Boric acid compounds

Abstract

The present application relates to a compound represented by formula 1, a pharmaceutically acceptable salt thereof or an isomer thereof, and a pharmaceutical composition comprising the same as an active ingredient and for treating or preventing a proteasome-mediated disease.

Description

Technical Field

[0001] This application claims priority based on Korean Patent Application No. 10-2020-0171958, filed on December 10, 2020, the entire disclosure of which is incorporated herein by reference.

[0002] This invention relates to boric acid compounds. Background Technology

[0003] The proteasome is part of an intracellular mechanism and plays a vital role in cell function and growth by degrading damaged or unwanted proteins through the pervasive protein-proteasome pathway. Proteasome inhibitors inhibit the proteasome, thereby inducing the excessive accumulation of abnormal proteins in cancer cells and inducing apoptosis in cancer cells.

[0004] Cancer cells are more sensitive to proteasome inhibitors than normal cells. Therefore, by inhibiting the hydrolytic activity of the proteasome, anti-cancer effects can be expected. Specifically, proteasome inhibitors selectively bind to and inhibit chymotrypsin-like activity within the proteasome, exceeding caspase-like activity, to reduce side effects and effectively treat cancer.

[0005] The anticancer effects of this proteasome inhibitor have been demonstrated in hematologic malignancies, and Velcade is marketed as a drug utilizing a proteasome inhibitor. However, side effects, such as drug resistance, have also been reported. Therefore, research continues on combination therapies using this drug and epidermal growth factor receptor (EGFR) kinase inhibitors (Korean Patent Publication No. 10-2007-0083719), and marker compositions for diagnosing resistance to this drug (Korean Patent Registration No. 10-1471274). However, there remains a need to develop alternative substances with fewer side effects.

[0006] As a proteasome inhibitor, carfilzomib selectively binds to chymotrypsin-like activity within the proteasome, exceeding caspase-like activity. However, its irreversible binding limits its practicality.

[0007] Therefore, the inventors continued to study compounds that selectively and reversibly bind to and inhibit chymotrypsin-like activity, and confirmed that a new class of boric acid compounds selectively and reversibly bind to chymotrypsin-like activity, thus completing this invention.

[0008] [Existing Technical Documents]

[0009] [Patent Literature]

[0010] (Patent Document 1) Korean Patent Publication No. 10-2007-0083719 (August 24, 2007)

[0011] (Patent Document 2) Korean Patent Registration No. 10-1471274 (December 3, 2014) Summary of the Invention

[0012] Technical issues

[0013] The purpose of this invention is to provide a compound that can selectively and reversibly bind to and inhibit chymotrypsin-like activity within the proteasome.

[0014] Technical solutions

[0015] One aspect of the present invention provides a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof:

[0016] [Formula 1]

[0017]

[0018] In the above formula,

[0019] R1 represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, or fused bicyclic;

[0020] R2 indicates hydrogen or alkyl;

[0021] R3 represents hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R2 and R3 can combine with each other to form a 3 to 6-membered aliphatic ring, wherein L2 is absent;

[0022] R4 indicates alkyl, cycloalkyl, or aryl;

[0023] L 1a (CH2) l (where l is an integer from 0 to 3) or C(CH2CH2);

[0024] L 1b It represents a direct bond, or indicates (C=O)NH, NH(C=O), NH, (CH2). m O (where m is an integer from 0 to 3), (C=O)N(CH3) or S(O2)NH;

[0025] L 1c (CH2) n (where n is an integer from 0 to 3), CHR5 or CR6R7, wherein R5, R6 and R7 are each independently a C1-C4 heteroalkyl or C1-C4 alkyl having 1 to 3 heteroatoms selected from O, N and S;

[0026] L2 represents (CH2) o (where o is an integer from 0 to 3), (CH2)p O (where p is an integer from 1 to 3), CHR8, CX1X2 or C(CH2CH2), wherein R8 is OH, a halogen or a C1-C3 alkyl group, and X1 and X2 are each independently a halogen;

[0027] L3 represents (CH2) q (where q is an integer from 0 to 3) or CHR9, where R9 is a C1-C3 alkyl group; and

[0028] Z1 and Z2 are each independently OH or OR. 10 R 10 Indicates alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, or OR in Z1 and Z2. 10 In the case of the two Rs 10 They can be combined to form C2-C20 cyclic borate esters having saturated, unsaturated, or optionally fused bicyclic rings, wherein the cyclic borate esters may be substituted with hydroxyl, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, aryloxy, or heteroaryl or heterocyclic alkyl containing one or two heteroatoms selected from N, O, and S atoms in the ring.

[0029] Another aspect of the present invention provides a pharmaceutical composition for inhibiting chymotrypsin-like activity in proteases, the composition comprising a compound of formula 1, a pharmaceutically acceptable salt thereof or an isomer thereof, and a pharmaceutically acceptable carrier.

[0030] Beneficial effects

[0031] The boric acid compounds of the present invention can selectively and reversibly bind to and inhibit chymotrypsin-like activity in the proteasome, exceeding caspase-like activity.

[0032] Because the boric acid compounds of the present invention exhibit excellent selectivity for the proteasomes in the targeted cancer cells, serious side effects can be minimized. Furthermore, since the boric acid compounds of the present invention are reversibly bound and subsequently dissociated, proteasome function can be restored. In this respect, they offer advantages in terms of high development potential and utilization. Detailed Implementation

[0033] The invention will be described in more detail below to aid in understanding. The terms or words used in the specification and claims should not be construed as limited to their ordinary or dictionary meanings, and should be interpreted as having meanings and concepts consistent with the technical spirit of the invention, based on the principle that the inventors can appropriately define the concepts of the terms in order to best interpret their invention.

[0034] In the definition of substituents in compounds of Formula 1 according to the invention, the term "alkyl" means an aliphatic hydrocarbon group. An alkyl group can be a "saturated alkyl" excluding an alkenyl or ynyl moiety or an "unsaturated alkyl" including at least one alkenyl or ynyl moiety. "Alkenyl" means a group including at least one carbon-carbon double bond, and "ynyl" means a group including at least one carbon-carbon triple bond. Alkyl groups can be branched or straight-chain.

[0035] Unless otherwise defined, an alkyl group can have 1 to 20 carbon atoms. An alkyl group can be of medium size and have 1 to 10 carbon atoms. An alkyl group can be a lower alkyl group and have 1 to 6 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, propenyl, butenyl, etc. For example, C1-C4 alkyl groups have 1 to 4 carbon atoms in their alkyl chain and are selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0036] Unless otherwise defined, the term "alkoxy" means an alkoxy group having 1 to 10 carbon atoms.

[0037] Unless otherwise defined, the term "cycloalkyl" refers to a saturated aliphatic 3- to 10-membered ring. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0038] The term "aryl" includes at least one ring having a covalent π-electron system and includes, for example, monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent carbon atom pairs) groups. That is, unless otherwise defined, aryl means 4 to 10-membered, preferably 6 to 10-membered aromatic monocyclic or polycyclic, including phenyl, naphthyl, etc.

[0039] Unless otherwise defined, the term "heteroaryl" means an aromatic 3- to 10-membered ring, preferably 4- to 8-membered, more preferably 5- to 6-membered ring, comprising 1 to 3 heteroatoms selected from N, O, and S, and capable of fusion with benzo[a] or C3-C8 cycloalkyl groups. Examples of monocyclic heteroaryl groups include thiazoles, azole, thiophene, furan, pyrrole, imidazole, isopropylamine azole, isothiazole, pyrazole, triazole, triazine, thiadiazole, tetraazole Diazoles, pyridines, pyridazines, pyrimidines, pyrazines, and similar groups, but not limited thereto. Examples of bicyclic heteroaryl groups include indole, indoline, benzothiophene, benzofuran, benzimidazole, and benzo[…]. azole, benzalkonium chloride Azole, benzothiazole, benzothiadiazole, benzotriazole, quinoline, isoquinoline, purine, puropyridine and similar groups, but not limited thereto.

[0040] Unless otherwise defined, the term "heterocyclic alkyl" means a 3- to 10-membered ring, preferably a 4- to 8-membered ring, more preferably a 5- to 6-membered ring, comprising 1 to 3 heteroatoms selected from N, O, and S, capable of fusion with benzo[a] or C3-C8 cycloalkyl groups, and is saturated or comprises 1 or 2 double bonds. Examples of heterocyclic alkyl groups include, but are not limited to, pyrrolidine, pyrrolidine, imidazoline, imidazoline, pyrazolidine, pyran, piperidine, morpholine, thiomorpholine, piperazine, and hydrofuran.

[0041] The term "fused bicyclic" refers to a ring in which two rings are fused, and includes bridging bicyclics, fused bicyclics, and spirocyclics. Fused bicyclic can also be used to encompass all fused bicyclic alkyl, fused bicyclic aryl, and fused bicyclic heteroaryl groups, where the definitions above apply to alkyl, aryl, and heteroaryl groups. Specifically, a fused bicyclic can be a fused bicyclic ring in which a substituted or unsubstituted 4- to 8-membered aliphatic ring or a 5- to 6-membered aromatic ring having 0 to 4 heteroatoms selected from O, N, and S is fused to a substituted or unsubstituted 4- to 8-membered aliphatic ring or a 5- to 6-membered aromatic ring having 0 to 4 heteroatoms selected from O, N, and S.

[0042] The term "direct bond" refers to the absence of functional groups, such as hydrocarbons, in the corresponding substituents, and can represent -(CH2). k - where k can be 0.

[0043] The term "halogen" refers to one or more of the elements selected from F, Cl, Br, and I.

[0044] In this invention, the wave " "or small angle brackets" "Used to indicate the stereochemical relationship between substituents bonded to the carbon or nitrogen atoms that form a double bond, including both E- and Z-isomers. Specifically," "This can refer to the bond between nitrogen and OH groups that form a double bond with carbon, including both E- and Z- isomers."

[0045] Unless otherwise defined, other terms and abbreviations used herein may be interpreted as having the meaning commonly understood by one of ordinary skill in the art to which this invention pertains.

[0046] One aspect of the present invention provides a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof:

[0047] [Formula 1]

[0048]

[0049] In the above formula,

[0050] R1 represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, or fused bicyclic;

[0051] R2 indicates hydrogen or alkyl;

[0052] R3 represents hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R2 and R3 can combine with each other to form a 3 to 6-membered aliphatic ring, wherein L2 is absent;

[0053] R4 indicates alkyl, cycloalkyl, or aryl;

[0054] L 1a (CH2) l (where l is an integer from 0 to 3) or C(CH2CH2);

[0055] L 1b It represents a direct bond, or it can represent (C=O)NH, NH(C=O), NH, (CH2). m O (where m is an integer from 0 to 3), (C=O)N(CH3) or S(O2)NH;

[0056] L 1c (CH2) n (where n is an integer from 0 to 3), CHR5 or CR6R7, wherein R5, R6 and R7 are each independently a C1-C4 heteroalkyl or C1-C4 alkyl having 1 to 3 heteroatoms selected from O, N and S;

[0057] L2 represents (CH2) o (where o is an integer from 0 to 3), (CH2) p O (where p is an integer from 1 to 3), CHR8, CX1X2 or C(CH2CH2), wherein R8 is OH, a halogen or a C1-C3 alkyl group, and X1 and X2 are each independently a halogen;

[0058] L3 represents (CH2) q (where q is an integer from 0 to 3) or CHR9, where R9 is a C1-C3 alkyl group; and

[0059] Z1 and Z2 are each independently OH or OR. 10 R 10 Indicates alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, or OR in Z1 and Z2. 10 In the case of the two Rs 10 They can be combined to form saturated, unsaturated, or optionally fused bicyclic C2-C20 cyclic borate esters, wherein the cyclic borate ester can be hydroxyl, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, aryloxy, or heteroaryl or heterocyclic alkyl containing one or two heteroatoms selected from N, O, and S atoms in the ring.

[0060] In one embodiment, R1 represents a C1-C6 alkyl, a C3-C6 cycloalkyl, a phenyl, a 5- to 6-membered heteroaryl or heterocycloalkyl containing one or two heteroatoms selected from N, O and S atoms, a fused bicycloalkyl, a fused bicycloaryl, or a fused bicycloaryl containing one to four heteroatoms selected from N, O and S atoms.

[0061] R2 represents hydrogen or C1-C6 alkyl;

[0062] R3 represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, or a 5- to 6-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S atoms, or R2 and R3 can combine with each other to form a 3- to 6-membered aliphatic ring, wherein L2 is absent;

[0063] R4 represents C1-C6 alkyl, C3-C6 cycloalkyl, or phenyl;

[0064] L 1a (CH2) l (where l is an integer from 0 to 3) or C(CH2CH2);

[0065] L 1b It represents a direct bond, or it can represent (C=O)NH, NH(C=O), NH, (CH2). m O (where m is an integer from 0 to 3), (C=O)N(CH3) or S(O2)NH;

[0066] L 1c (CH2) n (where n is an integer from 0 to 3), CHR5 or CR6R7, where R5 represents a C1-C4 heteroalkyl or C1-C4 alkyl having 1 to 3 heteroatoms selected from O, N and S, and R6 and R7 are each independently C1-C4 alkyl;

[0067] L2 represents (CH2) o (where o is an integer from 0 to 3), (CH2) p O (where p is an integer from 1 to 3), CHR8, CX1X2 or C(CH2CH2), wherein R8 is OH, a halogen or a C1-C3 alkyl group, and X1 and X2 are each independently a halogen;

[0068] L3 represents (CH2) q (where q is an integer from 0 to 3) or CHR9, where R9 is a C1-C3 alkyl group; and

[0069] Z1 and Z2 are each independently OH, or they can together form a cyclic borate ester with the following structure:

[0070]

[0071] Where r is 0 or 1, and R 11 and R 16 Each of these elements is independently hydrogen, hydroxyl, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, aryloxy, or a heteroaryl or heterocycloalkyl group containing one or two heteroatoms selected from N, O, and S atoms in the ring.

[0072] R 13 and R 15 It can be hydrogen, and R 14 and R 16 They can be combined to form substituted or unsubstituted cycloalkyl groups, or

[0073] R 13 and R 15 It can be non-existent, and R 14 and R 16 They can combine to form substituted or unsubstituted aryl groups, or

[0074] R 11 and R 12 Or R 13 and R 14 Or R 15 and R 16 They can be combined to form substituted or unsubstituted cycloalkyl groups.

[0075] In one embodiment, R1 may represent a phenyl group, a 5- to 6-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S atoms, a fused bicyclic aryl group, or a fused bicyclic heteroaryl group.

[0076] R1 may be substituted by one or more substituents selected from the following: halogen, amine, nitro, nitrile, acetonitrile, ether, haloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 heteroalkyl having one or two heteroatoms selected from N, O, and S atoms, C1-C6 alkoxy, phenyl, phenoxy, 5- to 6-membered heteroaryl or heterocycloalkyl containing one or two heteroatoms selected from N, O, and S atoms, or 5- to 6-membered heteroaryloxy or heterocycloalkoxy containing one or two heteroatoms selected from N, O, and S atoms, and R 12 (C=O)NH,R 12 It is hydrogen or C1-C3 alkyl, and the substituent may be replaced by one or more substituents selected from halogen, C1-C3 alkyl and C1-C3 alkoxy.

[0077] In one implementation, R2 may represent hydrogen.

[0078] In one embodiment, R3 may represent hydrogen, C1-C3 alkyl, or phenyl.

[0079] R3 can be substituted with halogen, methyl halide, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl or C1-C3 alkoxy, and the substituent can be further substituted with halogen.

[0080] In one embodiment, R4 may represent C1-C6 alkyl, C3-C6 cycloalkyl, or phenyl.

[0081] In one implementation, L 1a It can represent (CH2) l (where l is an integer from 0 to 3) or C(CH2CH2).

[0082] In one implementation, L 1b It can be a direct bond, or it can represent (C=O)NH, NH(C=O), NH, (CH2). m O (where m is an integer from 0 to 3), (C=O)N(CH3) or S(O2)NH.

[0083] In one implementation, L 1c (CH2) n (where n is an integer from 0 to 3), CHR5 or CR6R7, wherein R5 can be a C1-C3 heteroalkyl or C1-C4 alkyl having one or two heteroatoms selected from O, N and S, and R6 and R7 can each be a C1-C3 alkyl independently.

[0084] In one implementation, L2 represents (CH2). o (where o is an integer from 0 to 3), (CH2) p O (where p is an integer from 1 to 3), CHR8, CX1X2 or C(CH2CH2), wherein R8 can be OH, halogen or C1-C3 alkyl, and X1 and X2 can each be halogen independently.

[0085] In one implementation, L3 represents (CH2). q (where q is an integer from 0 to 3) or CHR9, where R9 can be a C1-C3 alkyl group.

[0086] In one embodiment, Z1 and Z2 may each be OH independently, or they may together form a cyclic borate ester having the following structure:

[0087]

[0088] Where r is 0 or 1, R 11 To R 16Each of the following is independently hydrogen, hydroxyl, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C5-C6 aryl, C5-C6 aryloxy, or a heteroaryl or heterocyclic alkyl containing one or two heteroatoms selected from N, O, and S atoms in the ring, wherein the substituent can be hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C5-C6 aryl, or C5-C6 aryloxy.

[0089] R 13 and R 15 It can be hydrogen, and R 14 and R 16 They can be combined to form substituted or unsubstituted 4- to 8-membered cycloalkyl groups, wherein the substituents can be hydroxyl, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C5-C6 aryl, or C5-C6 aryloxy.

[0090] R 13 and R 15 It can be non-existent, and R 14 and R 16 They can be combined to form substituted or unsubstituted 5- to 6-membered aryl groups, wherein the substituents can be hydroxyl, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C5-C6 aryl, or C5-C6 aryloxy.

[0091] R 11 and R 12 Or R 13 and R 14 Or R 15 and R 16 They can be combined to form substituted or unsubstituted 4- to 8-membered cycloalkyl groups, wherein the substituents can be hydroxyl, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C5-C6 aryl, or C5-C6 aryloxy.

[0092] In a preferred embodiment, R1 can be selected from:

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101] In addition, R2 can represent hydrogen.

[0102] In addition, R3 can represent hydrogen, C1-C3 alkyl or phenyl, and can be substituted with halogen, C1-C3 alkyl or C1-C3 alkoxy.

[0103] In addition, R4 can represent a C1-C6 branched alkyl group or a C3-C6 cycloalkyl group.

[0104] In one implementation, L 1a It can represent (CH2) l (where l is an integer from 0 to 3) or C(CH2CH2).

[0105] In one implementation, L 1b It can be a direct bond, or it can represent (C=O)NH, NH(C=O), NH, (CH2). m O (where m is an integer from 0 to 3), (C=O)N(CH3) or S(O2)NH.

[0106] In one implementation, L 1c It can represent (CH2) n (where n is an integer from 0 to 3) or CHR5, where R5 can be a C1-C3 heteroalkyl or C1-C4 alkyl having one or two heteroatoms selected from O, N and S.

[0107] In one implementation, L2 represents (CH2). o (where o is an integer from 0 to 3), (CH2) p O (where p is an integer from 1 to 3), CHR8, CX1X2 or C(CH2CH2), where R8 is OH, a halogen or a C1-C3 alkyl group, and X1 and X2 can each be a halogen independently.

[0108] In one implementation, L3 can represent (CH2). q (where q is an integer from 0 to 3).

[0109] For example, Z1 and Z2 can each be OH independently, or they can together form cyclic borate esters, including one or more selected from the following structures:

[0110]

[0111] In one implementation, Z1 and Z2 can each be OH.

[0112] On one hand, the present invention provides a compound represented by Formula 2, a pharmaceutically acceptable salt thereof, or an isomer thereof:

[0113] [Equation 2]

[0114]

[0115] In the above equation, the same definition of R1 can be independently applied to R. 1a R 1b and R 1c ,

[0116] The same definition of R² described above can be applied independently to R. 2a R 2b and R 2c ,

[0117] The same definition of R3 described above can be applied independently to R. 3a R 3b and R 3c ,

[0118] The same definition of R4 described above can be applied independently to R. 4a R 4b and R 4c ,

[0119] The above refers to L 1a The same definition can be applied independently to L. 1a1 L 1a2 and L 1a3 ,

[0120] The above refers to L 1b The same definition can be applied independently to L. 1b1 L 1b2 and L 1b3 ,

[0121] The above refers to L 1c The same definition can be applied independently to L. 1c1 L 1c2 and L 1c3 ,

[0122] The same definition of L2 described above can be applied independently to L. 2a L 2b and L 2c ,and

[0123] The same definition of L3 described above can be applied independently to L. 3a L 3b and L 3c .

[0124] According to the invention, the compound of formula 1, its pharmaceutically acceptable salt or its isomer inhibits chymotrypsin-like activity in the protease body.

[0125] The present invention provides a compound, a pharmaceutically acceptable salt thereof, or an isomer thereof, which can be used as an inhibitor of chymotrypsin-like activity in proteasomes.

[0126] This invention provides a compound, a pharmaceutically acceptable salt thereof, or an isomer thereof, for the prevention or treatment of proteasome-mediated diseases.

[0127] Compounds of Formula 1 according to the invention, pharmaceutically acceptable salts thereof, or isomers thereof are suitable for the prevention or treatment of proteasome-mediated diseases.

[0128] The present invention provides a pharmaceutical composition for inhibiting chymotrypsin-like activity in proteases, the composition comprising a compound of formula 1, a pharmaceutically acceptable salt thereof or an isomer thereof, and a pharmaceutically acceptable carrier.

[0129] Furthermore, various types of prodrugs that are converted into compounds of Formula 1 according to their intended purpose in vivo are also included within the scope of this invention.

[0130] The pharmaceutical compositions according to the present invention can be used for the prevention or treatment of proteasome-mediated diseases. These proteasome-mediated diseases can be, but are not limited to, cancer.

[0131] The cancer may be selected from brain tumors, benign astrocytomas, malignant astrocytomas, pituitary adenomas, intracranial meningiomas, brain lymphomas, oligodendrogliomas, craniopharyngiomas, ependymomas, brainstem tumors, head and neck tumors, laryngeal cancer, oropharyngeal cancer, nasal / sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, neuroblastoma, thoracic tumors, small cell lung cancer, non-small cell lung cancer, thymic carcinoma, mediastinal tumors, esophageal cancer, breast cancer, male breast cancer, abdominal tumors, gastric cancer, liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, small bowel cancer, colorectal cancer, anal cancer, bladder cancer, kidney cancer, male reproductive system tumors, penile cancer, urethral cancer, prostate cancer, female reproductive system tumors, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female external genital cancer, female urethral cancer, skin cancer, myeloma, leukemia, lymphoma, and malignant lymphoma, and preferably multiple myeloma.

[0132] Furthermore, the present invention provides the use of compounds of Formula 1, pharmaceutically acceptable salts thereof, or isomers thereof, for the preparation of medicaments for treating proteasome-mediated diseases. The proteasome-mediated diseases may be cancer, and specific examples are the same as described above.

[0133] Furthermore, the "pharmaceutical composition" may comprise the compounds of the present invention and other chemical components such as diluents, carriers, etc. Therefore, the pharmaceutical composition may, where necessary, comprise pharmaceutically acceptable carriers, diluents, excipients, or combinations thereof. The pharmaceutical composition facilitates the administration of the compound to a living organism. Various methods exist for administering the compound, including but not limited to oral, injection, aerosol, parenteral, and topical administration.

[0134] The term "carrier" refers to a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a common carrier that facilitates the introduction of many organic compounds into the cells or tissues of an organism.

[0135] The term "diluent" is defined as a compound that not only stabilizes the biologically active form of the compound of interest but also dilutes it in water in which the compound is dissolved. In this art, salts dissolved in buffer solutions are used as diluents. Commonly used buffer solutions are phosphate-buffered saline solutions that mimic the salt form of human bodily fluids. Because buffer solutions allow for pH control at low concentrations, buffer diluents hardly alter the biological activity of the compound.

[0136] The term "pharmaceutically acceptable" means that the properties of a compound do not impair its biological activity and physical properties.

[0137] Depending on the purpose, the compounds according to the invention can be formulated into various pharmaceutical dosage forms. To prepare the pharmaceutical compositions according to the invention, the active ingredient, particularly a compound of formula 1, its pharmaceutically acceptable salt or isomer thereof, is mixed with various pharmaceutically acceptable carriers, which can be selected according to the formulation to be prepared. For example, depending on the purpose, the pharmaceutical compositions according to the invention can be formulated into injectable formulations, oral formulations, etc.

