89)

[3060] A reaction, work-up, and purification were performed using the compounds of Reference Examples 60, 62, 79 to 81, 124, and 125 as the starting materials by the same method described in Example 37 to obtain the following Example compounds 90 to 96 (corresponding starting materials are not in order). However, if a free form is the final product (Example 91), the free form was obtained from purifying the compound without sodium hydroxide treatment. If hydrochloride is the final product (Examples 90, 92, and 93), the hydrochloride was obtained from purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE-US-00036 TABLE 3-17 Exam- Starting ple material Structural formula NMR and/or LCMS 90 Reference Example 79 [01033] embedded image LCMS: [M + H]+/Rt = 377.4/0.425 min.sup.C .sup.1H-NMR (CD.sub.3OD) δ: 7.16 (1H, d, J = 8.5 Hz), 6.34 (1H, d, J = 8.5 Hz), 5.15 (1H, s), 4.72-4.66 (1H, m), 4.54-4.48 (4H, m), 4.32-4.25 (1H, m), 4.13-4.05 (1H, m), 3.39-3.33 (1H, m), 2.72-2.67 (2H, m), 2.61-2.57 (1H, m), 2.09-2.05 (1H, m), 1.03-1.00 (2H, m). 91 Reference Example 80 [01034] embedded image LCMS: [M + H]+/Rt = 429.1/0.537 min.sup.C .sup.1H-NMR (CD.sub.3OD) δ: 7.19-7.17 (1H, m), 636-6.33 (1H, m), 5.22-5-11 (2H, m), 4.58-4.50 (2H, m), 4.36-4.33 (1H, m), 4.13-4.11 (1H, m), 3.68-3.66 (1H, m), 3.52-3.50 (2H, m), 2.84-2.81 (1H, m), 2.70 (2H, t, J = 7.9 Hz), 2.11-2.09 (1H, m), 1.06 (2H, t, J = 7.6 Hz). 92 Reference Example 81 [01035] embedded image LCMS: [M + H]+/Rt = 379.09/0.453 min.sup.C 93 Reference Example 60 [01036] LCMS: [M + H]+/Rt = 375.01/0.304 min.sup.A .sup.1H-NMR (CD.sub.3OD) δ: 7.16 (1H, d, J = 7.3 Hz), 6.35-6.33 (1H, m), 5.08-5.06 (1H, m), 4.62-4.59 (1H, m), 4.39-4.37 (1H, m), 4.22 (1H, d, J = 9.8 Hz), 3.97 (1H, d, J = 11.0 Hz), 3.52 (1H, t, J = 9.8 Hz), 3.38-3.35 (1H, m), 3.25-3.23 (1H, m), 2.93 (1H, t, J = 10.4 Hz), 2.70-2.68 (3H, m), 2.48-2.45 (1H, m), 2.39-2.35 (1H, m), 2.26-2.24 (1H, m), 1.73-1.68 (1H, m), 1.07 (2H, t, J = 7.9 Hz). 94 Reference Example 124 [01037] embedded image LCMS: [M + H]+/Rt = 466.23/0.486 min.sup.C .sup.1H-NMR (D.sub.2O) δ: 6.51 (1H, d, J = 8.5 Hz), 5.67 (1H, dd, J = 8.5, 2.7 Hz), 4.64-4.59 (1H, m), 4.22-4.16 (1H, m), 4.00-3.84 (3H, m), 3.65 (1H, dd, J = 10.7, 3.4 Hz), 2.87-2.82 (1H, m), 2.68 (3H, d, J = 3.1 Hz), 2.57 (3H, d, J = 8.5 Hz), 2.49-2.44 (1H, m), 2.23-2.14 (4H, m), 1.99-1.90 (2H, m), 1.07-1.03 (1H, m), 0.00 (2H, t, J = 7.0 Hz).

TABLE-US-00037 TABLE 3-18 95 Reference Example 125 [01038] embedded image LCMS: [M + H].sup.+/Rt = 466.28/0.482 min.sup.C .sup.1H-NMR (D.sub.2O) δ: 6.51 (1H, d, J = 7.9 Hz), 5.67 (1H, dd, J = 7.9, 2.4 Hz), 4.64-4.59 (1H, m), 4.19 (1H, dd, J = 15.9, 9.2 Hz), 4.00-3.84 (3H, m), 3.64 (1H, dd, J = 11.0, 3.4 Hz), 2.90-2.85 (1H, m), 2.68 (3H, d, J = 3.7 Hz), 2.57 (3H, d, J = 7.9 Hz), 2.52-2.46 (1H, m), 2.23-2.17 (4H, m), 1.98-1.92 (2H, m), 1.07 (1H, dd, J = 8.9, 4.0 Hz), 0.00 (2H, t, J = 7.0 Hz). 96 Reference Example 62 [01039] embedded image LCMS: [M + H].sup.+/Rt = 393.10/0.477 min.sup.C .sup.1H-NMR (D.sub.2O) δ: 6.49 (1H, d, J = 7.9 Hz), 5.67 (1H, d, J = 7.9 Hz), 4.98 (1H, dq, J = 53.1, 4.3 Hz), 4.64-4.58 (1H, m), 4.42-4.39 (1H, m), 4.20-4.15 (1H, m), 3.97 (1H, dd, J = 10.4, 6.1 Hz), 3.88 (1H, dd, J = 10.4, 3.7 Hz), 3.64 (1H, dd, J = 11.0, 3.1 Hz), 3.41-3.31 (1H, m), 3.07 (1H, dt, J = 20.0, 13.0 Hz), 2.84-2.67 (1H, m), 2.29-2.22 (1H, m), 2.18 (2H, t, J = 7.0 Hz), 2.15-2.02 (1H, m), 1.59-1.47 (1H, m), 0.00 (2H, t, J = 7.0 Hz).

[3061] The names of the compounds of Examples 90 to 96 are described below. [3062] 2-hydroxy-7-{[1-(4-hydroxyprolyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 90) [3063] 2-hydroxy-7-({1-[(4R)-4-(trifluoromethyl)-D-prolyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid (Example 91) [3064] 7-({1-[(4S)-4-fluoro-L-prolyl]azetidin-3-yl)oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 92) [3065] 2-hydroxy-7-({1-[(pyrrolidin-3-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 93) [3066] 8-[(1-{[(3R,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 94) [3067] 8-[(1-{[(3S,5R)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 95) [3068] 8-[(1-{[(2R,4S)-4-fluoropyrrolidin-2-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 96)

[3069] A reaction, work-up, and purification were performed using the compounds of Reference Examples 82 to 105 and 117 to 123 as the starting materials by the same method described in Example 38 to obtain the following Example compounds 97 to 127 (corresponding starting materials are not in order). However, if hydrochloride is the final product (Examples 119, 120, and 123), the hydrochloride was obtained from purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE-US-00038 TABLE 3-19 Starting Example material Structural formula NMR and/or LCMS 97 Reference Example 82 [01040] embedded image LCMS: [M + H].sup.+/Rt = 397.3/1.08 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.63 (1H, d, J = 8.1 Hz), 5.95 (1H, d, J = 8.1 Hz), 5.03-4.95 (1H, m), 4.64-4.52 (1H, m), 4.39-4.25 (2H, m), 4.09-3.95 (2H, m), 3.37-3.01 (2H, m), 2.62-2.20 (4H, m), 0.46 (2H, t, J = 8.1 Hz). 98 Reference Example 117 [01041] embedded image LCMS: [M + H].sup.+/Rt = 377.2/0.65 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.73 (1H, d, J = 8.1 Hz), 5.94 (1H, d, J = 8.1 Hz), 5.02-4.92 (1H, m), 4.62-4.52 (1H, m), 4.42-4.22 (3H, m), 4.08-4.00 (1H, m), 3.92-3.86 (1H, m), 3.22-3.16 (1H, m), 2.80-2.75 (1H, m), 2.57 (2H, t, J = 8.1 Hz), 2.10-2.01 (1H, m), 1.89-1.76 (1H, m), 0.45 (2H, t, J = 8.1 Hz). 99 Reference Example 83 [01042] embedded image LCMS: [M + H].sup.+/Rt = 389.3/0.91 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 4.99-4.89 (1H, m), 4.54-4.48 (1H, m), 4.33-4.19 (2H, m), 4.02-3.97 (1H, m), 3.00-2.95 (2H, m), 2.63-2.53 (4H, m), 2.19 (2H, d, J = 8.1 Hz), 1.99-1.81 (1H, m), 1.73-1.65 (2H, m), 1.33-1.14 (2H, m), 0.43 (2H, t, J = 8.1 Hz). 100 Reference Example 84 [01043] embedded image LCMS: [M + H].sup.+/Rt = 361.2/0.93 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 5.00-4.92 (1H, m), 4.58-4.52 (1H, m), 4.32-4.25 (2H, m), 4.02-3.97 (1H, m), 3.09-2.76 (5H, m), 2.56 (2H, d, J = 8.1 Hz), 2.03-1.85 (2H, m), 0.43 (2H, t, J = 8.1 Hz).

TABLE-US-00039 TABLE 3-20 101 Reference Example 118 [01044] embedded image LCMS: [M + H].sup.+/Rt = 377.2/0.54 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.72 (1H, d, J = 8.1 Hz), 5.94 (1H, d, J = 8.1 Hz), 5.04-4.94 (1H, m), 4.60-4.49 (1H, m), 4.40-4.24 (3H, m), 4.10-4.01 (1H, m), 3.72-3.66 (1H, m), 3.01-2.97 (1H, m), 2.81-2.75 (1H, m), 2.56 (2H, d, J = 8.1 Hz), 2.40-2.26 (1H, m), 1.76-1.67 (1H, m), 0.44 (2H, t, J = 8.1 Hz). 102 Reference Example 120 [01045] embedded image LCMS: [M + H].sup.+/Rt = 376.2/0.31 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.73 (1H, d, J = 8.1 Hz), 5.95 (1H, d, J = 8.1 Hz), 5.02-4.94 (1H, m), 4.61-4.49 (1H, m), 4.38-4.21 (2H, m), 4.09-4.00 (1H, m), 3.75-3.61 (1H, m), 3.49-3.29 (1H, m), 3.00-2.78 (1H, m), 2.56 (2H, d, J = 8.1 Hz), 2.41-2.18 (1H, m), 1.64-1.29 (2H, m), 0.45 (2H, t, J = 8.1 Hz). 103 Reference Example 121 [01046] embedded image LCMS: [M + H].sup.+/Rt = 418.3/0.74 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.77 (1H, d, J = 8.1 Hz), 5.97 (1H, d, J = 8.1 Hz), 5.02-4.96 (1H, m), 4.62-4.52 (1H, m), 4.40-4.23 (3H, m), 4.10-4.03 (1H, m), 3.76-3.72 (1H, m), 3.02-2.86 (2H, m), 2.57 (2H, d, J = 8.1 Hz), 2.48-2.35 (1H, m), 1.92 (3H, s), 1.75-1.63 (1H, m), 0.54-0.45 (2H, m). 104 Reference Example 119 [01047] embedded image LCMS: [M + H].sup.+/Rt = 377.2/0.55 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.76 (1H, d, J = 8.1 Hz), 5.98 (1H, d, J = 8.1 Hz), 5.03-4.97 (1H, m), 4.62-4.49 (2H, m), 4.39-4.22 (2H, m), 4.11-4.05 (1H, m), 3.69-3.65 (1H, m), 3.35-3.19 (1H, m), 2.89-2.80 (1H, m), 2.57 (2H, d, J = 8.1 Hz), 2.11-1.80 (2H, m), 0.50-0.42 (2H, m). 105 Reference Example 85 [01048] embedded image LCMS: [M + H].sup.+/Rt = 389.3/1.18 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.72 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 5.02-4.96 (1H, m), 4.59-4.47 (1H, m), 4.39-4.20 (2H, m), 4.08-4.00 (1H, m), 3.83-3.77 (1H, m), 2.80-2.54 (4H, m), 2.00-1.88 (1H, m), 1.59-1.50 (1H, m), 1.09 (3H, s), 1.06 (3H, s), 0.44 (2H, t, J = 8.1 Hz). 106 Reference Example 86 [01049] embedded image LCMS: [M + H].sup.+/Rt = 375.2/0.99 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.92 (1H, d, J = 8.1 Hz), 4.98-4.91 (1H, m), 4.53-4.47 (1H, m), 4.33-4.19 (2H, m), 4.03-3.96 (1H, m), 3.37-3.33 (1H, m), 3.08-2.80 (2H, m), 2.56 (2H, t, J = 8.1 Hz), 2.35-2.30 (2H, m), 2.06-1.90 (1H, m), 1.85-1.72 (2H, m), 1.43-1.29 (1H, m), 0.42 (2H, t, J = 8.1 Hz).