[0138] The compounds of the present invention can be formulated using known methods, using known pharmaceutical carriers and excipients, and inserted into unit dosage forms or multi-dosage containers. The formulation can be a solution, suspension, or emulsion in an oily or aqueous medium and contains conventional dispersants, suspending agents, or stabilizers. Furthermore, the formulation can be, for example, in dry powder form, which is used by dissolving in sterile, pyrogen-free water before use. The compounds of the present invention can be formulated into suppositories using conventional suppository bases such as cocoa butter or other glycerides. As solid dosage forms for oral administration, capsules, tablets, pills, powders, and granules can be prepared, with capsules and tablets being particularly useful. Tablets and pills are preferably enteric-coated. Solid dosage forms can be manufactured by mixing the compounds of the present invention with at least one inert diluent (e.g., sucrose, lactose, and starch) and a carrier (e.g., lubricants such as magnesium stearate, disintegrants, binders, etc.). If desired, the compounds according to the present invention or pharmaceutical compositions containing said compounds can be administered in combination with other drugs, such as other diabetes treatments.

[0139] Furthermore, the present invention provides a method for preventing or treating proteasome-mediated diseases, the method comprising administering a compound of Formula 1, a pharmaceutically acceptable salt thereof or an isomer thereof, or a pharmaceutical composition containing the thereof to a subject.

[0140] Subjects may be human subjects or non-human mammal subjects who require treatment or prevention of a proteasome-mediated disease. The proteasome-mediated disease may be cancer.

[0141] In this disclosure, the term "treatment" means stopping, delaying, or improving disease progression in a subject exhibiting disease symptoms. The term "prevention" means stopping, delaying, or improving disease signs in a subject at risk of exhibiting disease symptoms, even if he or she does not exhibit said symptoms.

[0142] The dosage of the compounds of Formula 1 of the present invention, their pharmaceutically acceptable salts, or isomers thereof depends on the physician's prescription and takes into account factors such as the patient's weight and age, the specific nature of the disease, and the severity of the disease. However, the typical dose for adults ranges from about 1 to 500 mg per day, depending on the frequency and intensity of administration. A range of about 1 to 300 mg per day may be sufficient for the typical daily dose for adults administered intramuscularly or intravenously, which can be given in separate unit doses. Higher daily doses may be preferred for some patients.

[0143] The present invention also provides a method for preparing compounds of Formula 1. Hereinafter, the method for preparing compounds of Formula 1 will be explained based on exemplary embodiments to aid in understanding the invention. However, those skilled in the art can prepare compounds of Formula 1 by various methods based on the structure of Formula 1, and such methods should be construed as being within the scope of the invention. That is, compounds of Formula 1 can be prepared by the synthetic methods described herein or by optionally combining various synthetic methods disclosed in the prior art, which should be construed as being within the scope of the invention. The method for preparing compounds of Formula 1 is not limited to the method described below.

[0144] In preparing the compounds of the present invention, the reaction sequence can be appropriately modified. That is, optional processes can be performed first or optional processes can be inserted to change the substituents, and any reagent other than the reagents shown can be used as needed. The compounds obtained in each process can be separated or purified by conventional methods such as recrystallization, distillation, or silica gel column chromatography. Furthermore, the compounds obtained in each process can be used in the next step without further purification or separation.

[0145] In the following schemes, all substituents are as defined above unless otherwise indicated. Reagents and starting materials are readily available commercially. Other reagents and materials can be produced by the synthetic methods described in the preparation examples and embodiments below, including known synthetic methods for structurally similar compounds. Unless otherwise specified, the compounds used as starting materials are known compounds or compounds that can be prepared from known compounds by known synthetic methods or similar methods.

[0146] The invention will be explained in more detail below by way of preparation examples and embodiments. However, the scope of the invention is not limited thereto.

[0147] Example

[0148] Preparation Example 1: 3-(((tert-butoxycarbonyl)amino)methyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0149] The title embodiment is obtained through the following processes (1) and (2).

[0150] (1) Preparation of tert-butyl (2-(hydroxyimino)ethyl)carbamate

[0151]

[0152] (2-Ketoethyl) tert-butyl carbamate (10.7 g, 67.2 mmol) was dissolved in methanol (50 ml), and 50% aqueous hydroxylamine (14.23 ml, 168 mmol) was added to it at room temperature, and the mixture was stirred for 16 hours. The solvent was distilled under reduced pressure to give the title compound (9.8 g, 84%), which was used in the next reaction without purification.

[0153] (2) 3-(((tert-butoxycarbonyl)amino)methyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0154]

[0155] The tert-butyl (2-(hydroxyimino)ethyl)carbamate (1.09 g, 6.26 mmol) obtained in (1) above was dissolved in dichloromethane (40 ml), and ethyl acrylate (0.75 ml, 6.88 mmol) was added to it at room temperature. A 4% aqueous solution of sodium hypochlorite (21 ml, 13.5 mmol) was slowly added to it at 0 °C, and the mixture was stirred for 18 hours while being heated to room temperature. The solvent was distilled under reduced pressure, an aqueous solution of sodium bicarbonate was added, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.67 g, 39%).

[0156] NMR: 1 H-NMR(400MHz, CDCl3); δ 5.04-4.99 (t, 3H), 4.91 (br s, 1H), 4.28-4.22 (q, 2H), 4.09-4.08 (d, 2H), 3.29-3.27 (d, 2H), 1.45 (s, 9H), 1.33-1.26(t, 3H)

[0157] MS (m / z): 273[M+H], 173[M-C5H7O2].

[0158] Preparation Example 2: 3-(((tert-butoxycarbonyl)amino)methyl)-4-methyl-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0159]

[0160] The title compound (0.076 g, 9%) was obtained by the preparation method of Preparation Example 1-(2) using methyl crotonate (0.48 ml, 4.5 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.523 g, 3.00 mmol) obtained in Preparation Example 1-(1).

[0161] NMR: 1 ¹H-NMR (400MHz, CDCl₃); δ 5.33 and 5.10 (¹H, 2 s), 4.63 and 4.55 (¹H, 2d), 4.17–4.02 (³H, m), 3.81 and 3.79 (³H, 2 s), 1.47–1.40 (¹²H, m)

[0162] Preparation Example 3: 3-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0163] The title compound was obtained through the following processes (1), (2) and (3).

[0164] (1) Preparation of (S)-(3-methyl-1-ketobutyl-2-yl)carbamate tert-butyl ester

[0165]

[0166] ((S)-1-hydroxymethyl-2-methyl-propyl)-tert-butyl carbamate (1.5 g, 7.38 g) was dissolved in dimethyl sulfoxide (10 ml), and 2-iodobenzoic acid (4.1 g, 14.76 mmol) was added at 0 °C. After stirring at room temperature for 18 hours, water was added, and the mixture was extracted with diethyl ether. The resulting organic layer was washed with brine, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (1.01 g, 68%).

[0167] NMR: 1 H-NMR(500MHz, CDCl3); δ 9.64 (s, 1H), 5.07 (br s, 1H), 4.24 (m,1H), 2.28-2.27 (m, 1H), 1.44 (s, 9H), 1.03-1.01 (d, 3H), 0.94-0.93 (d, 3H)

[0168] (2) Preparation of (S)-(1-(hydroxyimino)-3-methylbut-2-yl)carbamate tert-butyl ester

[0169]

[0170] The title compound (1.09, 99%) was obtained by the preparation method of Preparation Example 1-(1) using N-[(1S)-1-formyl-2-methyl-propyl] tert-butyl carbamate (1.01 g, 5.04 ml) obtained in (1) above.

[0171] (3) 3-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0172]

[0173] Using N-[(1S)-1-hydroxyiminomethyl-2-methylpropyl] tert-butyl carbamate (0.59 g, 2.73 mmol) and ethyl acrylate (0.36 ml, 3.27 mmol) obtained in (2) above, the title compound (0.72 g, 84%) was obtained by the preparation method of Preparation Examples 1-(2).

[0174] NMR: 1 H-NMR(400MHz, CDCl3); δ 5.02-4.97 (m, 1H), 4.37 (br s, 1H), 4.27-4.22 (m, 2H), 3.26-3.23 (m, 2H), 2.04-2.07 (m, 1H), 1.39 (s, 9H), 1.31-1.28(t, 3H), 1.04-0.91 (m, 6H)

[0175] MS (m / z): 315 [M+H]

[0176] Preparation Example 4: 3-((S)-1-((tert-butoxycarbonyl)amino)-3-methylbutyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0177] The title compound was obtained through the following processes (1) and (2).

[0178] (1) Preparation of (S)-(1-(hydroxyimino)-4-methylpentan-2-yl)carbamate tert-butyl ester

[0179]

[0180] The title compound (0.42 g, 99%) was obtained by the preparation method of Preparation Example 1-(1) using ((S)-1-formyl-3-methyl-butyl)-carbamate tert-butyl ester (0.39 g, 1.84 mmol).

[0181] (2) 3-((S)-1-((tert-butoxycarbonyl)amino)-3-methylbutyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0182]

[0183] Using the N-[(1S)-1-hydroxyiminomethyl-3-methyl-butyl]carbamate tert-butyl ester (0.61 g, 2.65 mmol) and ethyl acrylate (0.35 ml, 3.18 mmol) obtained in (1) above, the title compound (0.3 g, 34%) was obtained by the preparation method of Preparation Examples 1-(2).

[0184] NMR: 1 H-NMR (400MHz, CDCl3); δ 5.01-4.93 (m, 1H), 4.72 (br s, 1H), 4.52 (br s, 1H), 4.03-4.22 (q, 2H), 3.34-3.22 (m, 2H), 1.78-1.53 ​​(m, 3H), 1.32-1.29 (t, 3H), 0.96-0.91 (m, 6H)

[0185] MS (m / z): 329 [M+H]

[0186] Preparation Example 5: 5-(ethoxycarbonyl)-4,5-dihydroisocyano Preparation of azole-3-carboxylic acid

[0187] The title compound was obtained through the following processes (1), (2) and (3).

[0188] (1) Preparation of tert-butyl 2-chloro-2-(hydroxyimino)acetic acid

[0189]

[0190] The title compound was obtained by the method described in WO200633551A1.

[0191] (2) 4,5-Dihydroisocyanate Preparation of 3-(tert-butyl)5-ethyl azole-3,5-dicarboxylic acid

[0192]

[0193] The title compound (1.05 g, 62%) was obtained by the preparation method of Preparation Examples 1-(2) using tert-butyl 2-chloro-2-(hydroxyimino)acetate (1.25 g, 6.96 mmol) obtained in (1) above.

[0194] NMR: 1 H-NMR (400MHz, CDCl3); δ 5.18-5.13 (m, 1H), 4.38-4.24 (q, 2H), 3.52-3.40 (m, 2H), 1.55 (s, 9H), 1.34-1.30 (t, 3H)

[0195] MS (m / z): 244 [M+H]

[0196] (3) 5-(ethoxycarbonyl)-4,5-dihydroisocyano Preparation of azole-3-carboxylic acid

[0197]

[0198] The 4,5-dihydro-1,2- obtained in (2) above 3-tert-butyl-5-ethyl 3,5-dicarboxylic acid (1.05 g, 4.32 mmol) was dissolved in dichloromethane (20 ml). 4 N 1,4-diethyl hydrochloride was slowly added to the solution at 0 °C. An alkane solution (8.6 ml, 34.53 mmol) was prepared and stirred for 5 hours while being heated to room temperature. The solvent was then distilled under reduced pressure, and the mixture was separated by column chromatography to obtain the title compound (0.87 g, 99%).

[0199] MS (m / z): 188 [M+H]

[0200] Preparation Example 6: 5-Benzyl-3-(((tert-butoxycarbonyl)amino)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0201] The title compound was obtained through the following processes (1) and (2).

[0202] (1) Preparation of methyl 2-benzylmethacrylate

[0203]

[0204] 2-Phenylacetic acid (15 g, 92.5 mmol) was dissolved in methanol (100 ml). Thionyl chloride (20.15 ml, 27.75 mmol) was slowly added to the solution at 0 °C, and the mixture was stirred for 16 hours while the temperature was raised to room temperature. The solvent was distilled under reduced pressure, ethyl acetate was added, and the mixture was washed with an aqueous sodium bicarbonate solution. The organic layer was dehydrated on anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and dried under reduced pressure to give the title compound (16.32 g, 99%).

[0205] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.17-7.35 (m,5H), 6.23 (m,1H), 5.47 (m,1H), 3.74 (s,3H), 3.63 (s,2H)

[0206] (2) 5-Benzyl-3-(((tert-butoxycarbonyl)amino)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0207]

[0208] Using methyl 2-benzyl methacrylate (10.77 g, 61.1 mmol) obtained in (1) above and tert-butyl (2-(hydroxyimino)ethyl)carbamate (9.68 g, 55.6 mmol) obtained in Preparation Example 1-(1), a racemic mixture of the title compound (10.87 g, 56%) was obtained by the preparation method of Preparation Example 1-(2). This was achieved using CHIRALTECHNOLOGIES CHIRALPAK ® HPLC using an IA chiral column and ethanol / hexane eluent separated isomer 1, which has a short retention time, and isomer 2, which has a long retention time, and isomer 2 was used for the synthesis of the title compound.

[0209] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.32-7.22 (m, 5H), 4.55 (br s, 1H), 3.89-3.83 (m, 2H), 3.78 (s, 3H), 3.40-3.36 (d, 1H), 3.33-3.29 (d, 1H), 3.13-3.10(d, 1H), 2.98-2.94 (d, 1H), 1.44 (s, 9H)

[0210] MS (m / z): 349[M+H], 249[M-C5H7O2].

[0211] Preparation Example 7: 3-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0212]

[0213] The title compound (0.21 g, 31%) was obtained by the preparation method of Preparation Example 1-(2) using (2-(hydroxyimino)ethyl)carbamate tert-butyl ester (0.41 g, 2.35 mmol) and ethyl 2-methacrylate (0.35 ml, 2.82 mmol) obtained in Preparation Example 1-(1).

[0214] NMR: 1 H-NMR(400MHz, CDCl3); δ 4.91 (br s, 1H), 4.27-4.20 (q, 2H), 4.06-4.005 (d, 2H), 3.53-3.49 (d, 1H), 2.89-2.84 (d, 1H), 1.62 (s, 3H), 1.45 (s,9H), 1.33-1.25 (t, 3H)

[0215] MS (m / z): 287 [M+H]

[0216] Preparation Example 8: 3-(((tert-butoxycarbonyl)amino)methyl)-5-ethyl-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0217]

[0218] The title compound (0.25 g, 34%) was obtained by the preparation method of Preparation Example 1-(2) using (2-(hydroxyimino)ethyl)carbamate tert-butyl ester (0.43 g, 2.47 mmol) and ethyl 2-methylene-butyrate (0.51 g, 2.96 mmol) obtained in Preparation Example 1-(1).

[0219] NMR: 1H-NMR(400MHz, CDCl3); δ 4.89 (br s, 1H), 4.29-4.19 (q, 2H), 4.03(m, 2H), 3.45-3.41 (d, 1H), 2.91-2.87 (d, 1H), 1.96-1.91 (m, 2H), 1.44 (s,9H), 1.31-1.25 (t, 3H), 0.94-0.91 (t, 3H)

[0220] MS (m / z): 301 [M+H]

[0221] Preparation Example 9: 3-(((tert-butoxycarbonyl)amino)methyl)-5-propyl-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0222]

[0223] The title compound (0.27 g, 37%) was obtained by the preparation method of Preparation Example 1-(2) using (2-(hydroxyimino)ethyl)carbamate tert-butyl ester (0.4 g, 2.29 mmol) and ethyl 2-methylene-valerate (0.39 g, 2.75 mmol) obtained in Preparation Example 1-(1).

[0224] NMR: 1 H-NMR(500MHz, CDCl3); δ 4.88 (br s, 1H), 4.24-4.19 (m, 2H), 4.02(m, 2H), 3.45-3.41 (d, 1H), 2.91-2.88 (d, 1H), 1.89-1.87 (m, 2H), 1.44 (s,9H), 1.42-1.39 (m, 2H), 1.31-1.28 (t, 3H), 0.95-0.92 (t, 3H)

[0225] MS (m / z): 315 [M+H]

[0226] Preparation Example 10: 3-(((tert-butoxycarbonyl)amino)methyl)-5-isopropyl-4,5-dihydroisopropyl) Preparation of ethyl 5-oxazolium carboxylate

[0227] The title compound was obtained through the following processes (1) and (2).

[0228] (1) Preparation of ethyl 3-methyl-2-methylenebutyrate

[0229]

[0230] The title compound was obtained by the method described in Tetrahedron Letters, Vol. 24, No. 33, pp3477-3480.

[0231] (2) 3-(((tert-butoxycarbonyl)amino)methyl)-5-isopropyl-4,5-dihydroisopropyl) Preparation of ethyl 5-oxazolium carboxylate

[0232]

[0233] The title compound (0.21 g, 30%) was obtained by the preparation method of Preparation Example 1-(2) using tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.38 g, 2.18 mmol) obtained in Preparation Example 1-(1) and ethyl 3-methyl-2-methylene-butyrate (0.44 g, 2.62 mmol) obtained in (1) above.

[0234] NMR: 1 H-NMR (400MHz, CDCl3); δ 4.90 (br s, 1H), 4.32-4.15 (m, 2H), 4.04-3.99 (m, 2H), 3.43-3.39 (d, 1H), 2.94-2.90 (d, 1H), 2.40-2.30 (m, 1H), 1.46(s, 9H), 1.33-1.29 (t, 3H), 0.97-0.94 (t, 3H), 0.90-0.88 (d, 3H)

[0235] MS (m / z): 315 [M+H]

[0236] Preparation Example 11: 3-(((tert-butoxycarbonyl)amino)methyl)-5-isobutyl-4,5-dihydroisobutyl) Preparation of ethyl 5-oxazolium carboxylate

[0237] The title compound was obtained through processes (1) and (2).

[0238] (1) Preparation of ethyl 4-methyl-2-methylenepentanoate

[0239]

[0240] The title compound was obtained by the method described in Journal of Medicinal Chemistry, 2000, vol. 43, pp. 1398-1408.

[0241] (2) 3-(((tert-butoxycarbonyl)amino)methyl)-5-isobutyl-4,5-dihydroisobutyl) Preparation of ethyl 5-oxazolium carboxylate

[0242]

[0243] The title compound (0.41 g, 32%) was obtained by the preparation method of Preparation Example 1-(2) using tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.67 g, 3.90 mmol) obtained in Preparation Example 1-(1) and ethyl 4-methyl-2-methylenepentanoate (0.67 g, 4.29 mmol) obtained in (1) above.

[0244] NMR: 1 H-NMR (400MHz, CDCl3); δ 4.89 (br s, 1H), 4.27-4.18 (m, 2H), 4.03-4.02 (m, 2H), 3.14-3.43 (d, 1H), 2.92-2.88 (d, 1H), 1.92-1.88 (m, 1H), 1.44(s, 9H), 1.31-1.28 (t, 3H), 0.94-0.90 (dd, 6H)

[0245] MS (m / z): 329 [M+H]

[0246] Preparation Example 12: 5-Benzyl-3-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4,5-dihydroisocyano Preparation of methyl 5-azole carboxylate

[0247] The title compound was obtained through the following processes (1) and (2).

[0248] (1) Preparation of tert-butyl (2-(hydroxyimino)ethyl)(methyl)carbamate

[0249]

[0250] Using tert-butyl methylcarbamate (0.7 g, 3.99 mmol), methyl-(2-keto-ethyl)-tert-butyl carbamate (0.17 g, 25%) was obtained by the preparation method of Preparation Example 3-(1). Using tert-butyl methylcarbamate (0.17 g, 0.98 mmol), the title compound (0.16 g, 99%) was obtained by the preparation method of Preparation Example 1-(1).

[0251] (2) 5-Benzyl-3-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4,5-dihydroisocyano Preparation of methyl 5-azole carboxylate

[0252]

[0253] The title compound (0.24 g, 76%) was obtained by the preparation method of Preparation Example 1-(2) using tert-butyl (2-(hydroxyimino)ethyl)(methyl)carbamate (0.16 g, 0.85 mmol) obtained in (1) above and methyl 2-benzyl methacrylate (0.18 g, 1.02 mmol) obtained in Preparation Example 1-(1).

[0254] NMR: 1 H-NMR (500MHz, CDCl3); δ 7.31-7.23 (m, 5H), 4.10-4.02 (m, 1H), 3.87-3.82 (m, 1H), 3.78 (s, 3H), 3.34-3.31 (d, 2H), 3.09-3.06 (d, 1H), 2.90-2.87 (d, 1H), 2.55-2.47 (d, 3H), 1.43 (s, 9H)

[0255] MS (m / z): 363 [M+H]

[0256] Preparation Example 13: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(3-methoxybenzyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0257] The title compound was obtained through the following processes (1) and (2).

[0258] (1) Preparation of ethyl 2-(3-methoxybenzyl)acrylate

[0259]

[0260] Ethyl (diethoxy-phosphoryl)-ethyl acetate (1.5 g, 6.69 mmol) was dissolved in dichloroformamide (15 ml). Sodium hydride (0.29 g, 7.36 mmol) was slowly added at 0 °C, followed by the addition of 3-methoxybenzyl bromide (0.94 ml, 6.69 mmol) after 30 minutes, and the mixture was stirred at room temperature for 18 hours. After the reaction was complete, water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and then used in the next reaction without further purification.

[0261] The product obtained above (2.3 g, 6.68 mmol) and a 37% aqueous formaldehyde solution (3.4 ml, 42.75 mmol) were dissolved in water (15 ml), and potassium carbonate (2.8 g, 20.04 mmol) dissolved in water (5 ml) were added. After reflux and stirring at 90 °C for 16 hours, water was added, and extraction was performed with diethyl ether. The organic layer was washed with brine and dehydrated on anhydrous magnesium sulfate. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.78 g, 53%, 2 steps).

[0262] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.23-7.19 (m, 1H), 6.80-6.75 (m, 3H), 6.23(s, 1H), 5.47 (s, 1H), 4.21-4.09 (q, 2H), 3.79 (s, 3H), 3.61 (s, 2H), 1.29-1.24 (t, 3H)

[0263] (2) 3-(((tert-butoxycarbonyl)amino)methyl)-5-(3-methoxybenzyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0264]

[0265] The title compound (0.31 g, 44%) was obtained by the preparation method of Preparation Example 1-(2) using ethyl 2-(3-methoxybenzyl)acrylate (0.36 g, 1.63 mmol) obtained in (1) above and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.31 g, 1.80 mmol) obtained in Preparation Example 1-(1).

[0266] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.24-7.18 (m, 1H), 6.92-6.75 (m, 3H), 4.62(br s, 1H), 4.27-4.17 (m, 2H), 3.89 (m, 2H), 3.78 (s, 3H), 3.46-2.94 (m, 4H),1.44 (s, 9H), 1.31-1.26 (t, 3H)

[0267] MS (m / z): 393 [M+H]

[0268] Preparation Example 14: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(4-chlorobenzyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0269] The title compound was obtained through the following processes (1) and (2).

[0270] (1) Preparation of ethyl 2-(4-chlorobenzyl)acrylate

[0271]

[0272] Under nitrogen purging, sodium (0.79 g, 34.34 mmol) was added to ethanol (40 ml). Diethyl malonate (5 g, 31.22 mmol) was slowly added and stirred for 10 minutes, followed by the slow addition of 4-chlorobenzyl chloride (5.03 g, 31.22 mmol) dissolved in ethanol (10 ml). After stirring for 16 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain diethyl 2-(4-chloro-benzyl)-malonate (3.27 g, 37%).

[0273] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.26-7.24 (d, 2H), 7.15-7.13 (d, 2H), 4.22-4.12 (q, 2H), 3.62-3.60 (t, 1H), 3.19-3.17 (d, 2H), 1.23-1.20 (t, 3H)

[0274] Diethyl 2-(4-chloro-phenylmethyl)malonate (3.3 g, 11.48 mmol) was dissolved in ethanol (20 ml). Potassium hydroxide (0.61 g, 10.91 mmol) dissolved in ethanol (10 ml) was slowly added at 0 °C, followed by stirring for 48 hours. After titrating to pH 2 with 1 N hydrochloric acid, water was added, and the resulting product was extracted with ethyl acetate, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain monoethyl 2-(4-chloro-phenylmethyl)malonate (2.10 g, 71%).

[0275] NMR: 1H-NMR(400MHz, CDCl3); δ 7.27-7.26 (d, 2H), 7.15-7.12 (d, 2H), 4.20-4.12(q, 2H), 3.69-3.64 (t, 1H), 3.24-3.16 (dd, 2H), 1.26-1.20 (t, 3H)

[0276] The monoethyl 2-(4-chloro-phenylmethyl)malonate obtained above (2.1 g, 8.19 mmol) was dissolved in pyridine (15 ml). Paraformaldehyde (0.23 g, 7.78 mmol) and piperidine (0.081 ml, 0.82 mmol) were added sequentially, and the mixture was refluxed at 120 °C and stirred for 3 hours. Water was added, and the mixture was extracted with hexane. The organic layer was then washed sequentially with water, 1 N hydrochloric acid, water, an aqueous sodium carbonate solution, and brine, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (1.29 g, 70%).