TABLE-US-00040 TABLE 3-21 107 Reference Example 87 [01050] embedded image LCMS: [M + H].sup.+/Rt = 375.3/0.96 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 5.00-4.92 (1H, m), 4.63-4.52 (1H, m), 4.36-4.22 (2H, m), 4.06-3.96 (1H, m), 3.09-3.02 (1H, m), 2.66-2.53 (3H, m), 1.94-1.75 (2H, m), 1.63-1.27 (5H, m), 0.43 (2H, t, J = 8.1 Hz). 108 Reference Example 88 [01051] embedded image LCMS: [M + H].sup.+/Rt = 375.3/0.99 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 4.99-4.92 (1H, m), 4.60-4.53 (1H, m), 4.31-4.25 (2H, m), 4.01-3.95 (1H, m), 2.95 (2H, t, J = 8.1 Hz), 2.66-2.39 (5H, m), 1.88-1.43 (4H, m), 0.43 (2H, t, J = 8.1 Hz). 109 Reference Example 89 [01052] embedded image LCMS: [M + H].sup.+/Rt = 375.3/0.95 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 4.99-4.90 (1H, m), 4.58-4.53 (1H, m), 4.31-4.25 (2H, m), 4.01-3.96 (1H, m), 3.08-2.99 (2H, m), 2.66-2.40 (5H, m), 1.71-1.51 (4H, m), 0.43 (2H, t, J = 8.1 Hz). 110 Reference Example 90 [01053] embedded image LCMS: [M + H].sup.+/Rt = 362.2/1.31 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.63 (1H, d, J = 8.1 Hz), 5.84 (1H, d, J = 8.1 Hz), 4.91-4.83 (1H, m), 4.62-4.52 (1H, m), 4.35-4.21 (3H, m), 3.97-3.68 (3H, m), 2.47 (2H, t, J = 8.1 Hz), 2.19-2.01 (1H, m), 1.96-1.71 (3H, m), 0.41-0.31 (2H, m). 111 Reference Example 91 [01054] embedded image LCMS: [M + H].sup.+/Rt = 437.0/1.34 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.31-7.26 (4H, m), 7.21-7.15 (1H, m), 6.70 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 5.05-4.94 (1H, m), 4.65-4.54 (1H, m), 4.42-4.26 (2H, m), 4.11-4.03 (1H, m), 3.89 (1H, t, J = 8.1 Hz), 3.77-3.65 (1H, m), 3.39-3.20 (1H, m), 3.07-2.96 (1H, m), 2.85-2.53 (3H, m), 1.94-1.77 (1H, m), 0.42 (2H, t, J = 8.1 Hz). 112 Reference Example 92 [01055] embedded image LCMS: [M + H].sup.+/Rt = 373.3/0.96 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.91 (1H, d, J = 8.1 Hz), 5.00-4.91 (1H, m), 4.54-4.46 (1H, m), 4.36-4.26 (2H, m), 4.05-3.99 (2H, m), 2.77-2.71 (1H, m), 2.58-2.39 (3H, m), 1.95-1.87 (1H, m), 1.52-1.43 (1H, m), 0.63-0.55 (1H, m), 0.48-0.38 (3H, m).

TABLE-US-00041 TABLE 3-22 113 Reference Example 93 [01056] embedded image LCMS: [M + H].sup.+/Rt = 375.2/0.85 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.92 (1H, d, J = 8.1 Hz), 5.00-4.92 (1H, m), 4.65-4.55 (1H, m), 4.38-4.26 (2H, m), 4.07-3.99 (1H, m), 3.08-3.02 (1H, m), 2.95-2.88 (1H, m), 2.56 (2H, t, J = 8.1 Hz), 2.30-2.10 (5H, m), 1.88-1.79 (3H, m), 0.43 (2H, t, J = 8.1 Hz). 114 Reference Example 94 [01057] embedded image LCMS: [M + H].sup.+/Rt = 389.3/0.95 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.72 (1H, d, J = 8.1 Hz), 5.97-5.93 (1H, m), 4.96-4.86 (1H, m), 4.63-4.57 (1H, m), 4.31-4.20 (2H, m), 4.02-3.96 (1H, m), 3.00-2.84 (2H, m), 2.62-2.50 (3H, m), 2.35-2.23 (1H, m), 2.09-1.96 (3H, m), 1.89-1.80 (1H, m), 1.74-1.54 (2H, m), 1.26-1.10 (1H, m), 0.43 (2H, t, J = 8.1 Hz). 115 Reference Example 95 [01058] embedded image LCMS: [M + H]+/Rt = 391.3/0.9 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.72 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 5.00-4.80 (1H, m), 4.58-4.49 (1H, m), 4.33-4.21 (2H, m), 4.02-3.98 (1H, m), 3.90-3.76 (2H, m), 3.64-3.51 (1H, m), 2.95-2.47 (6H, m), 2.37-2.29 (1H, m), 2.22-2.12 (1H, m), 0.44 (2H, t, J = 8.1 Hz). 116 Reference Example 96 [01059] embedded image LCMS: [M + H].sup.+/Rt = 361.2/0.84 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.72 (1H, d, J = 8.1 Hz), 5.94 (1H, d, J = 8.1 Hz), 5.16-5.03 (1H, m), 4.56-4.50 (2H, m), 4.37-4.26 (2H, m), 3.78-3.65 (1H, m), 3.57-3.44 (3H, m), 2.89-2.68 (2H, m), 2.61-2.53 (3H, m), 0.43 (2H, t, J = 8.1 Hz). 117 Reference Example 97 [01060] embedded image LCMS: [M + H].sup.+/Rt = 390.3/0.34 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.95-5.91 (1H, m), 5.10-4.97 (1H, m), 4.44-3.61 (4H, m), 3.35-1.52 (10H, m), 0.43 (2H, t, J = 8.1 Hz). 118 Reference Example 98 [01061] LCMS: [M + H].sup.+/Rt = 389.3/0.98 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.80-6.73 (1H, m), 5.98-5.91 (1H, m), 5.00-4.76 (1H, m), 4.35-3.79 (4H, m), 3.22-3.00 (3H, m), 2.65-2.51 (2H, m), 2.33-1.29 (8H, m), 0.55-0.28 (2H, m). 119 Reference Example 122 [01062] embedded image LCMS: [M + H].sup.+/Rt = 376.2/0.41 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.18 (1H, d, J = 8.1 Hz), 6.41-6.30 (1H, m), 5.22-5.10 (1H, m), 4.89-4.69 (2H, m), 4.57-4.26 (2H, m), 4.20-4.05 (2H, m), 3.93-3.86 (1H, m), 3.57-3.47 (1H, m), 2.70 (2H, t, J = 8.1 Hz), 2.64-2.45 (2H, m), 1.07 (2H, t, J = 8.1 Hz).

TABLE-US-00042 TABLE 3-23 120 Reference Example 123 [01063] embedded image LCMS: [M + H].sup.+/Rt = 418.2/0.89 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.18 (1H, d, J = 8.1 Hz), 6.41-6.30 (1H, m), 5.20-5.12 (1H, m), 4.77-4.26 (5H, m), 4.14-4.05 (1H, m), 3.67-3.60 (1H, m), 3.36-3.30 (1H, m), 2.71 (2H, t, J = 8.1 Hz), 2.48-2.21 (2H, m), 1.98 (3H, s), 1.07 (2H, t, J = 8.1 Hz). 121 Reference Example 99 [01064] embedded image LCMS: [M + H].sup.+/Rt = 404.3/0.34 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.74-6.69 (1H, m), 5.98-5.92 (1H, m), 5.03-4.94 (1H, m), 4.64-4.47 (1H, m), 4.39-4.19 (2H, m), 4.05-3.97 (1H, m), 3.19-2.46 (7H, m), 2.00-1.80 (1H, m), 1.71-1.28 (4H, m), 0.43 (2H, t, J = 8.1 Hz). 122 Reference Example 104 [01065] embedded image LCMS: [M + H].sup.+/Rt = 389.3/1.05 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.74-6.69 (1H, m), 5.91-5.86 (1H, m), 4.94-4.83 (1H, m), 4.48-3.97 (4H, m), 3.12-2.86 (2H, m), 2.71-2.54 (3H, m), 2.26-2.14 (2H, m), 1.85-1.12 (6H, m), 0.42 (2H, t, J = 8.1 Hz). 123 Reference Example 105 [01066] embedded image LCMS: [M + H].sup.+/Rt = 404.1/0.84 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.18 (1H, d, J = 8.2 Hz), 6.41-6.31 (1H, m), 5.20-5.10 (1H, m), 4.81-4.64 (1H, m), 4.58-4.42 (2H, m), 4.38-4.25 (1H, m), 4.18-4.05 (1H, m), 3.68-3.50 (2H, m), 3.38-3.26 (1H, m), 2.85-2.67 (3H, m), 2.16-2.06 (1H, m), 1.06 (2H, t, J = 8.1 Hz). 124 Reference Example 100 [01067] embedded image LCMS: [M + H]+/Rt = 375.2/0.89 min.sup.B 1.sup.1H-NMR (CD.sub.3OD) δ: 6.77-6.62 (1H, m), 6.00-5.85 (1H, m), 4.99-4.91 (1H, m), 4.57-4.44 (1H, m), 4.35-4.16 (2H, m), 4.04-3.92 (1H, m), 3.10-2.81 (3H, m), 2.62-2.40 (4H, m), 2.29-2.19 (2H, m), 2.10-1.96 (1H, m), 1.56-1.37 (1H, m), 0.48-0.36 (2H, m). 125 Reference Example 101 [01068] embedded image LCMS: [M + H]+/Rt = 375.1/0.92 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.75-6.64 (1H, m), 5.99-5.88 (1H, m), 5.01-4.89 (1H, m), 4.59-4.42 (1H, m), 4.37-4.15 (2H, m), 4.03-3.90 (1H, m), 3.12-2.84 (3H, m), 2.61-2.39 (4H, m), 2.31-2.17 (2H, m), 2.11-1.95 (1H, m), 1.59-1.40 (1H, m), 0.47-0.32 (2H, m). 126 Reference Example 102 [01069] embedded image LCMS: [M + H]+/Rt = 375.1/0.99 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.77-6.65 (1H, m), 5.96-5.86 (1H, m), 4.97-4.84 (1H, m), 4.56-3.94 (4H, m), 3.41-3.26 (1H, m), 3.09-2.75 (2H, m), 2.62-2.49 (2H, m), 2.37-2.23 (2H, m), 2.09-1.70 (3H, m), 1.47-1.25 (1H, m), 0.49-0.33 (2H, m).

TABLE-US-00043 TABLE 3-24 127 Reference Example 103 [01070] embedded image LCMS: [M + H]+/Rt = 375.0/0.93 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 6.69 (1H, d, J = 8.2 Hz), 5.91 (1H, d, J = 8.2 Hz), 4.98- 4.85 (1H, m), 4.56-4.46 (1H, m), 4.35- 4.17 (2H, m), 4.05-3.94 (1H, m), 3.38- 3.26 (1H, m), 3.03-2.73 (2H, m), 2.61- 2.49 (2H, m), 2.37-2.26 (2H, m), 2.03- 1.88 (1H, m), 1.85-1.67 (2H, m), 1.46- 1.24 (1H, m), 0.46-0.37 (2H, m).

[3070] The names of the compounds of Examples 97 to 127 are described below. [3071] 8-{[1-(4,4-difluoro-L-prolyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo(4.4.0)deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 97) [3072] 4,4-dihydroxy-8-({1-[(4R)-4-hydroxy-L-prolyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 98) [3073] 4,4-dihydroxy-8-({1-[(piperidin-4-yl)acetyl)azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 99) [3074] 4,4-dihydroxy-8-{(1-(pyrrolidine-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 100) [3075] 4,4-dihydroxy-8-({1-[(4S)-4-hydroxy-L-prolyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 101) [3076] 8-({1-[(4S)-4-amino-L-prolyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 102) [3077] 8-({1-[(4S)-4-acetamido-L-prolyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 103) [3078] 4,4-dihydroxy-8-({1-[(3R)-3-hydroxy-L-prolyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo([4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 104) [3079] 8-{[1-(4,4-dimethyl-L-prolyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 105) [3080] 4,4-dihydroxy-8-({1-[(pyrrolidin-2-yl)acetyl)azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 106) [3081] 4,4-dihydroxy-8-({1-(piperidine-2-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 107) [3082] 4,4-dihydroxy-8-{[1-(piperidine-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 108) [3083] 4,4-dihydroxy-8-{[1-(piperidine-4-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 109) [3084] 4,4-dihydroxy-8-({1-[(2S)-oxolane-2-carbonyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 110) [3085] 4,4-dihydroxy-8-({1-[(4R)-4-phenyl-L-prolyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 111) [3086] 8-({1-[(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 112) [3087] 4,4-dihydroxy-8-{[1-(1-methyl-L-prolyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 113) [3088] 4,4-dihydroxy-8-({1-[(piperidin-3-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 114) [3089] 4,4-dihydroxy-8-({1-[(morpholin-2-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 115) [3090] 8-({1-[(azetidin-3-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 116) [3091] 8-({1-[amino(pyrrolidin-3-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 117) [3092] 4,4-dihydroxy-8-({1-[3-(pyrrolidin-2-yl)propanoyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 118) [3093] 7-({1-[(4R)-4-amino-L-prolyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid dihydrochloride (Example 119) [3094] 7-({1-[(4R)-4-acetamido-L-prolyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 120) [3095] 8-({1-[amino(piperidin-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 121) [3096] 4,4-dihydroxy-8-({1-[(piperidin-2-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 122) [3097] 7-({1-[(4S)-4-carbamoyl-L-prolyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 123) [3098] 4,4-dihydroxy-8-[(1-{[(3R)-pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 124) [3099] 4,4-dihydroxy-8-[(1-{[(3S)-pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 125) [3100] 4,4-dihydroxy-8-[(1-{[(2R)-pyrrolidin-2-yl]acetyl}azetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 126) [3101] 4,4-dihydroxy-8-[(1-{[(2S)-pyrrolidin-2-yl]acetyl}azetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 127)

[3102] The following Example compounds 128 and 129 were obtained by performing a reaction, work-up, and purification using the compounds of Reference Examples 61 and 126, respectively, as the starting materials by the same method described in Example 36, further dissolving the resulting crude product in water, adding an aqueous 2 N sodium hydroxide solution, and purifying by reversed phase chromatography.

TABLE-US-00044 TABLE 3-25 Exam- Starting ple material Structural formula NMR and/or LCMS 128 Reference Example 61 [01071] embedded image LCMS: [M + H].sup.+/Rt = 389.96/0.446 min.sup.F .sup.1H-NMR (D.sub.2O) δ: 6.90 (1H, d, J = 8.2 Hz), 6.07 (1H, d, J = 8.2 Hz), 5.01 (1H, m), 4.60 (1H, m), 4.28-4.40 (2H, m), 4.05 (1H, m), 2.94-3.09 (4H, m), 2.58-2.81 (4H, m), 2.45 (1H, m), 2.22-2.31 (2H, m), 0.38 (2H, m). 129 Reference Example 126 [01072] embedded image LCMS: [M + H].sup.+/Rt = 438.95/0.555 min.sup.F .sup.1H-NMR (D.sub.2O) δ: 6.90 (1H, d, J = 8.2 Hz), 6.07 (1H, d, J = 8.2 Hz), 5.03 (1H, m), 4.65 (1H, m), 4.42-4.32 (2H, m), 4.08 (1H, m), 3.60 (1H, m), 3.47- 3.12 (5H, m), 2.96-2.79 (2H, m), 2.60 (2H, m), 2.40 (1H, m), 0.39 (2H, m).