[0277] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.27-7.26 (d, 2H), 7.14-7.12 (d, 2H), 6.24(s, 1H), 5.47 (s, 1H), 4.20-4.15 (q, 2H), 3.59 (s, 2H), 1.28-1.24 (t, 3H)

[0278] (2) 3-(((tert-butoxycarbonyl)amino)methyl)-5-(4-chlorobenzyl)-4,5-dihydroisocyano Preparation of ethyl 5-oxazolium carboxylate

[0279]

[0280] The title compound (0.17 g, 19%) was obtained by the preparation method of Preparation Example 1-(2) using ethyl 2-(4-chlorobenzyl)acrylate (0.57 g, 2.53 mmol) obtained in (1) above and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.4 g, 2.30 mmol) obtained in Preparation Example 1-(1).

[0281] MS (m / z): 397 [M+H]

[0282] Preparation Example 15: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(2-chlorobenzyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0283]

[0284] Ethyl 2-(2-chlorobenzyl)acrylate was obtained by the method described in WO2006134485A1. The title compound (0.4 g, 38%) was obtained by the preparation method of Preparation Example 1-(2) using tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.31 g, 1.76 mmol) and ethyl 2-(2-chlorobenzyl)acrylate (0.36 g, 1.6 mmol) obtained in Preparation Example 1-(1).

[0285] MS (m / z): 397 [M+H]

[0286] Preparation Example 16: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(3-chlorobenzyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0287]

[0288] Ethyl 2-(3-chlorobenzyl)acrylate (0.96 g, 48%, 2 steps) was obtained using the preparation method of Preparation Example 13-(1) with 1.17 ml (8.92 mmol) of 3-chlorobenzyl bromide. The title compound (0.4 g, 38%) was obtained using the preparation method of Preparation Example 1-(2) with 0.47 g (2.67 mmol) of tert-butyl (2-(hydroxyimino)ethyl)carbamate obtained in Preparation Example 1-(1).

[0289] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.25-7.14 (m, 5H), 4.68 (br s, 1H), 4.27-4.16 (q, 2H), 3.93-3.92 (d, 2H), 3.43-3.38 (d, 1H), 3.29-3.26 (d, 1H), 3.12-3.09 (d, 1H), 2.96-2.92 (d, 1H), 1.44 (s, 9H), 1.28-1.25 (t, 3H)

[0290] MS (m / z): 397 [M+H]

[0291] Preparation Example 17: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(fluoro(phenyl)methyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0292] The title compound was obtained through the following processes (1) and (2).

[0293] (1) Preparation of ethyl 2-(fluoro(phenyl)methyl)acrylate

[0294]

[0295] Ethyl 2-(hydroxy-phenyl-methyl)acrylate (0.412 g, 2.0 mmol) was dissolved in dichloromethane (10 ml), and diethylaminosulfonium trifluoride (0.32 ml, 2.4 mmol) was added at -78 °C, followed by stirring for 2 hours. After quenching the reaction with aqueous sodium bicarbonate solution, the mixture was extracted twice with dichloromethane (20 ml), and the organic layer was dehydrated on anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.320 g, 77%).

[0296] NMR: 1 H-NMR(500MHz, CDCl3); δ 7.49-7.30 (5H, m), 6.49 (1H, dd), 6.33(1H, d), 6.05 (1H, s), 4.25-4.16 (2H, m), 1.27 (3H, t)

[0297] (2) 3-(((tert-butoxycarbonyl)amino)methyl)-5-(fluoro(phenyl)methyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0298]

[0299] Using ethyl 2-(fluoro(phenyl)meth)acrylate (0.244 g, 1.40 mmol) obtained in (1) above and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.320 g, 1.54 mmol) obtained in Preparation Example 1-(1), two types of title compounds were obtained by the preparation method of Preparation Example 1-(2), wherein isomer 1 has low polarity (0.089 g, 17%) and isomer 2 has high polarity (0.100 g, 19%).

[0300] Isomer 1

[0301] NMR: 1H-NMR(500MHz, CDCl3); δ 7.42-7.35 (5H, m), 5.86 (1H, d), 4.81 (1H,br s), 4.30-4.20 (2H, m), 3.98-3.88 (2H, m), 3.40 (1H, d), 3.25 (1H, d), 1.46(9H, s), 1.29 (3H, t)

[0302] Isomer 2

[0303] NMR: 1 H-NMR(500MHz, CDCl3); δ 7.46-7.38 (5H, m), 5.95 (1H, d), 4.56 (1H,br s), 4.34-4.24 (2H, m), 3.91-3.78 (2H, m), 3.55 (1H, d), 3.25 (1H, d), 1.46(9H, s), 1.31 (3H, t)

[0304] Preparation Example 18: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(3-methylbenzyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0305]

[0306] 2-(3-methyl-phenylmethyl)-ethyl acrylate (0.7 g, 52%, 2 steps) was obtained by the preparation method of Preparation Example 13-(1) using 3-methylbenzyl bromide (0.93 ml, 6.69 mmol).

[0307] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.20-6.99 (m, 4H), 6.22 (s, 1H), 5.45 (s,1H), 4.21-4.16 (q, 2H), 3.59 (s, 2H), 2.32 (s, 3H), 1.28-1.25 (t, 3H)

[0308] The title compound (0.38 g, 50%) was obtained by the preparation method of Preparation Example 1-(2) using ethyl 2-(3-methyl-phenylmethyl)acrylate (0.37 g, 1.83 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.35 g, 2.01 mmol) obtained in Preparation Example 1-(1).

[0309] NMR:1 H-NMR(400MHz, CDCl3); δ 7.19-7.02 (m, 4H), 4.59 (br s, 1H), 4.27-4.18 (q, 2H), 3.89 (m, 2H), 3.40-3.35 (d, 1H), 3.27-3.23 (d, 1H), 3.11-3.08(d, 1H), 2.98-2.93 (d, 1H), 2.32 (s, 3H), 1.43 (s, 9H), 1.29-1.24 (t, 3H)

[0310] MS (m / z): 377 [M+H]

[0311] Preparation Example 19: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(phenoxymethyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0312]

[0313] Ethyl 2-(phenoxymethyl)acrylate was obtained by the method described in US6747050. The title compound (0.59 g, 42%) was obtained by the preparation method of Preparation Example 1-(2) using tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.64 g, 3.67 mmol) and ethyl 2-(phenoxymethyl)acrylate (0.83 g, 4.04 mmol) obtained in Preparation Example 1-(1).

[0314] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.31-7.28 (m, 2H), 7.00-6.89 (m, 3H), 4.93(br s, 1H), 4.34-4.20 (m, 4H), 4.15-4.09 (d, 2H), 3.61-3.56 (d, 1H), 3.32-3.28 (d, 1H), 1.45 (s, 9H), 1.30-1.26 (t, 3H)

[0315] MS (m / z): 434 [M+H]

[0316] Preparation Example 20: 5-((1H-pyrazol-1-yl)methyl)-3-(((tert-butoxycarbonyl)amino)methyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0317] The title compound was obtained through the following processes (1) and (2).

[0318] (1) Preparation of ethyl 2-((1H-pyrazol-1-yl)meth)acrylate

[0319]

[0320] Ethyl 2-hydroxymethacrylate (2 g, 15.37 mmol) was dissolved in acetonitrile (20 ml). Potassium carbonate (38.42 mmol) and pyrazole (1.26 g, 18.44 mmol) were added sequentially, followed by reflux and stirring for 20 hours. Water was added, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with brine, dehydrated over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.5 g, 18%).

[0321] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.54-7.53 (m, 1H), 7.47-7.46 (m, 1H), 6.34-6.33 (m, 1H), 6.28-6.26 (t, 1H), 5.46-5.45 (m, 1H), 5.00 (s, 2H), 4.33-4.20 (q, 2H), 1.34-1.28 (t, 3H)

[0322] (2) 5-((1H-pyrazol-1-yl)methyl)-3-(((tert-butoxycarbonyl)amino)methyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0323]

[0324] The title compound (0.58 g, 59%) was obtained by the preparation method of Preparation Example 1-(2) using ethyl 2-((1H-pyrazol-1-yl)meth)acrylate (0.5 g, 2.77 mmol) obtained in (1) above and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.73 g, 4.16 mmol) obtained in Preparation Example 1-(1).

[0325] NMR: 1H-NMR (400MHz, CDCl3); δ 7.34-7.49 (m, 2H), 6.26-6.25 (m, 1H), 4.64-4.53 (m, 3H), 4.31-4.26 (q, 2H), 3.89-3.88 (m, 2H), 3.38 (s, 2H), 1.45(s, 9H), 1.34-1.30 (t, 3H)

[0326] MS (m / z): 353 [M+H]

[0327] Preparation Example 21: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(hydroxy(phenyl)methyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0328]

[0329] The title compound (1.95 g, 64%) was obtained by the preparation method of Preparation Example 1-(2) using ethyl 2-(hydroxy-phenyl-methyl)acrylate (1.40 g, 8.0 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (2.31 g, 11.2 mmol) obtained in Preparation Example 1-(1).

[0330] NMR: 1 ¹H-NMR (500MHz, CDCl₃); δ 7.44–7.26 (5H, m), 5.22 and 5.16 (1H, 2 d), 4.70 and 6.38; 4.41 (1H, 2 s), 4.25–4.19 (2H, m), 3.95–3.73 (2H, m), 3.35–3.26 (2H, m), 2.85 and 2.80 (1H, 2 s), 1.45 and 1.44 (9H, 2 s), 1.29–1.24 (3H, m)

[0331] Preparation Example 22: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(1-phenylethyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0332] The title compound was obtained through the following processes (1) and (2).

[0333] (1) Preparation of methyl 2-methylene-3-phenylbutyrate

[0334]

[0335] Palladium(II) acetate (0.045 g, 0.20 mmol) and 1,10-phenanthroline (0.040 g, 0.20 mmol) were dissolved in dimethylformamide (10 ml) and stirred for 30 min. Methyl (E)-2-methylbut-2-enoate (0.72 ml, 6.00 mmol) and phenylboronic acid (0.488 g, 4.0 mmol) were added to the solution, and the mixture was stirred at room temperature for 16 h under an oxygen bulb. Diethyl ether (50 ml) was added, and the mixture was washed with an aqueous sodium bicarbonate solution and brine. The organic layer was dehydrated on anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.546 g, 72%).

[0336] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.35-7.22 (5H, m), 6.33 (1H, s), 5.65 (1H,s), 3.72 (3H, s), 1.47 (2H, d)

[0337] (2) 3-(((tert-butoxycarbonyl)amino)methyl)-5-(1-phenylethyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0338]

[0339] The title compound (0.389 g, 52%) was obtained by the preparation method of Preparation Example 1-(2) using methyl 2-methylene-3-phenylbutyrate (0.546 g, 2.87 mmol) obtained in (1) above and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.357 g, 2.05 mmol) obtained in Preparation Example 1-(1).

[0340] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.35-7.27 (5H, m), 4.50-4.43 (1H, m), 3.89-3.81 (5H, m), 3.51-3.41 (1H, m), 3.24 (1H, d), 3.01 (1H, d), 1.47 (9H,s), 1.42 (3H, d)

[0341] Preparation Example 23: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(thiazol-4-ylmethyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0342] The title compound was obtained through the following processes (1) and (2).

[0343] (1) Preparation of ethyl 2-(thiazol-4-ylmethyl)acrylate

[0344]

[0345] Diethyl malonate (0.59 ml, 3.85 mmol) was dissolved in dimethylamide (10 ml). Sodium hydride (0.162 g, 4.05 mmol) and 4-chloromethylthiazole (0.52 g, 3.85 mmol) were added sequentially at 0 °C, followed by stirring at room temperature for 16 hours. The solvent was distilled under reduced pressure, water was added, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dehydrated over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give diethyl 2-thiazol-4-ylmethyl-malonate (0.55 g, 56%).

[0346] NMR: 1 H-NMR(400MHz, CDCl3); δ 8.74-8.73 (d, 1H), 7.06-7.05 (m, 1H), 4.24-4.11 (m, 2H), 3.95-3.91 (t, 1H), 3.43-3.41 (d, 2H), 1.24-1.21 (t, 3H)

[0347] The diethyl 2-thiazol-4-ylmethylmalonate obtained above (0.55 g, 2.14 mmol) was dissolved in ethanol (20 ml). Potassium hydroxide (0.114 g, 2.03 mmol) dissolved in ethanol (10 ml) was slowly added at 0 °C, and the mixture was stirred for 48 hours. After titrating to pH 2 with 1 N hydrochloric acid, water was added, and the resulting product was extracted with ethyl acetate, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound, monoethyl 2-thiazol-4-ylmethylmalonate (0.36 g, 73%).

[0348] NMR: 1 H-NMR(400MHz, CDCl3); δ 8.81 (d, 1H), 7.14-7.13 (m, 1H), 4.22-4.16(q, 2H), 3.93-3.89 (t, 1H), 3.47-3.43 (m, 2H), 1.25-1.20 (t, 3H)

[0349] The obtained 2-thiazolyl-4-ylmethylmalonate monoethyl ester (0.36 g, 1.56 mmol) was dissolved in pyridine (10 ml). Paraformaldehyde (0.045 g, 1.48 mmol) and piperidine (0.015 ml, 0.16 mmol) were added sequentially, and the mixture was refluxed at 120 °C and stirred for 3 hours. After adding water and extracting with hexane, the organic layer was washed sequentially with water, 1 N hydrochloric acid, water, an aqueous sodium carbonate solution, and brine, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.2 g, 65%).

[0350] NMR: 1 H-NMR (500MHz, CDCl3); δ 8.75-8.73 (m, 1H), 7.04-7.00 (m, 1H), 6.29 (s, 1H), 5.60 (s, 1H), 4.21-4.16 (q, 2H), 3.86 (2H), 1.26-1.23 (t, 3H)

[0351] (2) 3-(((tert-butoxycarbonyl)amino)methyl)-5-(thiazolyl-4-ylmethyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0352]

[0353] The title compound (0.30 g, 40%) was obtained by the preparation method of Preparation Example 1-(2) using ethyl 2-(thiazol-4-ylmethyl)acrylate (0.2 g, 1.01 mmol) obtained in (1) above and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.35 g, 2.03 mmol) obtained in Preparation Example 1-(1).

[0354] NMR: 1 H-NMR(500MHz, CDCl3); δ 8.72 (d, 1H), 7.20 (d, 1H), 4.76 (br s,1H), 4.28-4.22 (q, 2H), 3.92-3.94 (d, 2H), 3.49-3.27 (m, 4H), 1.45 (s, 9H),1.31-1.27 (t, 3H)

[0355] MS (m / z): 370 [M+H]

[0356] Preparation Example 24: 5-Benzyl-3-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0357]

[0358] Using (S)-1-methyl-2-keto-ethyl)-tert-butyl carbamate (0.5 g, 2.89 mmol), (S)-(1-(hydroxyimino)propyl-2-yl)carbamate (0.54 g, 99%) was obtained by the preparation method of Preparation Example 1-(1). Using (S)-(1-(hydroxyimino)propyl-2-yl)carbamate (0.44 g, 2.31 mmol) and methyl 2-phenylmethacrylate (0.45 g, 2.54 mmol) obtained in Preparation Example 6-(1), the title compound (0.36 g, 43%) was obtained by the preparation method of Preparation Example 1-(2).

[0359] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.29-2.20 (m, 3H), 4.79 (m, 1H), 4.31 (brs, 1H), 3.78-3.77 (d, 3H), 3.39-3.28 (m, 2H), 3.11-3.05 (m, 1H), 2.95-2.92(d, 1H), 1.43-1.41 (d, 9H), 1.14-1.13 (d, 3H)

[0360] MS (m / z): 363 [M+H]

[0361] Preparation Example 25: 5-Benzyl-3-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0362]

[0363] The title compound (1.62 g, 82%) was obtained by the preparation method of Preparation Example 1 (2) using (S)-(1-(hydroxyimino)-3-methylbut-2-yl)carbamate tert-butyl ester (1.09 g, 5.04 mmol) obtained in Preparation Example 3-(2) and methyl 2-phenylmethyl acrylate (0.98 g, 5.54 mmol) obtained in Preparation Example 6-(1).

[0364] NMR: 1H-NMR (500MHz, CDCl3); δ 7.31-7.23 (m, 5H), 4.85-4.4.59 (m, 1H), 4.22-4.13 (m 1H), 3.36-3.28 (m, 2H), 3.14-3.07 (m, 1H), 2.92-2.88 (m, 1H),1.95-1.88 (m, 1H), 1.42-1.41 (d, 9H), 0.82-0.56 (m, 6H)

[0365] MS (m / z): 391 [M+H]

[0366] Preparation Example 26: 5-Benzyl-3-((S)-1-((tert-butoxycarbonyl)amino)-3-methylbutyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0367]

[0368] The title compound (0.51 g, 67%) was obtained by the preparation method of Preparation Example 1 (2) using (S)-(1-(hydroxyimino)-4-methylpentan-2-yl)carbamate tert-butyl ester (0.42 g, 1.84 mmol) obtained in Preparation Example 4-(1) and methyl 2-benzylmethacrylate (0.39 g, 2.21 mmol) obtained in Preparation Example 6-(1).

[0369] NMR: 1 H-NMR (500MHz, CDCl3); δ 7.31-7.23 (m, 5H), 4.58 (m, 1H), 4.30 (m, 1H), 3.40-3.29 (m, 2H), 3.28-2.90 (m, 2H), 1.43-1.42 (d, 9H), 1.37-1.31 (m,3H), 0.86-0.81 (m, 6H)

[0370] MS (m / z): 405 [M+H]

[0371] Preparation Example 27: 5-Benzyl-3-((R)-1-((tert-butoxycarbonyl)amino)-2-methoxyethyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0372] The title compound was obtained through the following processes (1), (2), (3) and (4).

[0373] (1) Preparation of N-(tert-butoxycarbonyl)-O-methyl-L-serine methyl ester

[0374]

[0375] Methyl (S)-2-tert-butoxycarbonylamino-3-hydroxypropionate (1.5 g, 6.84 mmol) was dissolved in acetonitrile (20 ml), and silver(II) oxide (7.93 g, 34.21 mmol) and iodomethane (4.26 ml, 68.42 mmol) were added sequentially. The mixture was stirred at room temperature for 20 hours in the dark. After filtration through diatomaceous earth, the resulting product was distilled under reduced pressure and separated by column chromatography to give the title compound (0.58 g, 36%).

[0376] NMR: 1 H-NMR(400MHz, CDCl3); δ 5.35 (m, 1H), 4.43-4.41 (m, 1H), 3.81-3.79(m, 1H), 3.78 (s, 3H), 3.61-3.58 (m, 1H), 3.34 (s, 3H), 1.45 (s, 9H)

[0377] (2) Preparation of (S)-(1-methoxy-3-ketopropyl-2-yl)carbamate tert-butyl ester

[0378]

[0379] The N-(tert-butoxycarbonyl)-O-methyl-L-serine methyl ester (0.58 g, 2.49 mmol) obtained in (1) above was dissolved in toluene (10 ml) under nitrogen purging. A 1.5 M solution of diisobutylaluminum hydride in toluene (2.82 ml, 4.23 mmol) was added at -78 °C, and the mixture was stirred for 2 hours. After quenching with methanol (4 ml), 1 N hydrochloric acid aqueous solution was added, and the mixture was extracted with ethyl acetate. The resulting organic layer was dehydrated on anhydrous magnesium sulfate, filtered, and separated by column chromatography to obtain the title compound (0.42 g, 83%).

[0380] NMR: 1 H-NMR(400MHz, CDCl3); δ 9.64 (s, 1H), 5.40 (br s, 1H), 4.29 (m,1H), 3.92-3.90 (m, 1H), 3.64-3.61 (m, 1H), 3.34 (s, 3H), 1.46 (s, 9H)

[0381] (3) Preparation of (R)-(1-(hydroxyimino)-3-methoxypropyl-2-yl)carbamate tert-butyl ester

[0382]

[0383] The title compound (0.45 g, 99%) was obtained by the preparation method of Preparation Example 1-(1) using (S)-(1-methoxy-3-ketopropyl-2-yl)carbamate tert-butyl ester (0.42 g, 2.07 mmol) obtained in (2) above.

[0384] (4) 5-Benzyl-3-((R)-1-((tert-butoxycarbonyl)amino)-2-methoxyethyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0385]

[0386] The title compound (0.42 g, 52%) was obtained by the preparation method of Preparation Example 1-(2) using (R)-(1-(hydroxyimino)-3-methoxypropyl-2-yl)carbamate tert-butyl ester (0.45 g, 2.06 mmol) obtained in (3) above and methyl 2-benzyl methacrylate (0.44 g, 2.47 mmol) obtained in Preparation Example 6-(1).

[0387] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.30-7.22 (m, 5H), 5.15-4.93 (m, 1H), 4.46(m, 1H), 3.77 (dd, 3H), 3.50-3.27 (m, 4H), 3.26 (s, 3H), 3.17-2.95 (m, 2H),1.43-1.42 (d, 9H)

[0388] MS (m / z): 393 [M+H]

[0389] Preparation Example 28: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(2-methylbenzyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0390]

[0391] Using 2-methylbenzyl bromide (1.0 g, 5.4 mmol), ethyl 2-(2-methyl-benzyl)acrylate (0.84 g, 4.1 mmol) was obtained by the preparation method of Preparation Example 13-(1). Using ethyl 2-(2-methyl-benzyl)acrylate (0.082 g, 0.40 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.14 g, 0.80 mmol) obtained in Preparation Example 1-(1), the title compound (0.10 g, 68%) was obtained by the preparation method of Preparation Example 1-(2).

[0392] MS (m / z): 377 [M+H]

[0393] Preparation Example 29: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(difluoro(phenyl)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0394] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[0395] (1) Preparation of 2,2-difluoro-2-phenylethyl-1-ol

[0396]

[0397] 2-Bromoacetophenone (1.50 g, 7.54 mmol) was dissolved in benzene (15 ml), and diethylaminosulfonium trifluoride (2.0 ml, 15.1 mmol) was added at room temperature, followed by stirring at 60 °C for 48 hours. After cooling the reaction product to room temperature, water was added, and the mixture was extracted twice with diethyl ether (50 ml). The organic layer was dehydrated on anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give (2-bromo-1,1-difluoroethyl)benzene (1.12 g, 67%).

[0398] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.57-7.31 (5H, m), 3.81 (2H, dt)

[0399] (2-Bromo-1,1-difluoro-ethyl)-benzene (1.12 g, 5.07 mmol), potassium acetate (1.99 g, 20.3 mmol), and 18-C-6 crown ether (0.134 g, 0.507 mmol) were dissolved in dimethylacetamide (10 ml) and stirred at 150 °C for 18 hours. The reaction product was cooled to room temperature, water was added, and the mixture was extracted twice with diethyl ether (50 ml). The organic layer was dehydrated on anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain 2,2-difluoro-2-phenyl-ethyl acetate (0.634 g, 62%).

[0400] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.57-7.47 (5H, m), 4.57 (2H, dt), 2.13(3H, s)

[0401] 2,2-Difluoro-2-phenyl-ethyl acetate (0.634 g, 3.17 mmol) was dissolved in methanol (12 ml) and treated with 1N NaOH (3.2 ml), followed by stirring at room temperature for 2 hours. Water was added to the reaction product, methanol was removed under reduced pressure, and the mixture was extracted twice with dichloromethane (20 ml). The organic layer was dehydrated on anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.489 g, 98%).

[0402] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.58-7.47 (5H, m), 4.02 (2H, t)

[0403] (2) Preparation of 3,3-difluoro-2-hydroxy-3-phenylpropionitrile

[0404]

[0405] Oxaloyl chloride (0.29 ml, 3.38 mmol) was dissolved in dichloromethane (6 ml), the temperature was set to -78 °C, and dimethyl sulfoxide (0.49 ml, 6.90 mmol) was slowly added. After stirring the reaction mixture for 30 minutes, a solution of 2,2-difluoro-2-phenylethyl-1-ol (0.489 g, 3.09 mmol) obtained in (1) above was added in dichloromethane (2 ml), and the mixture was stirred for 30 minutes. After adding triethylamine (1.90 ml, 13.6 mmol) to the reaction product, the temperature was slowly raised to room temperature, and stirring was carried out for 18 hours. Water was added, and the mixture was extracted twice with dichloromethane (30 ml). The organic layer was dehydrated on anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure to give the title compound difluoro-phenyl-acetaldehyde (0.531 g).

[0406] The difluorophenylacetaldehyde (0.531 g) obtained above was dissolved in tetrahydrofuran (30 ml), and p-toluenesulfonic acid monohydrate (0.705 g, 3.71 mmol) and potassium cyanide (0.242 g, 3.72 mmol) were added sequentially. The mixture was then stirred at 40 °C for 3 hours. The reaction product was cooled to room temperature, water was added, the solvent was removed under reduced pressure, and the mixture was extracted three times with diethyl ether (20 ml). The organic layer was washed with an aqueous sodium bisulfite solution, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.327 g, 58%, 2 steps).