[3103] The names of the compounds of Examples 128 and 129 are described below. [3104] 4,4-dihydroxy-8-({1-[(piperazin-2-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 128) [3105] 8-({1-[(1,1-dioxo-1λ.sup.1-thiomorpholin-2-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt (Example 129)

[3106] The following Example compounds 130 to 137 were obtained by performing a reaction, work-up, and purification using the compounds of Reference Examples 128 and 131 to 137 as the starting materials (corresponding starting materials are not in order) by the same method described in Example 38, purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE-US-00045 TABLE 3-26 Exam- Starting ple material Structural formula NMR and/or LCMS 130 Reference Example 131 [01073] embedded image LCMS: [M + H].sup.+/Rt=406.1/0.86 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.19-7.11 (1H, m), 6.36-6.14 (1H, m), 5.16- 4.99 (1H, m), 4.74-4.65 (1H, m), 4.54-4.27 (2H, m), 4.12-3.96 (2H, m), 3.42-3.20 (2H, m), 2.73-2.54 (2H, m), 2.11-1.89 (5H, m), 1.09-0.68 (2H, m). 131 Reference Example 132 [01074] embedded image LCMS: [M + H].sup.+/Rt = 378.1/0.54 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.19-7.11 (1H, m), 6.34-6.10 (1H, m), 5.13- 4.99 (1H, m), 4.66-4.52 (1H, m), 4.47-4.01 (4H, m), 2.94-2.50 (4H, m), 1.09-0.64 (2H, m). 132 Reference Example 133 [01075] LCMS: [M + H].sup.+/Rt = 406.1/0.94 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.18-7.10 (1H, m], 6.64-6.09 (1H, m), 5.14- 5.03 (1H, m), 4.80-4.66 (1H, m), 4.46-4.27 (3H, m), 4.04-3.87 (2H, m), 2.80-2.52 (2H, m), 1.51-1.46 (3H, m), 1.36-1.33 (3H, m), 1.09-0.65 (2H, m). 133 Reference Example 135 [01076] embedded image LCMS: [M + H].sup.+/Rt = 392.1/ 0.88 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.17 (1H, d, J = 8.1 Hz), 6.39-6.28 (1H, m), 5.17-5.06 (1H, m), 4.99-4.80 (1H, m), 4.73-3.94 (4H, m), 3.74-3.67 (2H, m), 2.70 (2H, t, J = 8.1 Hz), 1.34 (3H, d, J = 8.1 Hz), 1.06 (2H, t, J = 8.1 Hz). 134 Reference Example 136 [01077] embedded image LCMS: [M + H].sup.+/Rt = 450.1/ 0.92 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 8.67-8.56 (1H, m), 7.18-7.10 (1H, m), 6.34- 6.10 (1H, m), 5.13-5.05 (1H, m), 4.93-4.66 (1H, m), 4.52-4.27 (3H, m), 4.23-4.13 (1H, m), 4.04-3.95 (1H, m), 3.08-2.52 (4H, m), 1.36-1.33 (3H, m), 1.09- 0.66 (2H, m). 135 Reference Example 134 [01078] embedded image LCMS: [M + H].sup.+/Rt = 449.1/ 0.85 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.17 (1H, d, J = 8.1 Hz), 6.38-6.28 (1H, m), 5.15-5.05 (1H, m), 4.92-4.64 (1H, m), 4.47-4.27 (3H, m), 4.22-4.15 (1H, m), 4.03-3.95 (1H, m), 2.96-2.86 (1H, m), 2.76- 2.65 (3H, m), 1.34 (3H, d, J = 5.4 Hz), 1.07 (2H, t, J = 8.1 Hz).

TABLE-US-00046 TABLE 3-27 136 Reference Example 128 [01079] embedded image LCMS: [M + H].sup.+/Rt = 422.1/0.88 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 8.84-8.56 (1H, m), 7.18-7.10 (1H, m), 6.34- 6.09 (1H, m), 5.13-4.59 (2H, m), 4.51-4.26 (3H, m), 4.13- 3.77 (4H, m), 2.79-2.51 (2H, m), 1.37-1.33 (3H, m), 1.09-0.64 (2H, m). 137 Reference Example 137 [01080] LCMS: [M + H].sup.+/Rt = 379.0/0.71 min.sup.B .sup.1H-NMR (CD.sub.3OD) δ: 7.17 (1H, d, J = 8.2 Hz), 6.78-6.32 (1H, m), 5.14-5.04 (1H, m), 4.67-4.61 (1H, m), 4.47-4.38 (1H, m), 4.31-4.22 (2H, m), 4.05-3.61 (1H, m), 3.00-2.78 (2H, m), 2.70 (2H, t, J = 8.1 Hz), 1.06 (2H, t, J = 8.1 Hz).

[3107] The names of the compounds of Examples 130 to 137 are described below. [3108] 7-({1-[(2S)-4-acetamido-2-aminobutanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 130) [3109] 7-{[1-(L-α-asparaginyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 131) [3110] 7-{[1-(L-alanyl-L-alanyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 132) [3111] 7-([1-(glycyl-D-alanyl)azetidin-3-yl]oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 133) [3112] N-[(2R)-1-{3-[(8-carboxy-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-7-yl)oxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-α-asparagine hydrochloride (Example 134) [3113] N.sup.1-[(2R)-1-{3-[(8-carboxy-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-7-yl)oxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-aspartamide hydrochloride (Example 135) [3114] N-[(2R)-1-{3-[(8-carboxy-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-7-yl)oxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-serinamide hydrochloride (Example 136) [3115] 7-({1-[(3S)-3-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 137)

[3116] The compounds of Reference Examples 138 and 139 were used as the starting materials to perform a reaction and work-up by the same method described in Example 4. Each of Example compounds 138 and 139 were obtained from purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE-US-00047 TABLE 3-28 Exam- Starting ple material Structural formula NMR and/or LCMS 138 Reference Example 138 [01081] embedded image LCMS: [M + H].sup.+/Rt = 401.26/ 0.58 min.sup.I .sup.1H-NMR (500 MHz, CD.sub.3OD) δ: 9.10-9.07 (1H, m), 7.93 (brs, 1H), 7.15 (1H, d, J = 8.0 Hz), 6.37- 6.22 (1H, m), 5.61-5.54 (1H, m), 5.16-4.75 (2H, m), 4.61-3.76 (3H, m), 2.74-2.69 (5H, m), 1.06 (2H, t, J = 8.0 Hz). 139 Reference Example 139 [01082] embedded image LCMS: [M + H].sup.+/Rt = 415.25/ 1.03 min.sup.I .sup.1H-NMR (500 MHz, CD.sub.3OD) δ: 8.91 (1H, brs), 7.95 (1H, brs), 7.14 (1H, d, J = 8.0 Hz), 6.38- 6.23 (1H, m), 5.75-5.58 (1H, m), 5.16-3.94 (6H, m), 3.01-3.81 (5H, m), 2.75-2.65 (5H, m), 1.06 (2H, t, J = 8.0 Hz).

[3117] The names of the compounds of Examples 138 and 139 are described below. [3118] 2-hydroxy-7-({1-[(1H-imidazol-4-yl)(methylamino)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid dihydrochloride (Example 138) [3119] 2-hydroxy-7-({1-[(1H-imidazol-4-yl)(methylamino)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid dihydrochloride (Example 139)

Example 140: 2-hydroxy-7-{[1-(2-methyl-D-seryl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

[3120] ##STR01083##

[3121] A reaction, work-up, and purification were performed using the compound of Reference Example 140 (245 mg, 0.317 mmol) as the starting material by the same method described in Example 36 to obtain the title compound (21.8 mg) as a white solid.

[3122] .sup.1H-NMR (0.1M HCl in CD.sub.3OD) δ: 7.18 (1H, d, J=8.5 Hz), 6.35 (1H, d, J=8.5 Hz), 5.14-5.10 (2H, m), 4.50-4.43 (2H, m), 4.12-4.04 (1H, m), 3.91 (1H, d, J=12.2 Hz), 3.72 (1H, d, J=12.2 Hz), 2.70 (2H, t, J=7.6 Hz), 1.52 (3H, s), 1.05 (2H, t, J=7.6 Hz).

[3123] LCMS: [M+H].sup.+/Rt=365.09/0.447 min.sup.C

[3124] The following Example compounds 141 to 148 were obtained by performing a reaction using the compounds of Reference Examples 141, 143, and 150 to 155, respectively, as the starting materials by the same method described in Example 36, followed by, as a work-up, concentrating a reaction mixture under reduced pressure and then purifying the mixture by reversed phase chromatography (Column: YMC-Actus pro C18, solution A: 0.05% TFA/water, solution B: 0.03% TPA/acetonitrile). However, if hydrochloride is the final product (Example 145), the hydrochloride was obtained from purifying the compound by reversed phase chromatography, followed by addition of hydrochloric acid and concentration.

TABLE-US-00048 TABLE 3-29 Exam- Starting ple material Structural formula NMR and/or LCMS 141 Reference Example 141 [01084] embedded image LCMS: [M + H].sup.+/Rt = 365/1.414 min.sup.G .sup.1H-NMR (D.sub.2O) δ: 7.08-6.89 (1H, m), 6.14-5.94 (1H, m), 4.96-4.67 (2H, m), 4.36-4.29 (2H, m), 4.02-3.92 (1H, m), 3.81-3.73 (1H, m), 3.63- 3.56 (1H, m), 2.52-2.25 (2H, m), 1.38- 1.33 (3H, m), 0.92-0.43 (2H, m). 142 Reference Example 143 [01085] embedded image LCMS: [M + H].sup.+/Rt = 404/1.400 min.sup.G .sup.1H-NMR (D.sub.2O) δ: 7.11-6.91 (1H, m), 6.15-5.89 (1H, m), 4.95-4.81 (1H, m), 4.48-4.38 (1H, m), 4.32-3.84 (4H, m), 3.57-3.39 (3H, m), 3.36-3.29 (1H, m), 2.99-2.67 (2H, m), 2.53-2.36 (2H, m), 0.94-0.45 (2H, m). 143 Reference Example 150 [01086] embedded image LCMS: [M + H].sup.+/Rt = 407/1.175 min.sup.G .sup.1H-NMR (D.sub.2O) δ: 7.09-6.89 (1H, m), 6.15-5.91 (1H, m), 4.94-4.63 (2H, m), 4.50-3.84 (4H, m), 2.53-2.33 (6H, m), 1.92-1.74 (2H, m), 0.93-0.43 (2H, m). 144 Reference Example 151 [01087] LCMS: [M + H].sup.+/Rt = 379/1.400 min.sup.G .sup.1H-NMR (D.sub.2O) δ: 6.94-6.80 (1H, m), 5.98-5.78 (1H, m), 4.35-3.36 (6H, m), 2.67 (2H, s), 2.35-2.20 (2H, m), 0.91- 0.60 (2H, m).

TABLE-US-00049 TABLE 3-30 145 Reference Example 152 [01088] embedded image LCMS: [M + H].sup.+/Rt = 393/1.217 min.sup.G .sup.1H-NMR (D.sub.2O) δ: 7.05-6.84 (1H, m), 6.13-5.85 (1H, m), 4.91-4.71 (1H, m), 4.47-3.87 (5H, m), 2.52-2.21 (4H, m), 2.01 (2H, brs), 0.91-0.40 (2H, m). 146 Reference Example 153 [01089] LCMS: [M + H].sup.+/Rt = 406/1.223 min.sup.G .sup.1H-NMR (D.sub.2O) δ: 7.05-6.82 (1H, m), 6.14-5.87 (1H, m), 4.92-4.74 (1H, m), 4.28-4.03 (4H, m), 3.46 (1H, brs), 2.50-1.74 (8H, m), 0.92-0.39 (2H, m). 147 Reference Example 154 [01090] embedded image LCMS: [M + H].sup.+/Rt = 378/1.208 min.sup.G .sup.1H-NMR (D.sub.2O) δ: 7.02-6.82 (1H, m), 6.08-5.83 (1H, m), 4.88-4.71 (1H, m), 4.39-3.83 (5H, m), 2.68 (2H, brs), 2.52-2.16 (2H, m), 0.70-0.37 (2H, m). 148 Reference Example 155 [01091] LCMS: [M + H].sup.+/Rt = 392/1.171 min.sup.G .sup.1H-NMR (D.sub.2O) δ: 7.07-6.81 (1H, m), 6.10-5.84 (1H, m), 4.78-4.67 (1H, m), 4.42-3.80 (5H, m), 2.50-2.33 (2H, m), 2.17 (2H, brs), 1.98-1.96 (2H, m), 0.91-0.38 (2H, m).

[3125] The names of the compounds of Examples 141 to 148 are described below. [3126] 2-hydroxy-7-{[1-(2-methyl-L-seryl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid trifluoroacetate (Example 141) [3127] 2-hydroxy-7-({1-[(3-oxopiperazin-2-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid trifluoroacetate (Example 142) [3128] 7-({1-[(3S)-3-amino-5-carboxypentanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid trifluoroacetate (Example 143) [3129] 7-({1-[(3R)-3-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid trifluoroacetate (Example 144) [3130] 7-({1-[(4R)-4-amino-4-carboxybutanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 145) [3131] 7-({1-[(3S)-3,6-diamino-6-oxohexanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid trifluoroacetate (Example 146) [3132] 7-{[1-(D-α-asparaginyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid trifluoroacetate (Example 147) [3133] 7-{[1-(D-α-glutaminyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid trifluoroacetate (Example 148)

[3134] The following Example compounds 149 and 150 were obtained by performing a reaction and work-up using the compounds of Reference Examples 146 and 147, respectively, as the starting materials by the same method described in Example 38, and purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE-US-00050 TABLE 3-31 Exam- Starting ple material Structural formula NMR and/or LCMS 149 Reference Example 146 [01092] embedded image LCMS: [M + H]+/Rt = 393.1/ 0.86 min.sup.B 1H-NMR (CD3OD) δ: 7.22-7.08 (1H, m), 6.38-6.06 (1H, m), 5.13-5.01 (1H, m), 4.67-4.52 (1H, m), 4.47-4.32 (1H, m), 4.28-4.18 (1H, m), 4.11-3.92 (2H, m), 2.76-2.62 (2H, m), 2.53-2.38 (2H, m), 2.28-2.04 (2H, m), 1.13-0.61 (2H, m). 150 Reference Example 147 [01093] embedded image LCMS: [M + H].sup.+/Rt = 392.1/ 0.86 min.sup.B 1H-NMR (CD3OD) δ: 7.24-7.08 (1H, m), 6.41-6.07 (1H, m), 5.14-5.00 (1H, m), 4.67-4.51 (1H, m), 4.46-4.32 (1H, m), 4.29-4.16 (1H, m), 4.08-3.88 (2H, m), 2.81-2.50 (2H, m), 2.49-2.34 (2H, m), 2.21-2.02 (2H, m), 1.14-0.64 (2H, m).