[0407] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.57-7.43 (5H, m), 4.80 (1H, t)

[0408] (3) Preparation of methyl 3,3-difluoro-2-hydroxy-3-phenylpropionate

[0409]

[0410] The 3,3-difluoro-2-hydroxy-3-phenylpropionitrile (0.327 g, 1.79 mmol) obtained in (2) above was dissolved in MeOH (8 ml), and 4 N HCl (8.0 ml) was added. The mixture was then stirred at 65 °C for 48 hours. The reaction product was cooled to room temperature, water was added, methanol was removed under reduced pressure, and the mixture was extracted twice with dichloromethane (20 ml). The organic layer was dehydrated on anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.318 g, 82%).

[0411] NMR:1 H-NMR(400MHz, CDCl3); δ 7.58-7.46 (5H, m), 4.60 (1H, dt), 3.87(3H, s), 3.26 (1H, d)

[0412] (4) Preparation of methyl 2-(difluoro(phenyl)meth)acrylate

[0413]

[0414] The methyl 3,3-difluoro-2-hydroxy-3-phenylpropionate (0.419 g, 1.94 mmol) obtained in (3) above was dissolved in dimethyl sulfoxide (15 ml), and 2-iodooxybenzoic acid (IBX, 1.29 g, 4.61 mmol) was added. The mixture was then stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction product, and the resulting solid was removed under reduced pressure. The filtrate was extracted twice with ethyl acetate (30 ml). The organic layer was dehydrated on anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain methyl 3,3-difluoro-2-keto-3-phenylpropionate (0.282 g, 68%).

[0415] Methyltriphenylphosphonium bromide (1.18 g, 3.30 mmol) and potassium tert-butoxide (0.356 g, 3.17 mmol) were dissolved in tetrahydrofuran (10 ml), and the mixture was stirred at room temperature for 1 hour. The reaction product was cooled to -30 °C, and a solution of the aforementioned methyl 3,3-difluoro-2-keto-3-phenylpropionate (0.282 g, 1.32 mmol) dissolved in tetrahydrofuran (2 ml) was added. The reaction product was slowly cooled to room temperature, and stirring was carried out at room temperature for 18 hours. After the addition of water, the resulting product was extracted twice with ethyl acetate (20 ml), dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.114 g, 41%).

[0416] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.67-7.43 (5H, m), 6.68 (1H, s), 6.40 (1H,s), 3.74 (3H, s)

[0417] (5) 3-(((tert-butoxycarbonyl)amino)methyl)-5-(difluoro(phenyl)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0418]

[0419] The title compound (0.173 g, 84%) was obtained by the preparation method of Preparation Example 1-(2) using methyl 2-(difluoro(phenyl)meth)acrylate (0.114 g, 0.537 mmol) obtained in (4) above and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.375 g, 2.15 mmol) obtained in Preparation Example 1-(1).

[0420] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.61-7.45 (5H, m), 4.28 (1H, d), 4.01 (2H, s), 3.77 (3H, s), 3.60 (2H, d), 1.49 (9H, s)

[0421] Preparation Example 30: 5-Benzyl-3-(2-((tert-butoxycarbonyl)amino)propyl-2-yl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0422] The title compound was obtained through the following processes (1) and (2).

[0423] (1) Preparation of tert-butyl (1-(hydroxyimino)-2-methylpropyl-2-yl)carbamate

[0424]

[0425] (1,1-Dimethyl-2-keto-ethyl)-tert-butyl carbamate was obtained by the method described in EP2036896 A1. The title compound (1.07 g, 99%) was obtained by the preparation method of Preparation Example 1-(1) using (1,1-dimethyl-2-keto-ethyl)-tert-butyl carbamate (1 g, 5.34 mmol).

[0426] (2) 5-Benzyl-3-(2-((tert-butoxycarbonyl)amino)propyl-2-yl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0427]

[0428] The title compound (0.37 g, 18%) was obtained by the preparation method of Preparation Example 1-(2) using tert-butyl 1-(1-(hydroxyimino)-2-methylpropyl-2-yl)carbamate (0.69 g, 3.41 mmol) obtained in (1) above and methyl 2-phenylmethyl acrylate (0.4 g, 2.27 mmol) obtained in Preparation Example 6-(1).

[0429] NMR: 1 H-NMR(500MHz, CDCl3); δ 7.29-7.22 (m, 5H), 4.77 (br s, 1H), 3.77(s, 3H), 3.41-3.36 (d, 1H), 3.36-3.31 (d, 1H), 3.17-3.13 (d, 1H), 2.98-2.94(d, 1H), 1.58 (s, 3H), 1.41 (s, 9H), 1.36 (s, 3H)

[0430] MS (m / z): 377 [M+H]

[0431] Preparation Example 31: 3-(((tert-butoxycarbonyl)amino)methyl)-5-pentyl-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0432] The title compound was obtained through the following processes (1) and (2).

[0433] (1) Preparation of ethyl 2-methylene-4-phenylbutyrate

[0434]

[0435] Ethyl (diethoxy-phosphoryl)-ethyl acetate (3.0 g, 13.38 mmol) was dissolved in dichloroformamide (30 ml). Sodium hydride (0.59 g, 14.72 mmol) was slowly added at 0 °C, and after 30 minutes, (2-bromo-ethyl)-benzene (1.83 ml, 13.38 mmol) was added, followed by stirring at room temperature for 18 hours. After the reaction was complete, water was added and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and used in the next reaction without separation.

[0436] The product obtained above (4.11 g, 12.50 mmol) and a 37% aqueous formaldehyde solution (6.3 ml, 80.01 mmol) were dissolved in water (30 ml), and potassium carbonate (5.2 g, 37.51 mmol) dissolved in water (10 ml) were added. After reflux and stirring at 90 °C for 16 hours, water was added, and extraction was performed with diethyl ether. The organic layer was washed with brine and dehydrated on anhydrous magnesium sulfate. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (1.39 g, 51%, 2 steps).

[0437] NMR: 1H-NMR (400MHz, CDCl3); δ 7.31-7.17 (m, 5H), 6.15 (s, 1H), 5.5 (s, 1H), 4.26-4.21 (q, 2H), 2.81-2.78 (t, 2H), 2.63-2.59 (t, 2H), 1.31-1.29 (t,3H)

[0438] (2) 3-(((tert-butoxycarbonyl)amino)methyl)-5-pentyl-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0439]

[0440] The title compound (0.27 g, 30%) was obtained by the preparation method of Preparation Example 1-(2) using ethyl 2-methylene-4-phenylbutyrate (0.5 g) obtained in (1) above and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.36 g) obtained in Preparation Example 1-(1).

[0441] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.29-7.13 (m, 5H), 4.87 (br s, 1H), 4.23-4.21 (m, 2H), 3.45-4.43 (d, 1H), 2.96-2.94 (d, 1H), 2.71-2.59 (m, 2H), 2.31-2.21 (m, 2H), 1.45 (s, 9H), 1.31-1.29 (t, 3H)

[0442] MS (m / z): 377 [M+H]

[0443] Preparation Example 32: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(2-(trifluoromethyl)benzyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0444]

[0445] Using 2-(trifluoromethyl)benzyl chloride (0.47 g, 2.42 mmol), ethyl 2-(2-trifluoromethyl-benzyl)acrylate (0.24 g, 0.93 mmol) was obtained by the preparation method of Preparation Example 13-(1). Using ethyl 2-(2-trifluoromethyl-benzyl)acrylate (0.24 g, 0.93 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.18 g, 1.02 mmol) obtained in Preparation Example 1-(1), the title compound (0.09 g, 22%) was obtained by the preparation method of Preparation Example 1-(2).

[0446] MS (m / z): 431 [M+H]

[0447] Preparation Example 33: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(2-fluorobenzyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0448]

[0449] Using 2-fluorobenzyl bromide (1.0 g, 5.3 mmol), ethyl 2-(2-fluoro-benzyl)acrylate (0.76 g, 3.65 mmol) was obtained by the preparation method of Preparation Example 13-(1). Using ethyl 2-(2-fluoro-benzyl)acrylate (0.21 g, 1.0 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.17 g, 1.0 mmol) obtained in Preparation Example 1-(1), the title compound (0.11 g, 30%) was obtained by the preparation method of Preparation Example 1-(2).

[0450] MS (m / z): 381 [M+H]

[0451] Preparation Example 34: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(2,6-difluorobenzyl)-4,5-dihydroisocyanuric acid Preparation of ethyl 5-oxazolium carboxylate

[0452]

[0453] Using 2,6-difluorobenzyl bromide (1.0 g, 4.83 mmol), ethyl 2-(2,6-difluoro-benzyl)acrylate (0.79 g, 3.49 mmol) was obtained by the preparation method of Preparation Example 13-(1). Using ethyl 2-(2,6-difluoro-benzyl)acrylate (0.79 g, 3.49 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (1.21 g, 6.38 mmol) obtained in Preparation Example 1-(1), the title compound (0.476 g, 34%) was obtained by the preparation method of Preparation Example 1-(2).

[0454] MS (m / z): 399 [M+H]

[0455] Preparation Example 35: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(2,4-difluorobenzyl)-4,5-dihydroisocyanuric acid Preparation of ethyl 5-oxazolium carboxylate

[0456]

[0457] Using 2,4-difluorobenzyl bromide (1 g, 4.8 mmol), ethyl 2-(2,4-difluoro-benzyl)acrylate (0.67 g, 3.0 mmol) was obtained by the preparation method of Preparation Example 13-(1). Using ethyl 2-(2,4-difluoro-benzyl)acrylate (0.30 g, 1.33 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.28 g, 1.6 mmol) obtained in Preparation Example 1-(1), the title compound (0.20 g, 37%) was obtained by the preparation method of Preparation Example 1-(2).

[0458] MS (m / z): 399 [M+H]

[0459] Preparation Example 36: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(1-phenylcyclopropyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0460] The title compound is obtained through the processes described in (2), (3), (4) and (5) below.

[0461] (1) Preparation of 1-phenylcyclopropion-1-carboxynitrile

[0462]

[0463] Phenylacetonitrile (4.46 g, 40.0 mmol), tetrabutylammonium bromide (0.129 g, 0.40 mmol), and potassium hydroxide (22.4 g, 400 mmol) were dissolved in water, and 1,2-dibromoethane (6.90 ml, 80.0 mmol) was added at 50 °C, followed by stirring for 2 hours. The reaction product was cooled to room temperature, water was added, and the mixture was extracted twice with diethyl ether (100 ml). The organic layer was dehydrated on anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (3.61 g, 63%).

[0464] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.42-7.31 (5H, m), 1.79-1.76 (2H, m), 1.47-1.44 (2H, m)

[0465] (2) Preparation of 2-hydroxy-2-(1-phenylcyclopropyl)acetonitrile

[0466]

[0467] The 1-phenylcyclopropane-1-carboxynitrile (3.61 g, 25.2 mmol) obtained in (1) above was dissolved in dichloromethane (40 ml), and a 1.5 M toluene solution of diisobutylaluminum hydride (18.5 ml, 27.8 mmol) was slowly added to it at 0 °C, followed by stirring at room temperature for 2 hours. 1 N HCl (150 ml) was slowly added to the reaction product at 0 °C, and the mixture was extracted twice with dichloromethane (100 ml). The organic layer was dehydrated on anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure to obtain 1-phenylcyclopropaneformaldehyde (3.19 g, 87%). Using the 1-phenylcyclopropaneformaldehyde (3.1 g, 21.8 mmol) obtained above, the title compound (2.69 g, 71%) was obtained by the preparation method of Preparation Example 29-(2).

[0468] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.53-7.36 (5H, m), 4.24 (1H, s), 2.46 (1H,br s), 1.19-1.06 (4H, m)

[0469] (3) Preparation of methyl 2-hydroxy-2-(1-phenylcyclopropyl)acetate

[0470]

[0471] The title compound (0.986 g, 83%) was obtained by the preparation method of Preparation Example 29-(3) using 1.0 g (5.77 mmol) of 2-hydroxy-2-(1-phenylcyclopropyl)acetonitrile obtained in (2) above.

[0472] NMR: 1 H-NMR(400MHz, CDCl3); 7.37-7.27 (5H, m), 3.78 (3H, s), 3.74 (1H,d), 2.87 (1H, d), 1.31-0.94 (4H, m)

[0473] (4) Preparation of methyl 2-(1-phenylcyclopropyl)acrylate

[0474]

[0475] The title compound (0.209 g, 40%) was obtained by the preparation method of Preparation Example 29-(4) using methyl 2-hydroxy-2-(1-phenylcyclopropyl)acetate (0.486 g, 2.36 mmol) obtained in (3) above.

[0476] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.33-7.18 (5H, m), 6.36 (1H, d), 5.88 (1H,d), 3.72 (3H, s), 1.23-1.13 (4H, m)

[0477] (5) 3-(((tert-butoxycarbonyl)amino)methyl)-5-(1-phenylcyclopropyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0478]

[0479] The title compound (0.277 g, 72%) was obtained by the preparation method of Preparation Example 1-(2) using methyl 2-(1-phenylcyclopropyl)acrylate (0.209 g, 1.03 mmol) obtained in (4) above and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.359 g, 2.06 mmol) obtained in Preparation Example 1-(1).

[0480] NMR: 1H-NMR(400MHz, CDCl3); δ 7.34-7.26 (5H, m), 4.28 (1H, d), 4.04 (2H, d), 3.79 (3H, s), 3.52 (1H, d), 3.22 (1H, d), 1.49-1.47 (10H, m), 0.95-0.83(3H, m)

[0481] Preparation Example 37: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(3,5-difluorobenzyl)-4,5-dihydroisocyanuric acid Preparation of ethyl 5-oxazolium carboxylate

[0482]

[0483] 2-(3,5-difluoro-benzyl)ethyl acrylate (0.37 g, 24%, 2 steps) was obtained using the preparation method of Example 13-(1) with 3,5-difluorobenzyl bromide (0.87 ml, 6.69 mmol). NMR: 1 H-NMR (400MHz, CDCl3); δ 6.76-6.63 (m, 3H), 6.29 (s, 1H), 5.54 (s, 1H), 4.21-4.09 (q, 2H), 3.61 (s, 2H), 1.28-1.24 (t, 3H)

[0484] The title compound (0.29, 41%) was obtained by the preparation method of Preparation Example 1-(2) using ethyl 2-(3,5-difluoro-benzyl)acrylate (0.36 g, 1.59 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.30 g, 1.75 mmol) obtained in Preparation Example 1-(1).

[0485] NMR: 1 H-NMR (400MHz, CDCl3); δ 6.81-6.70 (m, 3H), 4.72 (br s, 1H), 4.27-4.19 (m, 2H), 3.95-3.94 (d, 2H), 3.43-3.39 (d, 1H), 3.30-3.27 (d, 1H), 3.12-3.08 (d, 1H), 2.96-2.92 (d, 1H), 1.44 (s, 9H), 1.29-1.25 (t, 3H)

[0486] MS (m / z): 399 [M+H]

[0487] Preparation Example 38: 5-Benzyl-3-((S)-1-((tert-butoxycarbonyl)amino)-2-methoxyethyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0488] The title compound was obtained through the following processes (1) and (2).

[0489] (1) Preparation of (S)-(1-(hydroxyimino)-3-methoxypropyl-2-yl)carbamate tert-butyl ester

[0490]

[0491] Methyl (R)-2-tert-butoxycarbonylamino-3-hydroxypropionate (2.26 g, 10.31 mmol) was obtained by the preparation method of Preparation Example 27-(1). Methyl (R)-2-tert-butoxycarbonylamino-3-methoxypropionate (1.31 g, 54%) was obtained by the preparation method of Preparation Example 27-(1). Methyl (R)-2-tert-butoxycarbonylamino-3-methoxypropionate (1.31 g, 5.62 mmol) was obtained by the preparation method of Preparation Example 27-(2). Tert-butyl ((R)-1-methoxymethyl-2-keto-ethyl)-carbamate (0.89 g, 78%) was obtained by the preparation method of Preparation Example 1-(1). Tert-butyl ((R)-1-methoxymethyl-2-keto-ethyl)-carbamate (0.89 g, 4.38 mmol) was obtained by the preparation method of Preparation Example 1-(1).

[0492] (2) 5-Benzyl-3-((S)-1-((tert-butoxycarbonyl)amino)-2-methoxyethyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0493]

[0494] The title compound (0.93 g, 54%) was obtained by the preparation method of Preparation Example 1-(2) using (S)-(1-(hydroxyimino)-3-methoxypropyl-2-yl)carbamate tert-butyl ester (0.96 g, 4.39 mmol) obtained in (1) above and methyl 2-phenylmethyl acrylate (0.85 g, 4.84 mmol) obtained in Preparation Example 6-(1).

[0495] NMR: 1H-NMR (400MHz, CDCl3); δ 7.31-7.22 (m, 5H), 5.15-4.93 (m, 1H), 4.46 (m, 1H), 3.77-3.76 (dd, 3H), 3.49-3.27 (m, 4H), 3.26 (s, 3H), 3.17-2.95 (m,2H), 1.43-1.42 (d, 9H)

[0496] MS (m / z): 393 [M+H]

[0497] Preparation Example 39: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(3-fluorobenzyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0498]

[0499] Using 3-fluorobenzyl bromide (1.0 g, 5.3 mmol), ethyl 2-(3-fluoro-benzyl)acrylate (0.49 g, 2.35 mmol) was obtained by the preparation method of Preparation Example 13-(1). Using ethyl 2-(3-fluoro-benzyl)acrylate (0.49 g, 2.35 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.82 g, 4.7 mmol) obtained in Preparation Example 1-(1), the title compound (0.80 g, 80%) was obtained by the preparation method of Preparation Example 1-(2).

[0500] MS (m / z): 381 [M+H]

[0501] Preparation Example 40: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(methoxymethyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0502] The title compound was obtained through the following processes (1), (2), (3) and (4).

[0503] (1) Preparation of methyl 2-(((tert-butyldimethylsilyl)oxy)meth)acrylate

[0504]

[0505] 2-Hydroxymethyl methacrylate (0.5 g, 4.31 mmol) was dissolved in dimethylamide (10 ml). Imidazole (0.35 g, 5.17 mmol) and tert-butylchloro-dimethylsilane (0.78 g, 5.17 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 8 hours. The solvent was distilled under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with brine, dehydrated over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.99 g, 99%).

[0506] NMR: 1 H-NMR (400MHz, CDCl3); δ 6.18-6.17 (m, 1H), 5.84-5.85 (m, 1H), 4.29-4.28 (m, 2H), 3.67 (s, 3H), 0.84 (s, 9H), 0.09 (s, 6H)

[0507] (2) 3-(((tert-butoxycarbonyl)amino)methyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0508]

[0509] The title compound (0.29 g, 31%) was obtained by the preparation method of Preparation Example 1-(2) using methyl 2-(((tert-butyldimethylsilyl)oxy)meth)acrylate (0.59 g, 2.56 mmol) obtained in (1) above and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.36 g) obtained in Preparation Example 1-(1).

[0510] NMR: 1 H-NMR(400MHz, CDCl3); δ 4.86 (br s, 1H), 4.05-4.04 (d, 2H), 3.92-6.84 (q, 2H), 3.79 (s, 3H), 3.44-3.39 (d, 1H), 3.21-3.17 (d, 1H), 1.45 (s,9H), 0.86 (s, 9H), 0.06 (d, 6H)

[0511] MS (m / z): 403 [M+H]

[0512] (3) 3-(((tert-butoxycarbonyl)amino)methyl)-5-(hydroxymethyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0513]

[0514] The 3-(((tert-butoxycarbonyl)amino)methyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydroisocyanate obtained in (2) above Methyl 5-azole carboxylate (0.29 g, 0.72 mmol) was dissolved in tetrahydrofuran (10 mL), and 1 M tetrabutylammonium fluoride tetrahydrofuran solution (0.72 mL, 0.72 mmol) was added. After stirring at room temperature for 18 hours, water was added, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with brine and dehydrated over anhydrous magnesium sulfate. The filtrate was distilled under reduced pressure. The residue was separated by column chromatography to give the title compound (0.13 g, 62%).

[0515] MS (m / z): 289 [M+H]

[0516] (4) 3-(((tert-butoxycarbonyl)amino)methyl)-5-(methoxymethyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[0517]

[0518] The 3-(((tert-butoxycarbonyl)amino)methyl)-5-(hydroxymethyl)-4,5-dihydroisocyanate obtained in (3) above Methyl 5-azole carboxylate (0.075 g, 0.26 mmol) was dissolved in acetonitrile (5 ml), and silver(II) oxide (0.60 g, 2.6 mmol) and iodomethane (0.08 ml, 1.30 mmol) were added sequentially. The mixture was stirred at room temperature for 20 hours in the dark. After filtration through diatomaceous earth, the resulting product was distilled under reduced pressure and separated by column chromatography to give the title compound (0.05 g, 64%).

[0519] NMR: 1 H-NMR (400MHz, CDCl3); δ 4.94 (br s, 1H), 4.07-4.06 (m, 2H), 3.01 (s, 3H), 3.71-3.70 (m, 2H), 3.43-3.88 (d, 1H), 3.41 (s, 3H), 3.16-3.10 (d,1H), 1.45 (s, 9H)

[0520] MS (m / z): 303 [M+H]

[0521] Preparation Example 41: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(ethoxymethyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0522] The title compound was obtained through the following processes (1) and (2).

[0523] (1) Preparation of ethyl 2-(ethoxymethyl)acrylate

[0524]

[0525] Phosphorus tribromide (0.47 ml, 5.0 mmol) was added to a solution of ethyl 2-hydroxymethyl acrylate (1.30 g, 10.0 mmol) dissolved in dichloromethane (20 ml) at 0 °C. The temperature was then increased, and the mixture was stirred at room temperature for 2 hours. Dichloromethane (50 ml) was added to the reaction product, which was then washed with water and brine, dehydrated over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to give ethyl 2-bromomethyl acrylate (1.71 g, 91%).

[0526] Ethanol (0.046 g, 1.0 mmol) was dissolved in tetrahydrofuran (6 ml), and 0.5 M bis(trimethylsilyl)amide potassium (2.0 ml, 1.0 mmol) was slowly added to the solution, followed by stirring at room temperature for 10 minutes. A solution of the aforementioned 2-bromomethyl acrylate (0.193 g, 1.0 mmol) dissolved in tetrahydrofuran (2 ml) was added to the solution, and stirring was continued at room temperature for 1 hour. Water (20 ml) was added to the reaction product, and the mixture was extracted twice with dichloromethane (20 ml). The resulting organic layer was dehydrated on anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.118 g, 75%).

[0527] NMR: 1 H-NMR (500MHz, CDCl3); δ 6.26 (1H, d), 5.83 (1H, d), 4.18 (2H, q), 4.15 (2H, d), 3.53 (2H, q), 1.27 (3H, t), 1.20 (3H, t)

[0528] (2) 3-(((tert-butoxycarbonyl)amino)methyl)-5-(ethoxymethyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0529]

[0530] The title compound (0.051 g, 25%) was obtained by the preparation method of Preparation Example 1-(2) using ethyl 2-(ethoxymethyl)acrylate (0.118 g, 0.75 mmol) obtained in (1) above and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.108 g, 0.62 mmol) obtained in Preparation Example 1-(1).

[0531] NMR: 1 H-NMR(500MHz, CDCl3); δ 4.96 (1H, s), 4.24-4.18 (2H, m), 4.04-4.02(2H, m), 3.72-3.68 (2H, m), 3.55-3.51 (2H, m), 3.38 (1H, d), 3.14 (1H, d),1.42 (9H, s), 1.27 (3H, t), 1.14 (3H, t)

[0532] MS (m / z): 331 [M+H]

[0533] Preparation Example 42: 3-(((tert-butoxycarbonyl)amino)methyl)-3a,4,5,6-tetrahydro-6aH-cyclopentadiene[d]iso Preparation of methyl 6α-carboxylate

[0534]

[0535] The title compound (0.148 g, 25%) was obtained by the preparation method of Preparation Example 1-(2) using methyl 1-cyclopentenylcarbamate (0.252 g, 2.00 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.523 g, 3.00 mmol) obtained in Preparation Example 1-(1).

[0536] NMR: 1H-NMR (400MHz, CDCl3); δ 5.02 (1H, s), 4.05-3.92 (2H, m), 3.78 (1H, d), 3.74 (3H, s), 2.22-1.79 (5H, m), 1.59-1.51 (1H, m), 1.40 (9H, s)

[0537] Preparation Example 43: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(2,3-difluorobenzyl)-4,5-dihydroisocyanuric acid Preparation of ethyl 5-oxazolium carboxylate

[0538]

[0539] Ethyl 2-(2,3-difluoro-benzyl)acrylate (0.92 g, 61%, 2 steps) was obtained by the preparation method of Preparation Example 13-(1) using 2,3-difluorobenzyl bromide (0.84 ml, 6.69 mmol).

[0540] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.07-6.95 (m, 3H), 6.28 (s, 1H), 5.49 (s, 1H), 4.23-4.18 (q, 2H), 3.69 (s, 2H), 1.30-1.26 (t, 3H)

[0541] The title compound (0.23 g, 37%) was obtained by the preparation method of Preparation Example 1-(2) using ethyl 2-(2,3-difluoro-benzyl)acrylate (0.35 g, 1.57 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.3 g, 1.72 mmol) obtained in Preparation Example 1-(1).

[0542] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.12-6.99 (m, 3H), 4.62 (br s, 1H), 4.29-4.21 (m, 2H), 3.94-3.90 (m, 2H0, 3.48-3.44 (d, 1H), 3.30 (s, 2H), 2.98-2.93(d, 1H), 1.44 (s, 9H), 1.29-1.26 (t, 3H)

[0543] MS (m / z): 399 [M+H]

[0544] Preparation Example 44: 3-(((tert-butoxycarbonyl)amino)methyl)-5-((cyclohexyloxy)methyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0545] The title compound was obtained through the following processes (1) and (2).

[0546] (1) Preparation of ethyl 2-((cyclohexyloxy)meth)acrylate

[0547]

[0548] The title compound (0.20 g, 47%) was obtained by the preparation method of Preparation Example 41-(1) using cyclohexanol (0.20 g, 2.0 mmol).

[0549] NMR: 1 H-NMR(500MHz, CDCl3); δ 6.26 (1H, d), 5.88 (1H, d), 4.26 (2H, q), 4.20 (2H, d), 3.31 (1H, q), 1.93-1.78 (4H, m), 1.53-1.49 (1H, m), 1.31-1.23(8H, m)

[0550] (2) 3-(((tert-butoxycarbonyl)amino)methyl)-5-((cyclohexyloxy)methyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0551]

[0552] The title compound (0.200 g, 55%) was obtained by the preparation method of Preparation Example 1-(2) using tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.330 g, 1.88 mmol) obtained in Preparation Example 1-(1) and ethyl (2-((cyclohexyloxy)meth)acrylate (0.200 g, 0.94 mmol) obtained in (1) above.

[0553] NMR: 1 H-NMR(500MHz, CDCl3); δ 5.03 (1H, t), 4.24-4.21 (2H, m), 4.02-3.99(2H, m), 3.70 (1H, d), 3.66 (1H, d), 3.38 (1H, d), 3.29 (1H, t), 3.11 (1H,d), 1.78-1.60 (4H, m), 1.46-1.42 (10H, m), 1.29-1.18 (8H, m)

[0554] Preparation Example 45: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(3-(trifluoromethyl)benzyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0555]

[0556] 2-(3-trifluoromethyl-benzyl)ethyl acrylate (0.49 g, 28%, 2 steps) was obtained by the preparation method of Preparation Example 13-(1) using 3-trifluoromethylbenzyl bromide (1.02 ml, 6.69 mmol).

[0557] NMR: 1 H-NMR(400MHz, CDCl3); δ 4.79-7.39 (m, 4H), 6.28 (s, 1H), 5.51 (s,1H), 4.21-4.15 (q, 2H), 3.69 (s, 2H), 1.28-1.24 (t, 3H)

[0558] The title compound (0.25 g, 42%) was obtained by the preparation method of Preparation Example 1-(2) using ethyl 2-(3-trifluoromethyl-benzyl)acrylate (0.36 g, 1.38 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.24 g, 1.38 mmol) obtained in Preparation Example 1-(1).

[0559] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.54-7.40 (m, 4H), 4.68 (br s, 1H), 4.24-4.19 (q, 2H), 3.93-3.92 (d, 2H), 3.44-3.40 (d, 1H), 3.38-3.35 (d, 1H), 3.21-3.17 (d, 1H), 2.96-2.92 (d, 1H), 1.45 (s, 9H), 1.28-1.22 (t, 3H)

[0560] MS (m / z): 431 [M+H]

[0561] Preparation Example 46: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(3-(trifluoromethoxy)benzyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0562]

[0563] 2-(3-trifluoromethoxy-benzyl)ethyl acrylate (0.33 g, 32%, 2 steps) was obtained by the preparation method of Preparation Example 13-(1) using 3-trifluoromethoxy-benzyl bromide (0.64 ml, 3.92 ml).

[0564] NMR: 1H-NMR(400MHz, CDCl3); δ 7.33-7.29 (m, 1H), 7.15-7.06 (m, 3H), 6.27(s, 1H), 5.51 (s, 1H), 4.21-4.16 (q, 2H), 3.65 (s, 2H), 1.27-1.24 (t, 3H)

[0565] The title compound (0.35 g, 67%) was obtained by the preparation method of Preparation Example 1-(2) using ethyl 2-(3-trifluoromethoxy-benzyl)acrylate (0.33 g, 1.19 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.24 g, 1.38 mmol) obtained in Preparation Example 1-(1).

[0566] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.34-7.30 (m, 1H), 7.21-7.13 (m, 3H), 4.67(br s, 1H), 4.25-4.18 (q, 2H), 3.92-3.91 (d, 2H), 3.43-3.39 (d, 1H), 3.34-3.31 (d, 1H), 3.16-3.13 (d, 1H), 2.95-2.91 (d, 1H), 1.44 (s, 9H), 1.27-1.24(t, 3H)

[0567] MS (m / z): 447 [M+H]

[0568] Example 1: ((1R)-3-methyl-1-(3-phenyl-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[0569] The title compound was obtained through the following processes (1), (2), (3) and (4).

[0570] (1) 3-Phenyl-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0571]

[0572] N-hydroxyphenylcarbaminyl chloride (0.68 g, 4.3 mmol) was dissolved in tetrahydrofuran (20 ml), and ethyl acrylate (0.94 ml, 8.6 mmol) and diisopropylethylamine (1.5 ml, 8.6 mmol) were added at 0 °C. The mixture was stirred for 18 hours while being heated to room temperature. The solvent was distilled under reduced pressure, and an aqueous sodium bicarbonate solution was added, followed by two extractions with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.78 g, 82%).

[0573] MS (m / z): 220 [M+H]

[0574] (2) 3-Phenyl-4,5-dihydroisocyanate Preparation of 5-azole carboxylic acid

[0575]

[0576] The 3-phenyl-4,5-dihydroisocyanate obtained in (1) above Ethyl azole-5-carboxylate (0.78 g, 3.6 mmol) was dissolved in methanol (5 ml), to which 1.8 ml (10.8 mmol) of 6 N sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 5 hours. After titrating to pH 1 with 1 N hydrochloric acid solution, the mixture was extracted twice with ethyl acetate. The resulting organic layer was dehydrated on anhydrous magnesium sulfate, and the filtrate was distilled under reduced pressure to obtain a quantification of the title compound without further purification.

[0577] MS (m / z): 192 [M+H]

[0578] (3) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-phenyl-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[0579]

[0580] The 3-phenyl-4,5-dihydroisocyanate obtained in (2) above Azoxyl-5-carboxylic acid (0.11 g, 0.59 mmol), (R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborhexacyclopentan-2-yl)but-1-amine hydrochloride (0.18 g, 0.6 mmol) and O -(benzotriazol-1-yl)- N,N,N',N' Tetramethyltetrafluoroborate urea (0.21 g, 0.64 mmol) was dissolved in dimethylformamide (5 ml) at 0 °C. While maintaining the temperature, diisopropylethylamine (0.31 ml, 1.78 mmol) was slowly added, followed by stirring for 18 hours while the temperature was raised to room temperature. The solvent was distilled under reduced pressure, and an aqueous sodium bicarbonate solution was added, followed by two extractions with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.19 g, 76%).

[0581] MS (m / z): 439 [M+H]

[0582] (4) ((1R)-3-methyl-1-(3-phenyl-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[0583]

[0584] The N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-phenyl-4,5-dihydroisocyanate obtained in (3) above Azoxyl-5-carboxamide (0.19 g, 0.44 mmol) was dissolved in methanol (5 ml) and hexane (5 ml). After the sequential addition of isobutylboronic acid (0.23 g, 2.2 mmol) and 1 N hydrochloric acid aqueous solution (1.1 ml, 1.1 mmol), the mixture was stirred at room temperature for 18 hours. Methanol (5 ml) and hexane (5 ml) were added, and the methanol layer was separated. The hexane layer was further extracted with methanol (5 ml), and all methanol layers were distilled under reduced pressure. Ethyl acetate was added, and the resulting product was washed sequentially with aqueous sodium bicarbonate solution and brine, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.052 g, 38%).

[0585] MS (m / z): 305[M+H], 287[M-OH]

[0586] Example 2: ((1R)-3-methyl-1-(3-(pyrazin-2-yl)-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[0587] The title compound was obtained through the following processes (1), (2), (3), (4), (5) and (6).

[0588] (1) Preparation of pyrazine-2-carboxaldehyde

[0589]

[0590] The title compound was obtained by the method described in WO200540159A1.

[0591] (2) Preparation of pyrazine-2-carboxaldehyde oxime

[0592]

[0593] The pyrazine-2-carboxaldehyde (0.53 g, 4.90 mmol) obtained in (1) above was dissolved in dichloromethane (10 ml). Triethylamine (0.7 ml, 5.00 mmol) and hydroxylamine hydrochloride (0.38 g, 5.39 mmol) were added sequentially at 0 °C, and the mixture was stirred at room temperature for 2 hours. After distillation of the solvent under reduced pressure, water was added, and the mixture was extracted with diethyl ether. After dehydration with anhydrous magnesium sulfate, the filtered filtrate was separated by column chromatography to obtain the title compound (0.48 g, 79%).

[0594] NMR: 1 H-NMR(400MHz, CDCl3); δ 12.06 (br s, 1H), 9.00 (d, 1H), 8.67-8.62(m, 2H), 8.15 (s, 1H)

[0595] (3) 3-(pyrazin-2-yl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[0596]

[0597] The pyrazine-2-carboxaldehyde oxime (0.12 g, 0.97 mmol) obtained in (2) above was dissolved in dichloromethane (10 ml), and ethyl acrylate (0.096 ml, 0.97 mmol) was added to it at room temperature. A 4% aqueous solution of sodium hypochlorite (2.97 ml, 1.75 mmol) was slowly added to it at 0 °C, and the mixture was stirred for 18 hours while the temperature was raised to room temperature. The solvent was distilled under reduced pressure, and an aqueous solution of sodium bicarbonate was added, followed by two extractions with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.14 g, 65%).

[0598] NMR: 1 H-NMR (400MHz, CDCl3); δ 9.29 (d, 1H), 8.59-8.56 (m, 2H), 5.25-5.20 (m, 1H), 4.32-4.25 (q, 2H), 3.83-3.70 (m, 2H), 1.35-1.32 (t, 3H)

[0599] MS (m / z): 222 [M+H]

[0600] (4) 3-(pyrazin-2-yl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0601]

[0602] Using the 3-(pyrazin-2-yl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.14 g, 0.63 mmol) was used to prepare the title compound (0.1 g, 82%) by the method described in Examples 1-(2).

[0603] MS (m / z): 194 [M+H]

[0604] (5) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(pyrazin-2-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[0605]

[0606] Using the 3-(pyrazin-2-yl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.1 g, 0.52 mmol) was used to prepare the title compound (0.16 g, 70%) by the method described in Examples 1-(3).

[0607] MS (m / z): 441 [M+H]

[0608] (6) ((1R)-3-methyl-1-(3-(pyrazin-2-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[0609]

[0610] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(pyrazin-2-yl)-4,5-dihydroisocyano The title compound (0.067 g, 60%) was obtained by the preparation method of Examples 1-(4) (0.16 g, 0.36 mmol).

[0611] NMR: 1 H-NMR(400MHz, MeOD-d4); δ 9.20-9.19 (d, 1H), 8.69-8.68 (dd, 1H), 8.64-8.64 (d, 1H), 5.49-5.43 (m, 1H), 3.95-3.84 (m, 1H), 3.81-3.74 (m, 1H),2.95-2.90 (m, 1H), 1.69-1.63 (m, 1H), 1.44-1.37 (m, 2H), 0.94-0.92 (dd, 6H)

[0612] MS (m / z): 307[M+H], 289[M-OH]

[0613] Example 3: ((1R)-1-(3-(2,5-dichlorophenyl)-4,5-dihydroisocyanuric acid) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0614] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[0615] (1) Preparation of 2,5-dichlorobenzaldehyde oxime

[0616]

[0617] 2,5-Dichlorobenzaldehyde (0.3 g, 1.71 mmol) was dissolved in methanol (10 ml), and 50% aqueous hydroxylamine solution (0.21 ml, 3.43 mmol) was added to it at room temperature, followed by stirring for 16 hours. The title compound (0.32 g, 99%) was obtained by distillation of the solvent under reduced pressure and was immediately used in the next reaction without purification.

[0618] MS (m / z): 190 [M+H]

[0619] (2) 3-(2,5-dichlorophenyl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[0620]

[0621] The title compound (0.42 g 87%) was obtained by the preparation method of Examples 2-(3) using 2,5-dichlorobenzaldehyde oxime (0.32 g, 1.68 mmol) obtained in (1) above.

[0622] MS (m / z): 288 [M+H]

[0623] (3) 3-(2,5-dichlorophenyl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0624]

[0625] Using the 3-(2,5-dichlorophenyl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.42 g, 1.46 mmol) was used to prepare the title compound (0.37 g, 99%) by the method described in Examples 1-(2).

[0626] MS (m / z): 260 [M+H]

[0627] (4) 3-(2,5-dichlorophenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[0628]

[0629] Using the 3-(2,5-dichlorophenyl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.1 g, 0.38 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.16 g, 82%).

[0630] MS (m / z): 507 [M+H]

[0631] (5) ((1R)-1-(3-(2,5-dichlorophenyl)-4,5-dihydroisocyano) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0632]

[0633] Using the 3-(2,5-dichlorophenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.1 g, 85%) was obtained by the preparation method of Examples 1-(4) (0.1 g, 85%).

[0634] NMR: 1 H-NMR(400MHz, MeOD-d4); δ 7.67-7.65 (dd, 1H), 7.55-7.48 (m, 2H), 5.47-5.41 (m, 1H), 3.96-3.89 (m, 1H), 3.79-3.72 (m, 1H), 2.96-2.93 (m, 1H),1.71-1.65 (m, 1H), 1.44-1.38 (m, 2H), 0.95-0.93 (d, 6H)

[0635] MS (m / z): 373[M+H], 355[M-OH]

[0636] Example 4: ((1R)-1-(5-ethyl-3-phenyl-4,5-dihydroisocyanate) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0637] The title compound was obtained through the following processes (1), (2), (3) and (4).

[0638] (1) 5-Ethyl-3-phenyl-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[0639]

[0640] The title compound (0.91 g, 80%) was obtained by the preparation method of Example 1-(1) using N-hydroxyphenylcarbaminyl chloride (0.71 g, 4.6 mmol) and ethyl 2-methylene-butyrate (1.19 g, 9.28 mmol).

[0641] MS (m / z): 248 [M+H]

[0642] (2) 5-Ethyl-3-phenyl-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0643]

[0644] Using the 5-ethyl-3-phenyl-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.91 g, 3.7 mmol) was used to prepare the title compound (0.81 g, quantified) by the method described in Examples 1-(2).

[0645] MS (m / z): 220 [M+H]

[0646] (3) 5-Ethyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-phenyl-4,5-dihydroisocyanate Preparation of azole-5-carboxamide

[0647]

[0648] Using the 5-ethyl-3-phenyl-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.12 g, 0.57 mmol) was used to prepare the title compound (0.21 g, 79%) by the method described in Examples 1-(3).

[0649] MS (m / z): 467 [M+H]

[0650] (4) ((1R)-1-(5-ethyl-3-phenyl-4,5-dihydroisocyanate) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0651]

[0652] Using the 5-ethyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-phenyl-4,5-dihydroisocyano The title compound (0.025 g, 57%) was obtained by the preparation method of Examples 1-(4) (0.062 g, 0.13 mmol).

[0653] MS (m / z): 333[M+H], 315[M-OH]

[0654] Example 5: ((1R)-3-methyl-1-(5-methyl-3-phenyl-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[0655] The title compound was obtained through the following processes (1), (2), (3) and (4).

[0656] (1) 5-Methyl-3-phenyl-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[0657]

[0658] The title compound (1.0 g, 78%) was obtained by the preparation method of Example 2-(3) using N-hydroxyphenylcarbaminyl chloride (0.89 g, 5.7 mmol) and ethyl 2-methylene-butyrate (1.3 g, 11.5 mmol).

[0659] MS (m / z): 234 [M+H]

[0660] (2) 5-Methyl-3-phenyl-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0661]

[0662] Using the 5-methyl-3-phenyl-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (1.0 g, 4.45 mmol) was used to prepare the title compound (0.83 g, 91%) by the method described in Examples 1-(2).

[0663] MS (m / z): 206 [M+H]

[0664] (3) 5-Methyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-phenyl-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[0665]

[0666] Using the 5-methyl-3-phenyl-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.099 g, 0.48 mmol) was used to prepare the title compound (0.19 g, 89%) by the method described in Examples 1-(3).

[0667] MS (m / z): 453 [M+H]

[0668] (4) ((1R)-3-methyl-1-(5-methyl-3-phenyl-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[0669]

[0670] Using the 5-methyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-phenyl-4,5-dihydroisocyano The title compound (0.071 g, 52%) was obtained by the preparation method of Examples 1-(4) (0.19 g, 0.43 mmol).

[0671] MS (m / z): 319[M+H], 301[M-OH]

[0672] Example 6: ((1R)-1-(5-ethyl-3-(pyrazin-2-yl)-4,5-dihydroisocyanate) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0673] The title compound was obtained through the following processes (1), (2), (3) and (4).

[0674] (1) 5-Ethyl-3-(pyrazin-2-yl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[0675]

[0676] The title compound (0.16 g, 56%) was obtained by the preparation method of Example 2-(3) using pyrazine-2-carboxaldehyde oxime (0.15 g, 1.22 mmol) and ethyl 2-methylene-butyrate (0.19 g, 1.11 mmol) obtained in Example 2-(2).

[0677] NMR: 1 H-NMR(400MHz, CDCl3); δ 9.26 (d, 1H), 8.56-8.55 (d, 2H), 4.34-4.22(m, 2H), 3.94-3.89 (d, 1H), 3.41-3.36 (d, 1H), 2.13-2.01 (m, 2H), 1.34-1.31(t, 3H), 1.03-1.00 (t, 3H)

[0678] MS (m / z): 250 [M+H]

[0679] (2) 5-Ethyl-3-(pyrazin-2-yl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0680]

[0681] Using the 5-ethyl-3-(pyrazin-2-yl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.16 g, 0.62 mmol) was used to prepare the title compound (0.14 g, 99%) by the method described in Examples 1-(2).

[0682] MS (m / z): 222 [M+H]

[0683] (3) 5-Ethyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(pyrazin-2-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[0684]

[0685] Using 5-ethyl-3-(pyrazin-2-yl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.14 g, 0.63 mmol) was used to prepare the title compound (0.23 g, 76%) by the method described in Examples 1-(3).

[0686] MS (m / z): 469 [M+H]

[0687] (4) ((1R)-1-(5-ethyl-3-(pyrazin-2-yl)-4,5-dihydroisocyano) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0688]

[0689] The 5-ethyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(pyrazin-2-yl)-4,5-dihydroisocyano The title compound (0.098 g, 60%) was obtained by the preparation method of Examples 1-(4) (0.23 g, 0.49 mmol).

[0690] NMR: 1 H-NMR(400MHz, MeOD-d4); δ 9.17-9.16 (d, 1H), 8.68-8.67 (dd, 1H), 8.63-8.62 (d, 1H), 3.90-3.83 (m, 1H), 3.63-3.58 (m, 1H), 2.91-2.82 (m, 1H),2.22-2.14 (m, 1H), 2.09-2.03 (m, 1H), 1.73-1.64 (m, 1H), 1.49-1.35 (m, 2H),0.18-1.04 (m, 3H), 0.99-0.88 (m, 6H)

[0691] MS (m / z): 335[M+H], 317[M-OH]

[0692] Example 7: ((R)-1-((S)-5-benzyl-3-phenyl-4,5-dihydroisocyanate) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0693] The title compound was obtained through the following processes (1), (2) and (3).

[0694] (1) 5-Benzyl-3-phenyl-4,5-dihydro-1,2- Preparation of methyl 5-azole carboxylate

[0695]

[0696] N-hydroxyphenylcarbaminyl chloride (0.58 g, 3.7 mmol) was dissolved in tetrahydrofuran (10 ml), and 2-phenylmethylacrylic acid (0.5 g, 3.1 mmol) and diisopropylethylamine (0.8 ml, 4.6 mmol) were added at 0 °C. After stirring for 18 hours, 10 ml of 1 N hydrochloric acid solution was added while the mixture was heated to room temperature, and then stirred for 10 minutes. After distilling the tetrahydrofuran solvent under reduced pressure, the aqueous layer was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.12 g, 13%).

[0697] NMR: 1 H-NMR (400MHz, DMSO-d6); δ 7.59-7.17 (m, 10H), 3.74-3.70 (d, 1H), 3.34-3.17 (m, 4H)

[0698] MS (m / z): 296 [M+H]

[0699] (2) 5-Benzyl-3-phenyl-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0700]

[0701] Using the 5-benzyl-3-phenyl-4,5-dihydro-1,2- Methyl 5-azole carboxylate (0.126 g, 0.43 mmol) was used to prepare the title compound (0.12 g, quantified) by the method described in Examples 1-(2).

[0702] MS (m / z): 282 [M+H]

[0703] (3) ((R)-1-((S)-5-benzyl-3-phenyl-4,5-dihydroisocyanate) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0704]

[0705] At 0°C, the 5-benzyl-3-phenyl-4,5-dihydro-1,2-diphenyl ... Azoxyl-5-carboxylic acid (0.12 g, 0.41 mmol), (R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborhexacyclopentan-2-yl)but-1-amine hydrochloride (0.14 g, 0.45 mmol) and O -(benzotriazol-1-yl)- N,N,N',N' Tetramethyltetrafluoroborate urea (0.14 g, 0.45 mmol) was dissolved in dimethylformamide (5 ml). While maintaining the temperature, diisopropylethylamine (0.21 ml, 1.3 mmol) was slowly added, and the mixture was stirred for 18 hours while the temperature was raised to room temperature. The solvent was distilled under reduced pressure, an aqueous sodium bicarbonate solution was added, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous magnesium sulfate, and filtered. The 5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-phenyl-4,5-dihydroisocyanate was obtained by distilling the filtrate under reduced pressure. Zyrazole-5-carboxamide was dissolved in methanol (3 ml) and hexane (3 ml) without further purification. Isobutylboronic acid (0.060 g, 0.59 mmol) and 0.28 ml of 1 N hydrochloric acid aqueous solution were added sequentially, and the mixture was stirred at room temperature for 18 hours. Methanol (3 ml) and hexane (3 ml) were added, and the methanol layer was separated. The hexane layer was extracted again with methanol (3 ml), and all methanol layers were distilled under reduced pressure. Ethyl acetate was added, and the resulting product was washed sequentially with sodium bicarbonate aqueous solution and brine, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain two types of the title compound, wherein isomer 1 is of low polarity (0.060 g, 37%, 2 steps) and isomer 2 is of high polarity (0.070 g, 44%, 2 steps).

[0706] Isomer 1

[0707] MS (m / z): 395[M+H], 377[M-OH]

[0708] Isomer 2

[0709] MS (m / z): 395[M+H], 377[M-OH]

[0710] Example 8: ((1R)-1-(3-phenylmethyl-4,5-dihydroisocyanate) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0711] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[0712] (1) Preparation of phenyl-acetaldehyde oxime

[0713]

[0714] The title compound (1.11 g, 99%) was obtained using phenylacetaldehyde (1.0 g, 8.3 mmol) by the preparation method of Example 3-(1).

[0715] (2) 3-Benzyl-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[0716]

[0717] The title compound (1.09 g 57%) was obtained by the preparation method of Examples 2-(3) using phenyl-acetaldehyde oxime (1.11 g, 8.2 mmol) obtained in (1) above.

[0718] MS (m / z): 234 [M+H]

[0719] (3) 3-Benzyl-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0720]

[0721] Using the 3-benzyl-4,5-dihydro-1,2- obtained in (2) above Ethyl 5-oxazolium carboxylate (1.09 g, 4.7 mmol) was used to prepare the title compound (0.96 g, quantified) by the method described in Examples 1-(2).

[0722] MS (m / z): 206 [M+H]

[0723] (4) 3-Benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[0724]

[0725] Using the 3-benzyl-4,5-dihydro-1,2- obtained in (3) above Azoxyl-5-carboxylic acid (0.96 g, 4.7 mmol) was used to prepare the title compound (0.586 g, 28%) by the method described in Examples 1-(3).

[0726] MS (m / z): 453 [M+H]

[0727] (5) ((1R)-1-(3-phenylmethyl-4,5-dihydroisocyanate) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0728]

[0729] Using the 3-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.031 g, 36%) was obtained by the preparation method of Examples 1-(4) (0.122 g, 0.27 mmol).