[3135] The names of the compounds of Examples 149 and 150 are described below. [3136] 7-({1-[(4S)-4-amino-4-carboxybutanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 149) [3137] 7-{[1-(L-α-glutaminyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 150)

[3138] The following Example compounds 151 and 152 were obtained by performing a reaction and work-up using the compounds of Reference Examples 148 and 149, respectively, as the starting materials by the same method described in Example 4 and purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE-US-00051 TABLE 3-32 Exam- Starting ple material Structural formula NMR and/or LCMS 151 Reference Example 148 [01094] embedded image LCMS: [M + H].sup.+/Rt = 365.24/ 1.27 min.sup.I. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ: 7.18-7.09 (1H, s), 6.32 (1H, brs), 5.13-5.07 (1H, m), 4.78-4.69 (1H, m), 4.50-4.29 (2H, m), 4.10-3.96 (2H, m), 3.81-3.78 (1H, m), 2.67 (2H, t, J = 7.4 Hz), 1.26 (3H, t, J = 5.7 Hz), 1.03 (2H, t, J = 8.1 Hz). 152 Reference Example 149 [01095] embedded image LCMS: [M + H].sup.+/Rt = 365.24/ 1.23 min.sup.I. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ: 7.17-7.10 (1H, s), 6.33 (1H, brs), 5.12-5.07 (1H, m), 4.76-4.70 (1H, m), 4.51-4.30 (2H, m), 4.09-3.78 (3H, m), 2.67 (2H, brs), 1.26 (3H, t, J = 6.3 Hz), 1.03 (2H, t, J = 8.0 Hz).

[3139] The names of the compounds of Examples 151 and 152 are described below. [3140] 2-hydroxy-7-[(1-D-threonylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 151) [3141] 2-hydroxy-7-[(1-L-threonylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride (Example 152)

[3142] Pharmacological testing methods and results thereof for representative compounds of the invention are shown hereinafter, but the present invention is not limited to the Test Examples.

Test Example 1

[3143] Evaluation of minimum inhibitory concentration (MIC) of MEPM against N-lactamase producing bacteria

[3144] To evaluate the β-lactamase inhibitory activity of test compounds, the effect of combination of a test compound and a β-lactam agent against β-lactamase producing bacteria was evaluated. Meropenem (MEPM) was used as a β-lactam antimicrobial agent. The minimum inhibitory concentration (MIC) of MEPM against β-lactamase producing bacteria when a test compound was added at a fixed concentration (4 μg/mL) was measured by broth microdilution method (common ratio: 2). MIC of MEPM decreasing to less than 1/32 in combination with a test compound is indicated by A, decreasing from 1/32 to 1/16 is indicated by B, decreasing from ⅛ to ¼ is indicated by C, and decreasing to ½ or others are indicated by D. “-” represents untested cases.

TABLE-US-00052 TABLE 4 E. coli K. pneumoniae K. pneumoniae Example ATCC BAA-2340 ATCC BAA-2344 ATCC BAA-2524 number (KPC) (KPC) (OXA-48) 1 A A B 2 A A B 3 A A B 4 A A A 5 A B C 6 A A B 7 A A B 8 A A B 9 A A A 10 A A B 11 A B B 12 A A B 13 A A B 14 A A B 15 A A B 16 A — B 17 A B B 18 A A B 19 A A B 20 A B B 21 A B C 22 A A B 23 — A B 24 A A B 25 A A B 26 A A A 27 — A B 28 A A B 29 — A B 30 — A B 31 — A B 32 — A B 33 — A B 34 — A B 35 A A B

Test Example 2

[3145] Evaluation of minimum inhibitory concentration (MIC) of MEPM against β-lactamase producing bacteria

[3146] In the same manner as Test Example 1, E. coli ATCC BAA-2469 (NDM-1), K. pneumomiae ATCC BAA-2470 (NDM-1), K. pneumomiae NCTC 13439 (VIM-1), K. pneumomiae NCTC 13440 (VIM-1), E. coli NCTC 13476 (IMP), and the like can be used to evaluate metallo-β-lactamase inhibitory activity of test compounds.

Test Example 3

[3147] Evaluation of minimum inhibitory concentration (MIC) of MEPM against β-lactamase producing bacteria

[3148] To evaluate the β-lactamase inhibitory activity of test compounds, the effect of combination of a test compound and a β-lactam agent against β-lactamase producing bacteria was evaluated. Meropenem (MEPM) was used as a β-lactam antimicrobial agent. The minimum inhibitory concentration (MIC) of MEPM against β-lactamase producing bacteria when a test compound was added at a fixed concentration (4 μg/mL) was measured by broth microdilution method (common ratio: 2).

[3149] The numerical value of (MIC of MEPM in combination with a test compound)/(MIC of MEPM alone) are shown below (“-” represents untested cases).