[0730] MS (m / z): 319[M+H], 301[M-OH]

[0731] Example 9: ((1R)-1-(3-cyclohexyl-4,5-dihydroisocyanate) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0732] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[0733] (1) Preparation of cyclohexaneformaldehyde oxime

[0734]

[0735] The title compound (1.38 g, 88%) was obtained using cyclohexaneformaldehyde (1.5 ml, 12.4 mmol) by the preparation method of Example 3-(1).

[0736] (2) 3-Cyclohexyl-4,5-dihydroisocyanate Ethyl 5-oxazolium carboxylate

[0737]

[0738] The title compound (1.17 g, 48%) was obtained by the preparation method of Preparation Examples 1-(2) using cyclohexaneformaldehyde oxime (1.38 g, 10.9 mmol) obtained in (1) above.

[0739] MS (m / z): 226 [M+H]

[0740] (3) 3-Cyclohexyl-4,5-dihydroisocyanate Preparation of 5-azole carboxylic acid

[0741]

[0742] Using the 3-cyclohexyl-4,5-dihydroisocyanate obtained in (2) above Ethyl 5-oxazolium carboxylate (1.17 g, 5.2 mmol) was used to prepare the title compound (1.02 g, quantified) by the method described in Examples 1-(2).

[0743] MS (m / z): 198 [M+H]

[0744] (4) 3-Cyclohexyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[0745]

[0746] Using the 3-cyclohexyl-4,5-dihydroisocyanate obtained in (3) above Azoxyl-5-carboxylic acid (0.14 g, 0.72 mmol) was used to prepare the title compound (0.26 g, 81%) by the method described in Examples 1-(3).

[0747] MS (m / z): 445 [M+H]

[0748] (5) ((1R)-1-(3-cyclohexyl-4,5-dihydroisocyanate) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0749]

[0750] Using the 3-cyclohexyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborone-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.11 g, 62%) was obtained by the preparation method of Examples 1-(4) (0.26 g, 0.58 mmol).

[0751] MS (m / z): 311[M+H], 293[M-OH]

[0752] Example 10: ((1R)-1-(3-cyclopropyl-4,5-dihydroisocyanuric acid) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0753] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[0754] (1) Preparation of cyclopropane formaldehyde oxime

[0755]

[0756] The title compound (0.37 g, 61%) was obtained by the preparation method of Preparation Example 6-(1) using cyclopropaneformaldehyde (0.5 g, 7.13 mmol).

[0757] NMR: 1 H-NMR (400MHz, CDCl3); δ 6.02-6.00 (d, 1H), 2.32-2.25 (m, 1H), 0.97-0.93 (m, 2H), 0.65-0.61 (m, 2H)

[0758] (2) 3-Cyclopropyl-4,5-Dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[0759]

[0760] The title compound (0.33 g 41%) was obtained by the preparation method of Examples 2-(3) using the cyclopropaneformaldehyde oxime (0.37 g, 4.35 mmol) obtained in (1) above.

[0761] NMR: 1 H-NMR (500MHz, CDCl3); δ 4.96-4.92 (t, 1H), 4.24-4.10 (m, 2H), 3.08-3.06 (d, 2H), 1.79-1.77 (m, 1H), 1.30-1.25 (m, 3H), 0.98-0.79 (m, 4H)

[0762] MS (m / z): 184 [M+H]

[0763] (3) 3-Cyclopropyl-4,5-Dihydroisocyanate Preparation of 5-azole carboxylic acid

[0764]

[0765] Using the 3-cyclopropyl-4,5-dihydroisocyanate obtained in (2) above Ethyl 5-oxazolium carboxylate (0.33 g, 1.80 mmol) was used to prepare the title compound (0.25 g, 90%) by the method described in Examples 1-(2).

[0766] MS (m / z): 156 [M+H]

[0767] (4) 3-Cyclopropyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[0768]

[0769] Using the 3-cyclopropyl-4,5-dihydroisocyanate obtained in (3) above Azoxyl-5-carboxylic acid (0.07 g, 0.45 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.13 g, 72%).

[0770] MS (m / z): 403 [M+H]

[0771] (5) ((1R)-1-(3-cyclopropyl-4,5-dihydroisocyanate) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0772]

[0773] Using the 3-cyclopropyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.07 g, 81%) was obtained by the preparation method of Examples 1-(4) (0.13 g, 0.32 mmol).

[0774] NMR: 1H-NMR(500MHz, MeOD-d4); δ 5.16-5.12 (m, 1H), 3.27-3.24 (m, 1H), 3.07-3.02 (m, 1H), 2.83-2.78 (m, 1H), 1.82-1.77 (m, 1H), 1.65-1.60 (m, 1H),1.36-1.32 (m, 2H), 0.95-0.92 (m, 2H), 0.91-0.88 (d, 6H), 0.80-0.76 (m, 2H)

[0775] MS (m / z): 269[M+H], 251[M-OH]

[0776] Example 11: ((1R)-3-methyl-1-(3-pentyl-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[0777] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[0778] (1) Preparation of 3-phenyl-propanal oxime

[0779]

[0780] The title compound (0.55 g, 99%) was obtained using 3-phenyl-propanal (0.5 g, 3.7 mmol) by the preparation method of Example 3-(1).

[0781] (2) 3-(2-phenylethyl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[0782]

[0783] The title compound (0.45 g 49%) was obtained by the preparation method of Example 2-(3) using 3-phenyl-propanal oxime (0.55 g, 3.7 mmol) obtained in Example 11-(1).

[0784] MS (m / z): 248 [M+H]

[0785] (3) 3-(2-phenylethyl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0786]

[0787] Using the 3-(2-phenylethyl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.45 g, 1.8 mmol) was used to prepare the title compound (0.39 g, 98%) by the method described in Examples 1-(2).

[0788] MS (m / z): 220 [M+H]

[0789] (4) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-pentyl-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[0790]

[0791] Using the 3-(2-phenylethyl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.39 g, 1.8 mmol) was used to prepare the title compound (0.16 g, 19%) by the method described in Examples 1-(3).

[0792] MS (m / z): 467 [M+H]

[0793] (5) ((1R)-3-methyl-1-(3-pentyl-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[0794]

[0795] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborone-2-yl)butyl)-3-pentyl-4,5-dihydroisocyano The title compound (0.045 g, 37%) was obtained by the preparation method of Examples 1-(4) (0.16 g, 0.34 mmol).

[0796] MS (m / z): 333[M+H], 315[M+H]

[0797] Example 12: ((1R)-1-(3-(isoquinoline-1-yl)-4,5-dihydroisoquinoline-1-yl) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0798] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[0799] (1) Preparation of isoquinoline-1-carboxaldehyde oxime

[0800]

[0801] The title compound was obtained by the method described in WO200521516A1.

[0802] (2) 3-(isoquinolin-1-yl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[0803]

[0804] The title compound (0.74 g, 91%) was obtained by means of the preparation method in Examples 2-(3) using isoquinoline-1-carboxaldehyde oxime (0.52 g, 3.0 mmol) and ethyl acrylate (0.39 g, 3.9 mmol) obtained in (1) above.

[0805] NMR: 1 H-NMR(500MHz, CDCl3); δ 9.25-9.24 (d, 1H), 8.55-8.54 (d, 1H), 7.86-7.85 (d, 1H), 7.74-7.66 (m, 3H), 5.21-5.17 (m, 1H), 4.31-4.25 (q, 2H),4.10-3.97 (m, 2H), 1.34-1.31 (t, 3H)

[0806] MS (m / z): 271 [M+H]

[0807] (3) 3-(isoquinolin-1-yl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0808]

[0809] Using the 3-(isoquinolin-1-yl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.74 g, 2.7 mmol) was used to prepare the title compound (0.66 g, quantified) by the method described in Examples 1-(2).

[0810] MS (m / z): 243 [M+H]

[0811] (4) 3-(isoquinoline-1-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisoquinoline-1-yl) Preparation of azole-5-carboxamide

[0812]

[0813] Using the 3-(isoquinolin-1-yl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.08 g, 0.33 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.13 g, 81%).

[0814] MS (m / z): 490 [M+H]

[0815] (5) ((1R)-1-(3-(isoquinolin-1-yl)-4,5-dihydroisoquinolinyl) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0816]

[0817] Using the 3-(isoquinolin-1-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisoquinolin-1-yl) ...oboron-2-yl)butyl)-4,5-dihydroisoquinolin-1-yl)oboron-2-yl)butyl)oboron-2-yl)oboron-2-yl)oboron-2-yl The title compound (0.045 g, 47%) was obtained by the preparation method of Examples 1-(4) (0.13 g, 0.27 mmol).

[0818] MS (m / z): 356[M+H], 338[M+H]

[0819] Example 13: ((R)-1-((R)-5-isopropyl-3-(isoquinolin-1-yl)-4,5-dihydro ... Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0820] The title compound was obtained through the following processes (1), (2) and (3).

[0821] (1) 3-(isoquinoline-1-yl)-5-(propyl-2-yl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0822]

[0823] The title compound was obtained by the method described in WO2005021516A1.

[0824] (2) 5-Isopropyl-3-(isoquinoline-1-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisopropyl Preparation of azole-5-carboxamide

[0825]

[0826] Using (R)-5-isopropyl-3-isoquinoline-1-yl-4,5-dihydro-isoquinoline obtained in (1) above Azoxyl-5-carboxylic acid (0.073 g, 0.14 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.075 g, 61%).

[0827] MS (m / z): 490 [M+H]

[0828] (3) ((R)-1-((R)-5-isopropyl-3-(isoquinolin-1-yl)-4,5-dihydroisopropyl) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0829]

[0830] Using the 5-isopropyl-3-(isoquinolin-1-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisopropyl The title compound (0.035 g, 63%) was obtained by the preparation method of Examples 1-(4) (0.074 g, 0.14 mmol).

[0831] NMR: 1H-NMR(400MHz, CDCl3); δ 9.14-9.12 (d, 1H), 8.57-8.56 (d, 1H), 7.90-7.88 (d, 1H), 7.76-7.67 (m, 3H), 7.50-7.49 (d, 1H), 4.09-4.04 (d, 1H),3.88-3.84 (d, 1H), 3.005 (m, 1H), 2.47-2.40 (m, 1H), 1.72-1.43 (m, 3H), 1.67-1.10 (dd, 6H), 0.97-0.91 (dd, 6H)

[0832] MS (m / z): 398[M+H], 380[M-OH]

[0833] Example 14: ((1R)-1-(3-(3-(tert-butyl)phenyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0834] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[0835] (1) Preparation of 3-tert-butylbenzaldehyde oxime

[0836]

[0837] The title compound (0.54 g, 99%) was obtained using 3-tert-butylbenzaldehyde (0.5 g, 3.08 mmol) by the preparation method of Example 3-(1).

[0838] (2) 3-(3-tert-butylphenyl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[0839]

[0840] The title compound (0.41 g 98%) was obtained by the preparation method of Examples 2-(3) using 3-tert-butylbenzaldehyde oxime (0.27 g, 1.52 mmol) obtained in (1) above.

[0841] MS (m / z): 276 [M+H]

[0842] (3) 3-(3-tert-butylphenyl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0843]

[0844] Using the 3-(3-tert-butylphenyl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.41 g, 1.49 mmol) was used to prepare the title compound (0.37 g, 99%) by the method described in Examples 1-(2).

[0845] MS (m / z): 248 [M+H]

[0846] (4) 3-(3-(tert-butyl)phenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[0847]

[0848] Using 3-(3-tert-butylphenyl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.1 g, 0.40 mmol) was used to prepare the title compound (0.13 g, 66%) by the method described in Examples 1-(3).

[0849] MS (m / z): 495 [M+H]

[0850] (5) ((1R)-1-(3-(3-(tert-butyl)phenyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0851]

[0852] Using the 3-(3-(tert-butyl)phenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.06 g, 63%) was obtained by the preparation method of Examples 1-(4) (0.13 g, 0.27 mmol).

[0853] NMR: 1H-NMR(400MHz, MeOD-d4); δ 7.79 (s, 1H), 7.57-7.38 (m, 3H), 5.41-5.38 (m, 1H), 3.90-3.74 (m, 1H), 3.74-3.67 (m, 1H), 2.90 (m, 1H), 1.67 (m,1H), 1.43-1.38 (m, 2H), 1.36 (s, 9H), 0.94-0.91 (dd, 6H)

[0854] MS (m / z): 361[M+H], 343[M-OH]

[0855] Example 15: ((1R)-1-(3-(4-(tert-butyl)phenyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0856] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[0857] (1) Preparation of 4-tert-butylbenzaldehyde oxime

[0858]

[0859] The title compound (0.46 g, quantified) was obtained using 4-tert-butylbenzaldehyde (0.42 g, 2.6 mmol) by the preparation method of Example 3-(1).

[0860] (2) 3-(4-tert-butylphenyl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[0861]

[0862] The title compound (0.12 g 17%) was obtained by means of the preparation method in Examples 2-(3) using 4-tert-butylbenzaldehyde oxime (0.46 g, 2.6 mmol) obtained in (1) above.

[0863] MS (m / z): 276 [M+H]

[0864] (3) 3-(4-tert-butylphenyl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0865]

[0866] Using the 3-(4-tert-butylphenyl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.12 g, 0.44 mmol) was used to prepare the title compound (0.11 g, quantified) by the method described in Examples 1-(2).

[0867] MS (m / z): 248 [M+H]

[0868] (4) 3-(4-(tert-butyl)phenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[0869]

[0870] Using the 3-(4-tert-butylphenyl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.11 g, 0.44 mmol) was used to prepare the title compound (0.15 g, 68%) by the method described in Examples 1-(3).

[0871] MS (m / z): 495 [M+H]

[0872] (5) ((1R)-1-(3-(4-(tert-butyl)phenyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0873]

[0874] Using the 3-(4-(tert-butyl)phenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.047 g, 44%) was obtained by the preparation method of Examples 1-(4) (0.15 g, 0.30 mmol).

[0875] MS (m / z): 361[M+H], 343[M-OH]

[0876] Example 16: ((1R)-1-(3-(4-acetamidophenyl)-4,5-dihydroisocyanuric acid) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0877] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[0878] (1) Preparation of N-(4-formyl-phenyl)-acetamide oxime

[0879]

[0880] The title compound (0.99 g, quantified) was obtained using N-(4-formyl-phenyl)-acetamide (0.90 g, 5.5 mmol) by the preparation method of Example 3-(1).

[0881] MS (m / z): 179 [M+H]

[0882] (2) 3-(4-acetamidophenyl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[0883]

[0884] The title compound (0.69 g 45%) was obtained by the preparation method of Examples 2-(3) using N-(4-formyl-phenyl)-acetamide oxime (0.99 g, 5.5 mmol) obtained in (1) above.

[0885] MS (m / z): 277 [M+H]

[0886] (3) 3-(4-acetamidophenyl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0887]

[0888] Using the 3-(4-acetamidophenyl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.13 g, 0.46 mmol) was used to prepare the title compound (0.12 g, quantified) by the method described in Examples 1-(2).

[0889] MS (m / z): 249 [M+H]

[0890] (4) 3-(4-acetamidophenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[0891]

[0892] Using the 3-(4-acetamidophenyl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.11 g, 0.46 mmol) was used to prepare the title compound (0.05 g, 22%) by the method described in Examples 1-(3).

[0893] MS (m / z): 496 [M+H]

[0894] (5) ((1R)-1-(3-(4-acetamidophenyl)-4,5-dihydroisocyano) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0895]

[0896] Using the 3-(4-acetamidophenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridgedbenzi[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.022 g, 59%) was obtained by the preparation method of Examples 1-(4) (0.050 g, 0.1 mmol) of azole-5-carboxamide (0.050 g, 0.1 mmol).

[0897] MS (m / z): 362[M+H], 344[M-OH]

[0898] Example 17: ((1R)-3-methyl-1-(3-(naphth-2-yl)-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[0899] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[0900] (1) Preparation of naphthalene-2-carboxaldehyde oxime

[0901]

[0902] The title compound (1.70 g, 99%) was obtained using naphthalene-2-carboxaldehyde (1.56 g, 9.99 mmol) by the preparation method of Example 3-(1).

[0903] (2) 3-(naphthyl-2-yl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[0904]

[0905] The title compound (0.60 g 95%) was obtained by the preparation method of Examples 2-(3) using naphthalene-2-carboxaldehyde oxime (0.40 g, 2.3 mmol) obtained in (1) above.

[0906] NMR: 1 H-NMR (500MHz, CDCl3); δ 7.99-7.84 (m, 5H), 7.53-7.51 (m, 2H), 5.24-5.20 (m, 1H), 4.30-4.26 (m, 2H), 3.81-3.72 (m, 2H), 1.35-1.32 (t, 3H)

[0907] MS (m / z): 270 [M+H]

[0908] (3) 3-(naphthyl-2-yl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0909]

[0910] Using the 3-(naphthyl-2-yl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.60 g, 2.2 mmol) was used to prepare the title compound (0.53 g, 99%) by the method described in Examples 1-(2).

[0911] MS (m / z): 242 [M+H]

[0912] (4) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(naphthyl-2-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[0913]

[0914] Using the 3-(naphthyl-2-yl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.10 g, 0.41 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.185 g, 91%).

[0915] MS (m / z): 489 [M+H]

[0916] (5) ((1R)-3-methyl-1-(3-(naphth-2-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[0917]

[0918] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(naphthyl-2-yl)-4,5-dihydroisocyano The title compound (0.083 g, 62%) was obtained by the preparation method of Examples 1-(4) (0.184 g, 0.38 mmol).

[0919] NMR: 1 H-NMR(500MHz, CDCl3); δ 7.99-7.81 (m, 5H), 7.54-7.51 (m, 2H), 7.31(m, 1H), 5.32-5.17 (m, 1H), 3.88-3.66 (m, 2H), 3.09-2.79 (m, 1H), 1.62-1.28(m, 3H), 0.89-0.79 (m, 6H)

[0920] MS (m / z): 355[M+H], 337[M-OH]

[0921] Example 18: ((1R)-3-methyl-1-(3-(naphth-2-ylmethyl)-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[0922] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[0923] (1) Preparation of naphth-2-yl-acetaldehyde oxime

[0924]

[0925] The title compound (0.24 g, quantified) was obtained using the preparation method of Example 3-(1) with naphth-2-yl-acetaldehyde (0.22 g, 1.3 mmol).

[0926] (2) 3-[(naphthyl-2-yl)methyl]-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[0927]

[0928] The title compound (0.081 g 22%) was obtained by the preparation method of Examples 2-(3) using the naphth-2-yl-acetaldehyde oxime (0.24 g, 1.3 mmol) obtained in (1) above.

[0929] MS (m / z): 284 [M+H]

[0930] (3) 3-[(naphthyl-2-yl)methyl]-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0931]

[0932] Using the 3-[(naphthyl-2-yl)methyl]-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.081 g, 0.29 mmol) was used to prepare the title compound (0.073 g, quantified) by the method described in Examples 1-(2).

[0933] MS (m / z): 256 [M+H]

[0934] (4) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(naphthyl-2-ylmethyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[0935]

[0936] Using the 3-[(naphthyl-2-yl)methyl]-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.073 g, 0.29 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.038 g, 26%).

[0937] MS (m / z): 503 [M+H]

[0938] (5) ((1R)-3-methyl-1-(3-(naphth-2-ylmethyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[0939]

[0940] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(naphthyl-2-ylmethyl)-4,5-dihydroisocyano The title compound (0.008 g, 30%) was obtained by the preparation method of Examples 1-(4) (0.038 g, 0.08 mmol).

[0941] MS (m / z): 369 [M+H], 351 [M-OH]

[0942] Example 19: ((1R)-3-methyl-1-(3-(naphth-1-yl)-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[0943] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[0944] (1) Preparation of naphthalene-1-carboxaldehyde oxime

[0945]

[0946] The title compound (1.71 g, 99%) was obtained using naphthalene-1-carboxaldehyde (1.56 g, 9.99 mmol) by the preparation method of Example 3-(1).

[0947] MS (m / z): 172 [M+H]

[0948] (2) 3-(naphthyl-1-yl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[0949]

[0950] The title compound (0.53 g 85%) was obtained by the preparation method of Examples 2-(3) using naphthalene-1-carboxaldehyde oxime (0.4 g, 2.34 mmol) obtained in (1) above.

[0951] MS (m / z): 270 [M+H]

[0952] (3) 3-(naphthyl-1-yl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0953]

[0954] Using the 3-(naphthyl-1-yl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.53 g, 1.98 mmol) was used to prepare the title compound (0.47 g, 99%) by the method described in Examples 1-(2).

[0955] MS (m / z): 242 [M+H]

[0956] (4) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(naphthyl-1-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[0957]

[0958] Using the 3-(naphthyl-1-yl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.1 g, 0.41 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.15 g, 70%).

[0959] MS (m / z): 517 [M+H]

[0960] (5) ((1R)-3-methyl-1-(3-(naphth-1-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[0961]

[0962] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(naphthyl-1-yl)-4,5-dihydroisocyano The title compound (0.07 g, 70%) was obtained by the preparation method of Examples 1-(4) (0.15 g, 0.29 mmol).

[0963] NMR: 1 H-NMR(400MHz, MeOD-d4); δ 8.88-8.82 (m, 1H), 8.02-7.95 (m, 2H), 7.72-7.55 (m, 4H), 5.45-5.40 (m, 1H), 4.12-4.04 (m, 1H), 3.89-3.82 (m, 1H),2.96-2.94 (m, 1H), 1.72-1.68 (m, 1H), 1.46-1.39 (m, 2H), 0.95-0.91 (m, 6H)

[0964] MS (m / z): 355 [M+H]

[0965] Example 20: ((1R)-1-(3-([1,1'-biphenyl]-3-yl)-4,5-dihydroisocyanate) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0966] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[0967] (1) Preparation of biphenyl-3-carboxaldehyde oxime

[0968]

[0969] The title compound (0.54 g, 99%) was obtained using biphenyl-3-carboxaldehyde (0.5 g, 2.74 mmol) by the preparation method of Example 3-(1).

[0970] MS (m / z): 198 [M+H]

[0971] (2) 3-(3-phenylphenyl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[0972]

[0973] The title compound (0.26 g 87%) was obtained by the preparation method of Examples 2-(3) using biphenyl-3-carboxaldehyde oxime (0.2 g, 1.01 mmol) obtained in (1) above.

[0974] NMR: 1H-NMR (400MHz, CDCl3); δ 7.91-7.90 (m, 1H), 7.67-7.60 (m, 4H), 7.51-7.36 (m, 4H), 5.22-5.17 (m, 1H), 4.32-4.25 (q, 2H), 3.76-3.63 (m, 2H),1.33-1.28 (t, 3H)

[0975] MS (m / z): 296 [M+H]

[0976] (3) 3-(3-phenylphenyl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0977]

[0978] Using the 3-(3-phenylphenyl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.26 g, 0.88 mmol) was used to prepare the title compound (0.23 g, 99%) by the method described in Examples 1-(2).

[0979] MS (m / z): 268 [M+H]

[0980] (4) 3-([1,1'-biphenyl]-3-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[0981]

[0982] Using 3-(3-phenylphenyl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.1 g, 0.37 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.17 g, 88%).

[0983] MS (m / z): 515 [M+H]

[0984] (5) ((1R)-1-(3-([1,1'-biphenyl]-3-yl)-4,5-dihydroisocyanate) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[0985]

[0986] Using the 3-([1,1'-biphenyl]-3-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.089 g, 71%) was obtained by the preparation method of Examples 1-(4) (0.17 g, 0.33 mmol).

[0987] NMR: 1 H-NMR(500MHz, MeOD-d4); δ 7.93-7.93 (m, 1H), 7.22-7.62 (m, 4H), 7.53-7.34 (m, 4H), 5.40-5.37 (m, 1H), 3.91-3.83 (m, 1H), 3.76-3.70 (m, 1H),2.88-2.84 (m, 1H), 1.66-1.61 (m, 1H), 1.40-1.33 (m, 2H), 0.92-0.87 (dd, 6H)

[0988] MS (m / z): 381 [M+H]

[0989] Example 21: ((1R)-3-methyl-1-(3-(quinolin-2-yl)-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[0990] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[0991] (1) Preparation of quinoline-2-carboxaldehyde oxime

[0992]

[0993] The title compound (1.72 g, quantified) was obtained using quinoline-2-carboxaldehyde (1.57 g, 10.0 mmol) by the preparation method of Example 3-(1).

[0994] (2) 3-(quinolin-2-yl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[0995]

[0996] The title compound (0.49 g, 78%) was obtained by the preparation method of Examples 2-(3) using quinoline-2-carboxaldehyde oxime (0.40 g, 2.3 mmol) obtained in (1) above.

[0997] MS (m / z): 271 [M+H]

[0998] (3) 3-(quinolin-2-yl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[0999]

[1000] Using the 3-(quinolin-2-yl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.49 g, 1.8 mmol) was used to prepare the title compound (0.39 g, 89%) by the method described in Examples 1-(2).

[1001] MS (m / z): 243 [M+H]

[1002] (4) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(quinolin-2-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1003]

[1004] Using the 3-(quinolin-2-yl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.08 g, 0.33 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.13 g, 82%).

[1005] MS (m / z): 490 [M+H]

[1006] (5) ((1R)-3-methyl-1-(3-(quinolin-2-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1007]

[1008] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(quinolin-2-yl)-4,5-dihydroisocyano The title compound (0.045 g, 47%) was obtained by the preparation method of Examples 1-(4) (0.13 g, 0.27 mmol).

[1009] MS (m / z): 356 [M+H]

[1010] Example 22: ((1R)-1-(3-(isoquinoline-3-yl)-4,5-dihydroisoquinoline-3-yl) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1011] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1012] (1) Preparation of isoquinoline-3-carboxaldehyde oxime

[1013]

[1014] The title compound (0.39 g, 99%) was obtained by the preparation method of Example 3-(1) using isoquinoline-3-carboxaldehyde (0.36 g, 2.3 mmol).

[1015] MS (m / z): 173 [M+H]

[1016] (2) 3-(isoquinoline-3-yl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1017]

[1018] The title compound (0.38 g 62%) was obtained by the preparation method of Examples 2-(3) using isoquinoline-3-carboxaldehyde oxime (0.39 g, 2.3 mmol) obtained in (1) above.

[1019] MS (m / z): 271 [M+H]

[1020] (3) 3-(isoquinolin-3-yl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1021]

[1022] Using the 3-(isoquinolin-3-yl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.38 g, 1.41 mmol) was used to prepare the title compound (0.34 g, quantified) by the method described in Examples 1-(2).

[1023] MS (m / z): 243 [M+H]

[1024] (4) 3-(isoquinoline-3-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisoquinoline Preparation of azole-5-carboxamide

[1025]

[1026] Using the 3-(isoquinolin-3-yl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.08 g, 0.33 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.09 g, 56%).

[1027] MS (m / z): 490 [M+H]

[1028] (5) ((1R)-1-(3-(isoquinolin-3-yl)-4,5-dihydroisoquinolinyl) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1029]

[1030] Using the 3-(isoquinoline-3-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisoquinoline-3-yl) ... The title compound (0.043 g, 66%) was obtained by the preparation method of Examples 1-(4) (0.09 g, 0.18 mmol).

[1031] MS (m / z): 356 [M+H]

[1032] Example 23: ((1R)-3-methyl-1-(3-(quinolin-4-yl)-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[1033] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1034] (1) Preparation of quinoline-4-carboxaldehyde oxime

[1035]

[1036] The title compound (0.82 g, 99%) was obtained using quinoline-4-carboxaldehyde (0.76 g, 4.8 mmol) by the preparation method of Example 3-(1).

[1037] (2) 3-(quinolin-4-yl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1038]

[1039] The title compound (0.87 g 67%) was obtained by the preparation method of Examples 2-(3) using quinoline-4-carboxaldehyde oxime (0.82 g, 4.8 mmol) obtained in (1) above.

[1040] MS (m / z): 271 [M+H]

[1041] (3) 3-(quinolin-4-yl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1042]

[1043] Using the 3-(quinolin-4-yl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.87 g, 3.2 mmol) was used to prepare the title compound (0.77 g, 99%) by the method described in Examples 1-(2).

[1044] MS (m / z): 243 [M+H]

[1045] (4) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(quinolin-4-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1046]

[1047] Using the 3-(quinolin-4-yl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.091 g, 0.37 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.092 g, 50%).

[1048] MS (m / z): 490 [M+H]

[1049] (5) ((1R)-3-methyl-1-(3-(quinolin-4-yl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamido)butyl)boronic acid

[1050]

[1051] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(quinolin-4-yl)-4,5-dihydroisocyano The title compound (0.062 g, 93%) was obtained by the preparation method of Examples 1-(4) (0.092 g, 0.19 mmol).

[1052] MS (m / z): 356 [M+H]

[1053] Example 24: ((R)-1-((S)-5-benzyl-3-(3-(tert-butyl)phenyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1054] The title compound was obtained through the following processes (1), (2), (3) and (4).

[1055] (1) 5-Benzyl-3-(3-tert-butylphenyl)-4,5-dihydro-1,2- Preparation of methyl 5-azole carboxylate

[1056]

[1057] The title compound (0.37 g, 93%) was obtained by the preparation method of Example 2-(3) using 3-tert-butylbenzaldehyde oxime (0.2 g, 1.13 mmol) obtained in Example 14-(1) and methyl 2-phenylmethyl acrylate (0.37 g, 1.24 mmol) obtained in Preparation Example 6-(1).

[1058] NMR:1 H-NMR(400MHz, CDCl3); δ 7.68-7.67 (d, 1H), 7.44-7.42 (m, 1H), 7.34-7.24 (7H), 3.82-3.75 (d, 1H), 3.77 (s, 3H), 3.41-3.38 (d, 1H), 3.32-3.27(m, 2H), 1.31(s, 9H)

[1059] MS (m / z): 352 [M+H]

[1060] (2) 5-Benzyl-3-(3-tert-butylphenyl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1061]

[1062] Using the 5-benzyl-3-(3-tert-butylphenyl)-4,5-dihydro-1,2- Methyl 5-azole carboxylate (0.37 g, 1.05 mmol) was used to prepare the title compound (0.35 g, 99%) by the method described in Examples 1-(2).

[1063] MS (m / z): 338 [M+H]

[1064] (3) 5-Benzyl-3-(3-tert-butylphenyl)-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boron tricyclic[6.1.1.0] 2,6 [dec-4-yl]butyl]-4,5-dihydro-1,2- Preparation of azole-5-carboxamide

[1065]

[1066] Using the 5-benzyl-3-(3-tert-butylphenyl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.1 g, 0.30 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.1 g, 58%).

[1067] MS (m / z): 585 [M+H], 433 [MC] 10 H 15 O]

[1068] (4) ((R)-1-((S)-5-benzyl-3-(3-(tert-butyl)phenyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1069]

[1070] Using the 5-benzyl-3-(3-tert-butylphenyl)-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boron tricyclo[6.1.1.0] obtained in (3) above. 2,6 [dec-4-yl]butyl]-4,5-dihydro-1,2- The title compound (0.03 g, 80%) was obtained by the preparation method of Examples 1-(4) (0.05 g, 0.086 mmol).

[1071] NMR: 1 H-NMR(500MHz, MeOD-d4); δ 7.67-7.66 (m, 1H), 7.50-7.49 (m, 1H), 7.40-7.22 (m, 7H), 3.82-3.79 (d, 1H), 3.58-3.55 (d, 1H), 3.43-3.40 (d, 1H),3.27-3.24 (d, 1H), 2.74-2.41 (m, 1H), 1.48-1.43 (m, 1H), 1.31 (s, 9H), 1.28-1.21 (m, 2H), 0.81-0.79 (dd, 6H)

[1072] MS (m / z): 451[M+H], 433[M-OH]

[1073] Example 25: ((1R)-3-methyl-1-(3-(6-phenylpyridin-2-yl)-4,5-dihydroisocyanuric acid) Preparation of azole-5-carboxamido)butyl)boronic acid

[1074] The title compound was obtained through the following processes (1), (2), (3), (4), (5) and (6).

[1075] (1) Preparation of 6-phenyl-pyridine-2-carboxaldehyde

[1076]

[1077] The title compound was obtained by the method described in WO200982573A1.

[1078] (2) Preparation of 6-phenyl-pyridine-2-carboxaldehyde oxime

[1079]

[1080] The title compound (0.36 g, 98%) was obtained by the preparation method of Example 3-(1) using 6-phenyl-pyridine-2-carboxaldehyde (0.34 g, 1.86 mmol) obtained in (1) above.

[1081] (3) 3-(6-phenylpyridin-2-yl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1082]

[1083] The title compound (0.53 g, 99%) was obtained by the preparation method of Examples 2-(3) using 6-phenylpyridine-2-carboxaldehyde oxime (0.36 g, 1.82 mmol) obtained in (2) above.

[1084] MS (m / z): 297 [M+H]

[1085] (4) 3-(6-phenylpyridin-2-yl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1086]

[1087] Using the 3-(6-phenylpyridin-2-yl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.53 g, 1.79 mmol) was used to prepare the title compound (0.48 g, 99%) by the method described in Examples 1-(2).

[1088] MS (m / z): 269 [M+H]

[1089] (5) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(6-phenylpyridin-2-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1090]

[1091] Using the 3-(6-phenylpyridin-2-yl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.06 g, 0.22 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.06 g, 52%).

[1092] MS (m / z): 517 [M+H]

[1093] (6) ((1R)-3-methyl-1-(3-(6-phenylpyridin-2-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1094]

[1095] The N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(6-phenylpyridin-2-yl)-4,5-dihydroisocyano-3-O-B-2-yl)-Butyl)-3-(6-phenylpyridin-2-yl)-4,5-dihydroisocyano-3-O-B-2- ... The title compound (0.03 g, 68%) was obtained by the preparation method of Examples 1-(4) (0.06 g, 0.12 mmol).

[1096] NMR: 1 H-NMR(500MHz, MeOD-d4); δ 8.09-8.07 (m, 2H), 7.92-7.89 (m, 3H), 7.48-7.42 (m, 3H), 5.44-5.40 (m, 1H), 3.99-3.87 (m, 2H), 2.87-2.85 (m, 1H),1.67-1.61 (m, 1H), 1.40-1.33 (m, 2H), 0.90-0.87 (m, 6H)

[1097] MS (m / z): 382[M+H], 365[M-OH]

[1098] Example 26: ((1R)-3-methyl-1-(3-(4-(pyridin-2-yl)phenyl)-4,5-dihydroisocyanuric acid Preparation of azole-5-carboxamido)butyl)boronic acid

[1099] The title compound was obtained through the following processes (1), (2), (3), (4), (5) and (6).

[1100] (1) Preparation of 4-pyridin-2-ylbenzaldehyde

[1101]

[1102] The title compound was obtained by the method described in the European Journal of Organic Chemistry, 2008, #12, pp. 2049-2055.

[1103] (2) Preparation of 4-pyridin-2-ylbenzaldehyde oxime

[1104]

[1105] The title compound (0.39 g, 99%) was obtained by the preparation method of Example 3-(1) using 4-pyridin-2-yl-benzaldehyde (0.36 g, 1.97 mmol) obtained in (1) above.

[1106] MS (m / z): 199 [M+H]

[1107] (3) 3-[4-(pyridin-2-yl)phenyl]-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate

[1108]

[1109] The title compound (0.42 g, 72%) was obtained by the preparation method of Examples 2-(3) using 4-pyridin-2-ylbenzaldehyde oxime (0.39 g, 1.97 mmol) obtained in (2) above.

[1110] MS (m / z): 297 [M+H]

[1111] (4) 3-[4-(pyridin-2-yl)phenyl]-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1112]

[1113] Using the 3-[4-(pyridin-2-yl)phenyl]-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.42 g, 1.41 mmol) was used to prepare the title compound (0.38 g, 99%) by the method described in Examples 1-(2).

[1114] MS (m / z): 269 [M+H]

[1115] (5) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(4-(pyridin-2-yl)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1116]

[1117] Using the 3-[4-(pyridin-2-yl)phenyl]-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.12 g, 0.45 mmol) was used to prepare the title compound (0.13 g, 56%) by the method described in Examples 1-(3).

[1118] MS (m / z): 516 [M+H], 364 [MC] 10 H 15 O]

[1119] (6) ((1R)-3-methyl-1-(3-(4-(pyridin-2-yl)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1120]

[1121] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(4-(pyridin-2-yl)phenyl)-4,5-dihydroisocyano The title compound (0.06 g, 62%) was obtained by the preparation method of Examples 1-(4) (0.13 g, 0.25 mmol).

[1122] NMR: 1H-NMR (500MHz, MeOD-d4); δ 8.63-8.62 (m, 1H0, 8.05-8.03 (m, 2H), 7.91-7.83 (m, 4H), 7.36-7.37 (m, 1H), 5.42-5.38 (m, 1H), 3.90-3.84 (m, 1H),3.75-3.68 (m, 1H), 2.89-2.84 (m, 1H), 1.67-1.63 (m, 1H), 1.40-1.33 (m, 2H),0.90-0.89 (dd, 6H)

[1123] MS (m / z): 382[M+H], 364[M-OH]

[1124] Example 27: ((1R)-1-(3-([1,1'-biphenyl]-4-yl)-4,5-dihydroisocyanate) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1125] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1126] (1) Preparation of biphenyl-4-carboxaldehyde oxime

[1127]

[1128] The title compound (0.55 g, quantified) was obtained using biphenyl-4-carboxaldehyde (0.51 g, 2.8 mmol) by the same method used in Example 3-(1) to prepare Example 6-(1).

[1129] (2) 3-(4-phenylphenyl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1130]

[1131] The title compound (0.62 g 75%) was obtained by the preparation method of Examples 2-(3) using biphenyl-4-carboxaldehyde oxime (0.55 g, 2.8 mmol) obtained in (1) above.

[1132] MS (m / z): 297 [M+H]

[1133] (3) 3-(4-phenylphenyl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1134]

[1135] Using the 3-(4-phenylphenyl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.62 g, 2.1 mmol) was used to prepare the title compound (0.43 g, 78%) by the method described in Examples 1-(2).

[1136] MS (m / z): 269 [M+H]

[1137] (4) 3-([1,1'-biphenyl]-4-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1138]

[1139] Using the 3-(4-phenylphenyl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.083 g, 0.31 mmol) was used to prepare the title compound (0.11 g, 68%) by the method described in Examples 1-(3).

[1140] MS (m / z): 516 [M+H]

[1141] (5) ((1R)-1-(3-([1,1'-biphenyl]-4-yl)-4,5-dihydroisocyanate Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1142]

[1143] Using the 3-([1,1'-biphenyl]-4-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.041 g, 50%) was obtained by the preparation method of Examples 1-(4) (0.11 g, 0.21 mmol).

[1144] MS (m / z): 381[M+H], 363[M-OH]

[1145] Example 28: ((1R)-1-(3-(5-(3-fluorophenyl)pyridin-2-yl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1146] The title compound was obtained through the following processes (1), (2), (3), (4), (5) and (6).

[1147] (1) Preparation of 5-(3-fluoro-phenyl)-pyridine-2-carboxaldehyde

[1148]

[1149] The title compound was obtained by the method described in US2013 / 40981A1.

[1150] (2) Preparation of 5-(3-fluoro-phenyl)-pyridine-2-carboxaldehyde oxime

[1151]

[1152] The title compound (0.17 g, 98%) was obtained by the preparation method of Example 3-(1) using 5-(3-fluoro-phenyl)-pyridine-2-carboxaldehyde (0.16 g, 0.80 mmol) obtained in (1) above.

[1153] MS (m / z): 217 [M+H]

[1154] (3) 3-[5-(3-fluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1155]

[1156] The title compound (0.16 g, 64%) was obtained by the preparation method of Examples 2-(3) using 5-(3-fluoro-phenyl)-pyridine-2-carboxaldehyde oxime (0.17 g, 0.80 mmol) obtained in (2) above.

[1157] NMR: 1H-NMR (400MHz, CDCl3); δ 8.82-8.81 (dd, 1H), 8.13-8.11 (dd, 1H), 7.93-7.91 (dd, 1H), 7.50-7.38 (m, 2H), 7.33-7.30 (m, 1H), 7.16-7.11 (m, 1H),5.25-5.20 (m, 1H), 4.32-4.25 (q, 2H), 3.86-3.82 (d, 2H), 1.35-1.32 (t, 3H)

[1158] MS (m / z): 315 [M+H]

[1159] (4) 3-[5-(3-fluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1160]

[1161] Using the 3-[5-(3-fluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.16 g, 0.51 mmol) was used to prepare the title compound (0.14 g, 99%) by the method described in Examples 1-(2).

[1162] MS (m / z): 287 [M+H]

[1163] (5) 3-(5-(3-fluorophenyl)pyridin-2-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1164]

[1165] Using the 3-[5-(3-fluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.07 g, 0.24 mmol) was used to prepare the title compound (0.09 g, 69%) by the method described in Examples 1-(3).

[1166] MS (m / z): 534 [M+H]

[1167] (6) ((1R)-1-(3-(5-(3-fluorophenyl)pyridin-2-yl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1168]

[1169] Using the 3-(5-(3-fluorophenyl)pyridin-2-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridgedbenzi[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.045 g, 67%) was obtained by the preparation method of Examples 1-(4) (0.09 g, 0.17 mmol).

[1170] NMR: 1 H-NMR(500MHz, MeOD-d4); δ 8.88-8.87 (d, 1H), 8.13-8.04 (m, 2H), 7.53-7.49 (m, 3H), 7.18-7.15 (m, 1H), 5.43-5.40 (m, 1H), 3.93-3.87 (m, 1H),3.81-3.75 (m, 1H), 2.88-2.87 (m, 1H), 1.66-1.62 (m, 1H), 1.40-1.35 (m, 2H),0.90-0.89 (dd, 6H)

[1171] MS (m / z): 400[M+H], 382[M-OH]

[1172] Example 29: ((1R)-3-methyl-1-(3-(quinolin-3-yl)-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[1173] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1174] (1) Preparation of quinoline-3-carboxaldehyde oxime

[1175]

[1176] The title compound (0.48 g, quantified) was obtained using quinoline-3-carboxaldehyde (0.44 g, 2.8 mmol) by the preparation method of Example 3-(1).

[1177] MS (m / z): 173 [M+H]

[1178] (2) 3-(quinolin-3-yl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1179]

[1180] The title compound (0.53 g 70%) was obtained by the preparation method of Examples 2-(3) using quinoline-3-carboxaldehyde oxime (0.48 g, 2.8 mmol) obtained in (1) above.

[1181] NMR: 1 H-NMR (400MHz, CDCl3); δ 8.17-8.06 (m, 3H), 7.84-7.56 (m, 3H), 5.26-5.23 (m, 1H), 4.30-4.27 (q, 2H), 3.95-3.93 (d, 2H), 1.34-1.32 (t, 3H)

[1182] MS (m / z): 271 [M+H]

[1183] (3) 3-(quinolin-3-yl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1184]

[1185] Using the 3-(quinolin-3-yl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.53 g, 2.0 mmol) was used to prepare the title compound (0.47 g, 99%) by the method described in Examples 1-(2).

[1186] MS (m / z): 243 [M+H]

[1187] (4) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(quinolin-3-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1188]

[1189] Using the 3-(quinolin-3-yl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.13 g, 0.52 mmol) was used to prepare the title compound (0.099 g, 39%) by the method described in Examples 1-(3).

[1190] MS (m / z): 490 [M+H]

[1191] (5) ((1R)-3-methyl-1-(3-(quinolin-3-yl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamido)butyl)boronic acid

[1192]

[1193] The N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(quinolin-3-yl)-4,5-dihydroisocyano The title compound (0.039 g, 57%) was obtained by the preparation method of Examples 1-(4) (0.094 g, 0.19 mmol).

[1194] MS (m / z): 356[M+H], 338[M-OH]

[1195] Example 30: ((1R)-3-methyl-1-(3-(quinolin-6-yl)-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[1196] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1197] (1) Preparation of quinoline-6-carboxaldehyde oxime

[1198]

[1199] The title compound (0.60 g, quantified) was obtained using quinoline-6-carboxaldehyde (0.55 g, 3.5 mmol) by the preparation method of Example 3-(1).

[1200] MS (m / z): 173 [M+H]

[1201] (2) 3-(quinolin-6-yl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1202]

[1203] The title compound (0.35 g 37%) was obtained by the preparation method of Examples 2-(3) using quinoline-6-carboxaldehyde oxime (0.60 g, 3.5 mmol) obtained in (1) above.

[1204] MS (m / z): 271 [M+H]

[1205] (3) 3-(quinolin-6-yl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1206]

[1207] Using the 3-(quinolin-6-yl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.35 g, 1.3 mmol) was used to prepare the title compound (0.27 g, 84%) by the method described in Examples 1-(2).

[1208] MS (m / z): 243 [M+H]

[1209] (4) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(quinolin-6-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1210]

[1211] Using the 3-(quinolin-6-yl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.10 g, 0.42 mmol) was used to prepare the title compound (0.045 g, 22%) by the method described in Examples 1-(3).

[1212] MS (m / z): 490 [M+H]

[1213] (5) ((1R)-3-methyl-1-(3-(quinolin-6-yl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamido)butyl)boronic acid

[1214]

[1215] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(quinolin-6-yl)-4,5-dihydroisocyano The title compound (0.014 g, 43%) was obtained by the preparation method of Examples 1-(4) (0.045 g, 0.09 mmol).

[1216] MS (m / z): 356[M+H], 338[M-OH]

[1217] Example 31: ((1R)-3-methyl-1-(3-(4-(pyridin-3-yl)phenyl)-4,5-dihydroisocyanuric acid Preparation of azole-5-carboxamido)butyl)boronic acid

[1218] The title compound was obtained through the following processes (1), (2), (3), (4), (5) and (6).

[1219] (1) Preparation of 4-pyridin-3-ylbenzaldehyde

[1220]

[1221] The title compound was obtained by the method described in Journal of Medicinal Chemistry, 2005, vol 48, pp. 224-239.

[1222] (2) Preparation of 4-pyridin-3-ylbenzaldehyde oxime

[1223]

[1224] The title compound (0.46 g, 99%) was obtained by the preparation method of Example 3-(1) using 4-pyridin-3-yl-benzaldehyde (0.43 g, 2.34 mmol) obtained in (1) above.

[1225] MS (m / z): 199 [M+H]

[1226] (3) 3-[4-(pyridin-3-yl)phenyl]-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1227]

[1228] The title compound (0.42 g, 61%) was obtained by the preparation method of Examples 2-(3) using 4-pyridin-3-yl-benzaldehyde oxime (0.46 g, 2.32 mmol) obtained in (2) above.

[1229] MS (m / z): 297 [M+H]

[1230] (4) 3-[4-(pyridin-3-yl)phenyl]-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1231]

[1232] Using the 3-[4-(pyridin-3-yl)phenyl]-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.42 g, 1.41 mmol) was used to prepare the title compound (0.37 g, 98%) by the method described in Examples 1-(2).

[1233] MS (m / z): 269 [M+H]

[1234] (5) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(4-(pyridin-3-yl)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1235]

[1236] Using the 3-[4-(pyridin-3-yl)phenyl]-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.1 g, 0.37 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.13 g, 68%).

[1237] MS (m / z): 516 [M+H]

[1238] (6) ((1R)-3-methyl-1-(3-(4-(pyridin-3-yl)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1239]

[1240] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(4-(pyridin-3-yl)phenyl)-4,5-dihydroisocyano The title compound (0.07 g, 73%) was obtained by the preparation method of Examples 1-(4) (0.13 g, 0.25 mmol).

[1241] NMR: 1 H-NMR(500MHz, MeOD-d4); δ 8.84 (d, 1H), 8.54-8.54 (m, 1H), 8.15-8.13 (m, 1H), 7.86-7.76 (m, 4H), 7.54-7.52 (m, 1H), 5.42-5.39 (m, 1H), 3.89-3.83 (m, 1H), 3.74-3.69 (m, 1H), 2.89-2.86 (m, 1H), 1.67-1.63 (m, 1H), 1.40-1.36 (m, 2H), 0.90-0.88 (dd, 6H)

[1242] MS (m / z): 382[M+H], 364[M-OH]

[1243] Example 32: ((1R)-3-methyl-1-(3-(6-phenylpyridin-3-yl)-4,5-dihydroisocyanuric acid) Preparation of azole-5-carboxamido)butyl)boronic acid

[1244] The title compound was obtained through the following processes (1), (2), (3), (4), (5) and (6).

[1245] (1) Preparation of 6-phenyl-pyridine-3-carboxaldehyde

[1246]

[1247] The title compound was obtained by the method described in Journal of Organic Chemistry, 2006, vol. 71, pp. 9589-9594.

[1248] (2) Preparation of 6-phenyl-pyridine-3-carboxaldehyde oxime

[1249]

[1250] The title compound (0.48 g, 99%) was obtained by the preparation method of Preparation Example 6-(1) using 6-phenyl-pyridine-3-carboxaldehyde (0.44 g, 2.40 mmol) obtained in (1) above.

[1251] MS (m / z): 199 [M+H]

[1252] (3) 3-(6-phenylpyridin-3-yl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1253]

[1254] The title compound (0.5 g, 70%) was obtained by the preparation method of Preparation Example 1-(2) using 6-phenylpyridine-3-carboxaldehyde oxime (0.48 g, 2.42 mmol) obtained in (2) above.

[1255] NMR: 1 H-NMR (400MHz, CDCl3); δ 8.89-8.88 (dd, 1H), 8.16-8.03 (m, 3H), 7.82-7.79 (d, 1H), 7.52-7.44 (m, 3H), 5.25-5.21 (m, 1H), 4.32-4.27 (q, 2H),3.76-3.64 (m, 2H), 1.36-1.33 (t, 3H)

[1256] MS (m / z): 297 [M+H]

[1257] (4) 3-(6-phenylpyridin-3-yl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1258]

[1259] Using the 3-(6-phenylpyridin-3-yl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.3 g, 1.01 mmol) was used to prepare the title compound (0.25 g, 92%) by the method described in Examples 1-(2).