TABLE-US-00053 TABLE 5 E. coli K. pneumoniae K. pneumoniae Example ATCC BAA-2340 ATCC BAA-2344 ATCC BAA-2524 number (KPC) (KPC) (OXA-48) 1 0.031/8 0.063/32 0.063/1 2 0.031/8 0.031/32 0.063/1 3 0.031/8 0.063/32 0.063/1 4 0.016/4 0.031/32 0.031/2 5 0.125/8 2/32 0.125/1 6 0.031/4 0.125/32 0.063/1 7 0.031/4 0.031/32 0.063/1 8 0.031/8 0.063/32 0.063/2 9 0.016/4 0.063/32 0.031/2 10 0.031/4 0.063/32 0.063/2 11 0.063/4 2/32 0.063/1 12 0.031/4 0.063/32 0.063/1 13 0.031/8 0.063/32 0.063/2 14 0.031/8 0.125/32 0.063/2 15 0.031/8 0.063/32 0.063/1 16 0.031/8 0.0125/32 0.063/1 17 0.031/8 2/32 0.063/1 18 0.016/8 0.031/32 0.063/2 19 0.16/8 0.031/32 0.063/2 20 0.031/8 2/32 0.063/1 21 0.125/8 2/32 0.125/1 22 0.016/8 0.031/32 0.063/2 23 — 0.063/32 0.063/2 24 0.016/8 0.5/32 0.063/2 25 0.016/8 0.063/32 0.063/2 26 0.16/8 0.063/32 0.031/2 27 — 0.063/32 0.063/2 28 0.016/8 0.031/32 0.063/2 29 — 0.063/32 0.063/2 30 — 0.125/32 0.125/2 31 — 0.063/32 0.063/2 32 — 0.063/32 0.063/2 33 — ≤0.063/32 ≤0.063/1 34 — 0.063/32 0.063/2 35 0.031/4 0.063/32 0.063/1 36 — ≤0.063/16 ≤0.063/1 37 — ≤0.031/16 ≤0.031/1 38 — ≤0.063/16 ≤0.063/2 39 — 1/16 ≤0.063/2 40 — ≤0.063/16 ≤0.063/1 41 — ≤0.063/16 ≤0.063/1 42 — ≤0.063/16 ≤0.063/2 43 — ≤0.063/16 ≤0.063/1 44 — ≤0.063/16 ≤0.063/1 45 — ≤0.063/16 ≤0.063/2 46 — ≤0.063/16 ≤0.063/2 47 — ≤0.063/16 ≤0.063/2 48 — ≤0.063/16 ≤0.063/2 49 — ≤0.063/16 ≤0.063/2 50 — ≤0.063/16 ≤0.063/1 51 — ≤0.063/32 ≤0.063/2 52 — ≤0.063/16 ≤0.063/1 53 — 0.25/16 ≤0.063/1 54 — 0.25/16 ≤0.063/2 55 — ≤0.031/32 ≤0.031/1 56 — 0.25/16 ≤0.031/1 57 — ≤0.063/16 ≤0.063/1 58 — ≤0.063/16 ≤0.063/2 59 — ≤0.063/32 ≤0.063/2 60 — 0.125/32 ≤0.063/2 61 — ≤0.063/16 ≤0.063/2 62 — ≤0.063/16 0.063/2≤ 63 — ≤0.063/16 ≤0.063/2 64 — ≤0.063/16 ≤0.063/2 65 — ≤0.063/16 ≤0.063/2 66 — ≤0.063/16 ≤0.063/2 67 — ≤0.063/16 ≤0.063/2 68 — ≤0.063/16 ≤0.063/1 69 — ≤0.063/16 ≤0.063/1 70 — ≤0.063/16 ≤0.063/2 71 — ≤0.063/16 ≤0.063/1 72 — ≤0.063/16 ≤0.063/1 73 — ≤0.063/16 ≤0.063/2 74 — 0.25/32 0.125/1 75 — 1/32 ≤0.063/1 76 — 4/32 0.25/1 77 — ≤0.063/16 ≤0.063/2 78 — ≤0.063/16 ≤0.063/1 79 — ≤0.063/16 ≤0.063/1 80 — ≤0.063/16 ≤0.063/1 81 — ≤0.063/16 ≤0.063/1 82 — ≤0.063/16 ≤0.063/1 83 — ≤0.063/32 ≤0.063/2 84 — ≤0.063/32 ≤0.063/2 85 — ≤0.063/32 ≤0.063/2 86 — ≤0.063/32 ≤0.063/2 87 — ≤0.063/18 ≤0.063/1 88 — ≤0.063/32 ≤0.063/2 89 — ≤0.063/16 ≤0.063/1 90 — ≤0.063/16 ≤0.063/1 91 — ≤0.063/16 ≤0.063/1 92 — ≤0.063/16 ≤0.063/2 93 — ≤0.063/16 ≤0.063/2 94 — ≤0.063/16 ≤0.063/1 95 — ≤0.063/16 ≤0.063/1 96 — ≤0.063/16 ≤0.063/1 97 — ≤0.063/16 ≤0.063/2 98 — ≤0.063/16 ≤0.063/2 99 — ≤0.063/16 ≤0.063/2 100 — ≤0.063/16 ≤0.063/2 101 — ≤0.063/16 ≤0.063/2 102 — ≤0.063/16 ≤0.063/2 103 — ≤0.063/16 ≤0.063/2 104 — ≤0.063/32 ≤0.063/2 105 — ≤0.063/32 ≤0.063/2 106 — ≤0.063/16 ≤0.063/2 107 — ≤0.063/16 ≤0.063/2 108 — ≤0.063/16 ≤0.063/2 109 — ≤0.063/16 ≤0.063/2 110 — ≤0.063/16 ≤0.063/2 111 — ≤0.063/16 ≤0.063/2 112 — ≤0.063/16 ≤0.063/2 113 — ≤0.063/16 ≤0.063/2 114 — ≤0.063/16 ≤0.063/2 115 — ≤0.063/16 ≤0.063/2 116 — ≤0.063/16 ≤0.063/2 117 — ≤0.063/16 ≤0.063/2 118 — ≤0.063/16 ≤0.063/2 119 — 0.125/16 ≤0.063/1 120 — ≤0.063/16 ≤0.063/1 121 — ≤0.063/16 ≤0.063/2 122 — ≤0.063/16 ≤0.063/2 123 — ≤0.063/32 ≤0.063/2 124 — ≤0.063/16 ≤0.063/2 125 — ≤0.063/16 ≤0.063/2 126 — ≤0.063/16 ≤0.063/2 127 — ≤0.063/16 ≤0.063/2 128 — ≤0.063/16 ≤0.063/1 129 — ≤0.063/16 ≤0.063/1 130 — ≤0.063/16 ≤0.063/1 131 — ≤0.063/16 ≤0.063/1 132 — ≤0.063/16 ≤0.063/1 133 — ≤0.063/16 ≤0.063/1 134 — ≤0.063/16 ≤0.063/1 135 — ≤0.063/16 ≤0.063/1 136 — ≤0.063/16 ≤0.063/1 137 — ≤0.063/16 ≤0.063/2 138 — ≤0.063/16 ≤0.063/2 139 — ≤0.063/16 ≤0.063/2 140 — ≤0.063/64 ≤0.063/2 141 — ≤0.063/64 ≤0.063/2 142 — ≤0.063/64 ≤0.063/2 143 — ≤0.063/64 ≤0.063/2 144 — ≤0.063/64 ≤0.063/2 145 — ≤0.063/64 ≤0.063/2 146 — ≤0.063/64 ≤0.063/2 147 — ≤0.063/64 ≤0.063/2 148 — ≤0.063/64 ≤0.063/2 149 — 0.125/64 ≤0.063/2 150 — ≤0.063/64 ≤0.063/2 151 — ≤0.063/64 ≤0.063/2 152 — ≤0.063/64 ≤0.063/2

[3150] As disclosed above, the present invention is exemplified by the use of its preferred embodiments. However, it is understood that the scope of the present invention should be interpreted based solely on the Claims. It is also understood that any patent, any patent application, and any other references cited herein should be incorporated herein by reference in the same manner as the contents are specifically described herein.

INDUSTRIAL APPLICABILITY

[3151] The compound of the invention exhibits a potent inhibitory action against β-lactamase and is useful as a therapeutic agent and/or prophylactic agent for sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, or the like, urinary tract infection, genital infection, eye infection, or odontogenic infection.

OXO-SUBSTITUTED COMPOUND

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C07F5/025

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A61K31/407

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A61K31/69

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A61K2300/00

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A61P11/02

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A61P27/02

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A61P1/16

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C07F5/02

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