[1260] MS (m / z): 269 [M+H]

[1261] (5) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(6-phenylpyridin-3-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1262]

[1263] Using the 3-(6-phenylpyridin-3-yl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.08 g, 0.30 mmol) was used to prepare the title compound (0.13 g, 85%) by the method described in Examples 1-(3).

[1264] MS (m / z): 516 [M+H]

[1265] (6) ((1R)-3-methyl-1-(3-(6-phenylpyridin-3-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1266]

[1267] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(6-phenylpyridin-3-yl)-4,5-dihydroisocyano The title compound (0.063 g, 65%) was obtained by the preparation method of Examples 1-(2) (0.13 g, 0.25 mmol) of azole-5-carboxamide.

[1268] NMR: 1 H-NMR(500MHz, MeOD-d4); δ 8.91-8.90 (m, 1H), 8.18-8.17 (m, 1H), 8.03-8.01 (m, 3H), 7.51-7.43 (m, 3H), 5.44-5.40 (m, 1H), 3.90-3.84 (m, 1H),3.79-3.70 (m, 1H), 2.90-2.85 (m, 1H), 1.67-1.63 (m, 1H), 1.40-4.35 (m, 2H),0.91-0.89 (dd, 6H)

[1269] MS (m / z): 382[M+H], 364[M-OH]

[1270] Example 33: ((1R)-3-methyl-1-(3-(5-phenylpyridin-3-yl)-4,5-dihydroisocyanuric acid) Preparation of azole-5-carboxamido)butyl)boronic acid

[1271] The title compound was obtained through the following processes (1), (2), (3), (4), (5) and (6).

[1272] (1) Preparation of 5-phenyl-pyridine-3-carboxaldehyde

[1273]

[1274] The title compound was obtained by the method described in WO200770818A1.

[1275] (2) Preparation of 5-phenyl-pyridine-3-carboxaldehyde oxime

[1276]

[1277] The title compound (0.51 g, 99%) was obtained by the preparation method of Example 3-(1) using 5-phenyl-pyridine-3-carboxaldehyde (0.47 g, 2.56 mmol) obtained in (1) above.

[1278] MS (m / z): 199 [M+H]

[1279] (3) 3-(5-phenylpyridin-3-yl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1280]

[1281] The title compound (0.57 g, 83%) was obtained by the preparation method of Examples 2-(3) using 5-phenylpyridine-3-carboxaldehyde oxime (0.51 g, 2.57 mmol) obtained in (2) above.

[1282] MS (m / z): 297 [M+H]

[1283] (4) 3-(5-phenylpyridin-3-yl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1284]

[1285] Using the 3-(5-phenylpyridin-3-yl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.57 g, 1.92 mmol) was used to prepare the title compound (0.46 g, 89%) by the method described in Examples 1-(2).

[1286] MS (m / z): 269 [M+H]

[1287] (5) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(5-phenylpyridin-3-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1288]

[1289] Using the 3-(5-phenylpyridin-3-yl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.08 g, 0.30 mmol) was used to prepare the title compound (0.09 g, 59%) by the method described in Examples 1-(3).

[1290] MS (m / z): 516 [M+H]

[1291] (6) ((1R)-3-methyl-1-(3-(5-phenylpyridin-3-yl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1292]

[1293] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(5-phenylpyridin-3-yl)-4,5-dihydroisocyano The title compound (0.054 g, 81%) was obtained by the preparation method of Examples 1-(4) (0.09 g, 0.17 mmol).

[1294] NMR: 1H-NMR(500MHz, MeOD-d4); δ 8.87-8.84 (dd, 2H), 8.34-8.33 (m, 1H), 7.70-7.69 (m, 2H), 7.53-7.42 (m, 3H), 5.45-5.41 (m, 1H), 3.94-3.88 (m, 1H),3.80-3.74 (m, 1H), 2.90-2.85 (m, 1H), 1.67-1.61 (m, 1H), 1.40-1.34 (m, 2H),0.91-0.88 (dd, 6H)

[1295] MS (m / z): 382[M+H], 364[M-OH]

[1296] Example 34: ((1R)-3-methyl-1-(3-(3-(pyridin-2-yl)phenyl)-4,5-dihydroisocyanuric acid Preparation of azole-5-carboxamido)butyl)boronic acid

[1297] The title compound was obtained through the following processes (1), (2), (3), (4), (5) and (6).

[1298] (1) Preparation of 3-pyridin-2-ylbenzaldehyde

[1299]

[1300] The title compound was obtained by the method described in WO20032202772A1.

[1301] (2) Preparation of 3-pyridin-2-ylbenzaldehyde oxime

[1302]

[1303] The title compound (0.55 g, 99%) was obtained by the preparation method of Example 3-(1) using 3-pyridin-2-yl-benzaldehyde (0.51 g, 2.78 mmol) obtained in (1) above.

[1304] MS (m / z): 199 [M+H]

[1305] (3) 3-[3-(pyridin-2-yl)phenyl]-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1306]

[1307] The title compound (0.58 g, 70%) was obtained by the preparation method of Examples 2-(3) using 3-pyridin-2-yl-benzaldehyde oxime (0.55 g, 2.77 mmol) obtained in (2) above.

[1308] NMR: 1 H-NMR (400MHz, CDCl3); δ 8.71-8.70 (d, 1H), 8.29-8.28 (d, 1H), 8.07-8.05 (dd, 1H), 7.81-7.77 (m, 3H), 7.55-7.51 (t, 1H), 7.27-7.26 (m, 1H),5.23-5.18 (m, 1H), 4.31-4.26 (q, 2H), 3.80-3.68 (m, 2H), 1.35-1.32 (t, 3H)

[1309] MS (m / z): 297 [M+H]

[1310] (4) 3-[3-(pyridin-2-yl)phenyl]-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1311]

[1312] Using the 3-[3-(pyridin-2-yl)phenyl]-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.58 g, 1.95 mmol) was used to prepare the title compound (0.52 g, 98%) by the method described in Examples 1-(2).

[1313] MS (m / z): 269 [M+H]

[1314] (5) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(3-(pyridin-2-yl)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1315]

[1316] Using 3-[3-(pyridin-2-yl)phenyl]-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.08 g, 0.30 mmol) was used to prepare the title compound (0.04 g, 26%) by the method described in Examples 1-(3).

[1317] MS (m / z): 516 [M+H]

[1318] (6) ((1R)-3-methyl-1-(3-(3-(pyridin-2-yl)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1319]

[1320] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(3-(pyridin-2-yl)phenyl)-4,5-dihydroisocyano The title compound (0.021 g, 71%) was obtained by the preparation method of Examples 1-(4) (0.04 g, 0.078 mmol).

[1321] NMR: 1 H-NMR(500MHz, MeOD-d4); δ 8.63-8.62 (m, 1H), 8.29 (m, 1H), 8.05-8.04 (m, 1H), 7.35-7.89 (m, 2H), 7.81-7.79 (m, 1H), 7.59-7.56 (m, 1H), 7.40-7.37 (m, 1H), 5.43-5.40 (m, 1H), 3.93-3.87 (m, 1H), 3.78-3.71 (m, 1H), 2.87-2.85 (m, 1H), 1.66-1.63 (m, 1H), 1.40-1.33 (m, 2H), 0.90-0.88 (dd, 6H)

[1322] MS (m / z): 382[M+H], 364[M-OH]

[1323] Example 35: ((1R)-1-(5-phenylmethyl-3-(5'-chloro-2'-methoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1324] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1325] (1) Preparation of 3-bromobenzaldehyde oxime

[1326]

[1327] The title compound (2.03 g, 100%) was obtained using 3-bromobenzaldehyde (1.85 g, 10.0 mmol) by the preparation method of Example 3-(1).

[1328] NMR: 1 H-NMR (400MHz, CDCl3); δ 8.08 (1H, s), 7.81 (1H, s), 7.56-7.24 (4H, m)

[1329] (2) 5-Benzyl-3-(3-bromophenyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[1330]

[1331] The title compound (1.01 g, 90%) was obtained by the preparation method of Example 2-(3) using 3-bromobenzaldehyde oxime (0.60 g, 3.0 mmol) obtained in (1) above and methyl 2-phenylmethyl acrylate (0.58 g, 3.3 mmol) obtained in Preparation Example 6-(1).

[1332] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.70 (1H, s), 7.52-7.10 (8H, m), 3.79 (3H,s), 3.73 (1H, d), 3.39 (1H, d), 3,29-3.22 (2H, m)

[1333] MS (m / z): 374 [M+H]

[1334] (3) 5-Benzyl-3-(5'-chloro-2'-methoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[1335]

[1336] The 5-benzyl-3-(3-bromophenyl)-4,5-dihydroisocyanate obtained in (2) above Methyl 5-oxazolium-5-carboxylate (0.154 g, 0.412 mmol), 5-chloro-2-methoxyphenylboronic acid (0.093 g, 0.499 mmol), potassium carbonate (0.29 g, 2.06 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) and dichloro complex (0.034 g, 0.042 mmol) with 1,4-dioxazolium-5-carboxylate The alkane (10 ml) and water (1 ml) were mixed and stirred at 80 °C for 3 hours. The solvent was distilled under reduced pressure, and the remaining residue was separated by column chromatography to obtain the title compound (0.189 g, 100%).

[1337] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.67 (1H, s), 7.57 (1H, d), 7.51 (1H, d), 7.42-7.24 (8H, m), 6.89 (1H, d), 3.78 (1H, d), 3.77 (3H, s), 3.41-3.27 (3H,m)

[1338] MS (m / z): 436 [M+H]

[1339] (4) 5-Benzyl-3-[3-(5-chloro-2-methoxyphenyl)phenyl]-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boron tricyclic[6.1.1.0] 2,6 [dec-4-yl]butyl]-4,5-dihydro-1,2- Preparation of azole-5-carboxamide

[1340]

[1341] Using the 5-benzyl-3-(5'-chloro-2'-methoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydroisocyanate obtained in (3) above Methyl 5-azole carboxylate (0.189 g, 0.434 mmol) was prepared by the methods described in Examples 1-(2) and 1-(3) to obtain the title compound (0.163 g, 49%, 2 steps).

[1342] MS (m / z): 669 [M+H]

[1343] (5) ((1R)-1-(5-benzyl-3-(5'-chloro-2'-methoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1344]

[1345] The 5-benzyl-3-[3-(5-chloro-2-methoxyphenyl)phenyl]-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boron tricyclo[6.1.1.0] obtained in (4) above was used. 2,6 [dec-4-yl]butyl]-4,5-dihydro-1,2- The title compound (0.069 g, 72%) was obtained by the preparation method of Examples 1-(4) (0.119 g, 0.180 mmol).

[1346] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.79-6.91 (12H, m), 3.84-3,74 (4H, m), 3.53-3.26 (3H, m), 3.07-2.54 (1H, m), 1.42-0.83 (9H, m)

[1347] MS (m / z): 535 [M+H]

[1348] Example 36: ((1R)-1-(5-phenylmethyl-3-(3-(isoquinoline-1-yl)phenyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1349] The title compound was obtained through the following processes (1), (2), (3) and (4).

[1350] (1) 5-Benzyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]-4,5-dihydro-1,2- Preparation of methyl 5-azole carboxylate

[1351]

[1352] The 5-benzyl-3-(3-bromophenyl)-4,5-dihydroisocyanate obtained in (2) above Methyl 5-azole carboxylate (0.655 g, 1.75 mmol), dipinalloyl diborane (0.889 g, 3.50 mmol), potassium acetate (0.689 g, 7.02 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) and its dichloro complex (0.143 g, 0.175 mmol) were mixed with dimethylacetamide (15 ml) and stirred at 80 °C for 1 hour. The solvent was distilled under reduced pressure, and the remaining residue was separated by column chromatography to obtain the title compound (0.733 g, 100%).

[1353] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.92-7.84 (3H, m), 7.39 (1H, t), 7.34-7.26(5H, m), 3.86 (1H, d), 3.82 (3H, s), 3.45-3.31 (3H, m), 1.38 (12H, s)

[1354] (2) 5-Benzyl-3-[3-(isoquinolin-1-yl)phenyl]-4,5-dihydro-1,2- Preparation of methyl 5-azole carboxylate

[1355]

[1356] Using the 5-benzyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)phenyl]-4,5-dihydro-1,2- Methyl 5-oxazolium carboxylate (0.142 g, 0.337 mmol) and 1-bromoisoquinoline were used to prepare the title compound (0.101 g, 71%) by the method described in Example 35-(3).

[1357] NMR: 1 H-NMR(400MHz, CDCl3); δ 8.60 (1H, d), 8.02-7.53 (9H, m), 7.29-7.25(5H, m), 3.82 (1H, d), 3.78 (3H, s), 3.41-3.27 (3H, m)

[1358] (3) 5-Benzyl-3-(3-(isoquinoline-1-yl)phenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroiso Preparation of azole-5-carboxamide

[1359]

[1360] Using the 5-benzyl-3-[3-(isoquinolin-1-yl)phenyl]-4,5-dihydro-1,2- Methyl 5-azole carboxylate (0.101 g, 0.239 mmol) was used to prepare the title compound (0.076 g, 48%, 2 steps) by the methods described in Examples 1-(2) and 1-(3).

[1361] MS (m / z): 656 [M+H]

[1362] (4) ((1R)-1-(5-benzylmethyl-3-(3-(isoquinolin-1-yl)phenyl)-4,5-dihydroisoquinoline) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1363]

[1364] Using the 5-benzyl-3-(3-(isoquinolin-1-yl)phenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridgedbenziro[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroiso The title compound (0.040 g, 66%) was obtained by the preparation method of Examples 1-(4) (0.076 g, 0.239 mmol).

[1365] NMR: 1 H-NMR (500MHz, CD3OD); δ 8.48-8.47 (1H, m), 7.99-7.61 (9H, m), 7.33-7.22 (5H, m), 3.88-3.83 (1H, m), 3.67-3.59 (1H, m), 3.41 (1H, d), 3.29-3.26 (4H, m), 2.76-2.69 (1H, m), 1.41-1.06 (3H, m), 0.80-0.76 (6H, m)

[1366] MS (m / z): 522 [M+H]

[1367] Example 37: ((1R)-3-methyl-1-(3-(3-(trifluoromethoxy)phenyl)-4,5-dihydroisocyanuric acid Preparation of azole-5-carboxamido)butyl)boronic acid

[1368] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1369] (1) Preparation of 3-trifluoromethoxy-benzaldehyde oxime

[1370]

[1371] The title compound (0.54 g, 99%) was obtained using 3-trifluoromethoxybenzaldehyde (0.5 g, 2.63 mmol) by the preparation method of Example 3-(1).

[1372] MS (m / z): 206 [M+H]

[1373] (2) 3-[3-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate

[1374]

[1375] The title compound (0.63 g 79%) was obtained by the preparation method of Examples 2-(3) using 3-trifluoromethoxy-benzaldehyde oxime (0.54 g, 2.63 mmol) obtained in (1) above.

[1376] MS (m / z): 304 [M+H]

[1377] (3) 3-[3-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1378]

[1379] Using the 3-[3-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.63 g, 2.08 mmol) was used to prepare the title compound (0.57 g, 99%) by the method described in Examples 1-(2).

[1380] MS (m / z): 276 [M+H]

[1381] (4) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(3-(trifluoromethoxy)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1382]

[1383] Using the 3-[3-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.07 g, 0.25 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.11 g, 83%).

[1384] MS (m / z): 523 [M+H]

[1385] (5) ((1R)-3-methyl-1-(3-(3-(trifluoromethoxy)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1386]

[1387] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(3-(trifluoromethoxy)phenyl)-4,5-dihydroisocyano The title compound (0.065 g, 80%) was obtained by the preparation method of Examples 1-(4) (0.11 g, 0.21 mmol).

[1388] NMR: 1 H-NMR(500MHz, MeOD-d4); δ 7.68-7.64 (m, 2H), 7.56-7.53 (t, 1H), 7.38-7.37 (d, 1H), 5.41-5.37 (m, 1H), 3.85-3.79 (m, 1H), 3.70-3.63 (m, 1H),2.88-2.84 (m, 1H), 1.65-1.61 (m, 1H), 1.39-1.34 (m, 2H), 0.89-0.88 (dd, 6H)

[1389] MS (m / z): 389[M+H], 371[M-OH]

[1390] Example 38: ((1R)-3-methyl-1-(3-(4-(trifluoromethoxy)phenyl)-4,5-dihydroisocyanuric acid Preparation of azole-5-carboxamido)butyl)boronic acid

[1391] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1392] (1) Preparation of 4-trifluoromethoxy-benzaldehyde oxime

[1393]

[1394] The title compound (1.0 g, quantitative) was obtained by the preparation method of Preparation Example 6-(1) using 4-trifluoromethoxybenzaldehyde (0.93 g, 4.9 mmol).

[1395] MS (m / z): 206 [M+H]

[1396] (2) 3-[4-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1397]

[1398] The title compound (0.94 g, 64%) was obtained by the preparation method of Examples 2-(3) using 1.0 g, 4.9 mmol of 4-trifluoromethoxy-benzaldehyde oxime obtained in (1) above.

[1399] MS (m / z): 304 [M+H]

[1400] (3) 3-[4-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1401]

[1402] Using the 3-[4-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.94 g, 3.1 mmol) was used to prepare the title compound (0.77 g, 90%) by the method described in Examples 1-(2).

[1403] MS (m / z): 276 [M+H]

[1404] (4) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(4-(trifluoromethoxy)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1405]

[1406] Using the 3-[4-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.099 g, 0.36 mmol) was used to prepare the title compound (0.10 g, 54%) by the method described in Examples 1-(3).

[1407] MS (m / z): 523 [M+H]

[1408] (5) ((1R)-3-methyl-1-(3-(4-(trifluoromethoxy)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1409]

[1410] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(4-(trifluoromethoxy)phenyl)-4,5-dihydroisocyano The title compound (0.014 g, 19%) was obtained by the preparation method of Examples 1-(4) (0.10 g, 0.19 mmol).

[1411] MS (m / z): 389[M+H], 371[M-OH]

[1412] Example 39: ((1R)-3-methyl-1-(3-(2-(trifluoromethoxy)phenyl)-4,5-dihydroisocyanuric acid Preparation of azole-5-carboxamido)butyl)boronic acid

[1413] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1414] (1) Preparation of 2-trifluoromethoxy-benzaldehyde oxime

[1415]

[1416] The title compound (0.54 g, quantified) was obtained using 2-trifluoromethoxybenzaldehyde (0.50 g, 2.6 mmol) by the preparation method of Example 3-(1).

[1417] MS (m / z): 206 [M+H]

[1418] (2) 3-[2-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1419]

[1420] The title compound (0.60 g, 75%) was obtained by the preparation method of Examples 2-(3) using 2-trifluoromethoxy-benzaldehyde oxime (0.54 g, 2.6 mmol) obtained in (1) above.

[1421] MS (m / z): 304 [M+H]

[1422] (3) 3-[2-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1423]

[1424] Using the 3-[2-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.60 g, 2.0 mmol) was used to prepare the title compound (0.55 g, quantified) by the method described in Examples 1-(2).

[1425] MS (m / z): 276 [M+H]

[1426] (4) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(2-(trifluoromethoxy)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1427]

[1428] Using the 3-[2-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.091 g, 0.33 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.12 g, 69%).

[1429] MS (m / z): 523 [M+H]

[1430] (5) ((1R)-3-methyl-1-(3-(2-(trifluoromethoxy)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1431]

[1432] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(2-(trifluoromethoxy)phenyl)-4,5-dihydroisocyano The title compound (0.063 g, 71%) was obtained by the preparation method of Examples 1-(4) (0.12 g, 0.23 mmol).

[1433] MS (m / z): 389[M+H], 371[M-OH]

[1434] Example 40: ((1R)-3-methyl-1-(3-(3-phenoxyphenyl)-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[1435] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1436] (1) Preparation of 3-phenoxy-benzaldehyde oxime

[1437]

[1438] The title compound (0.32 g, 99%) was obtained using 3-phenoxybenzaldehyde (0.3 g, 1.51 mmol) by the preparation method of Example 3-(1).

[1439] MS (m / z): 214 [M+H]

[1440] (2) 3-(3-phenoxyphenyl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1441]

[1442] The title compound (0.44 g 93%) was obtained by the preparation method of Examples 2-(3) using 3-phenoxy-benzaldehyde oxime (0.32 g, 1.51 mmol) obtained in (1) above.

[1443] MS (m / z): 312 [M+H]

[1444] (3) 3-(3-phenoxyphenyl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1445]

[1446] Using the 3-(3-phenoxyphenyl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.44 g, 1.41 mmol) was used to prepare the title compound (0.4 g, 99%) by the method described in Examples 1-(2).

[1447] MS (m / z): 284 [M+H]

[1448] (4) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(3-phenoxyphenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1449]

[1450] Using the 3-(3-phenoxyphenyl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.08 g, 0.28 mmol) was used to prepare the title compound (0.12 g, 80%) by the method described in Examples 1-(3).

[1451] MS (m / z): 531 [M+H]

[1452] (5) ((1R)-3-methyl-1-(3-(3-phenoxyphenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1453]

[1454] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridgedbenziro[d][1,3,2]dioxaborane-2-yl)butyl)-3-(3-phenoxyphenyl)-4,5-dihydroisocyano The title compound (0.055 g, 61%) was obtained by the preparation method of Examples 1-(4) (0.12 g, 0.23 mmol).

[1455] NMR: 1 H-NMR(500MHz, MeOD-d4); δ 7.43-7.32 (m, 5H), 7.15-7.00 (m, 5H), 5.36-5.33 (m, 1H), 3.81-3.75 (m, 1H), 3.64-3.85 (m, 1H), 2.86-2.83 (m, 1H),1.64-1.61 (m, 1H), 1.38-1.27 (m, 2H), 0.89-0.88 (dd, 6H)

[1456] MS (m / z): 397[M+H], 379[M-OH]

[1457] Example 41: ((1R)-3-methyl-1-(3-(3-(pyridin-2-yloxy)phenyl)-4,5-dihydroisocyanuric acid Preparation of azole-5-carboxamido)butyl)boronic acid

[1458] The title compound was obtained through the following processes (1), (2), (3), (4), (5) and (6).

[1459] (1) Preparation of 3-(pyridin-2-yloxy)-benzaldehyde

[1460]

[1461] The title compound was obtained by the method described in EP1688138A1.

[1462] (2) Preparation of 3-(pyridin-2-yloxy)-benzaldehyde oxime

[1463]

[1464] The title compound (0.23 g, 99%) was obtained by the preparation method of Example 3-(1) using 3-(pyridin-2-yloxy)-benzaldehyde (0.21 g, 1.05 mmol) obtained in (1) above.

[1465] MS (m / z): 215 [M+H]

[1466] (3) 3-[3-(pyridin-2-yloxy)phenyl]-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1467]

[1468] The title compound (0.3 g, 89%) was obtained by the preparation method of Examples 2-(3) using 3-(pyridin-2-yloxy)-benzaldehyde oxime (0.23 g, 1.07 mmol) obtained in (2) above.

[1469] MS (m / z): 313 [M+H]

[1470] (4) 3-[3-(pyridin-2-yloxy)phenyl]-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1471]

[1472] Using the 3-[3-(pyridin-2-yloxy)phenyl]-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.3 g, 0.96 mmol) was used to prepare the title compound (0.27 g, 99%) by the method described in Examples 1-(2).

[1473] MS (m / z): 285 [M+H]

[1474] (5) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(3-(pyridin-2-yloxy)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1475] Using the 3-[3-(pyridin-2-yloxy)phenyl]-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.09 g, 0.32 mmol) was used to prepare the title compound (0.1 g, 59%) by the method described in Examples 1-(3).

[1476] MS (m / z): 532 [M+H]

[1477] (6) ((1R)-3-methyl-1-(3-(3-(pyridin-2-yloxy)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1478]

[1479] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(3-(pyridin-2-yloxy)phenyl)-4,5-dihydroisocyano The title compound (0.046 g, 62%) was obtained by the preparation method of Examples 1-(4) (0.1 g, 0.19 mmol).

[1480] NMR: 1 H-NMR(500MHz, MeOD-d4); δ 8.12-8.11 (m, 1H), 7.85-7.82 (m, 1H), 7.53-7.47 (m, 3H), 7.21-7.19 (m, 2H), 7.00-6.98 (m, 1H), 5.38-5.35 (m, 1H),3.84-3.78 (m, 1H), 3.68-3.63 (m, 1H), 2.86-2.82 (m, 1H), 1.65-1.61 (m, 1H),1.38-1.32 (m, 2H), 0.90-0.88 (dd, 6H)

[1481] MS (m / z): 398[M+H], 380[M-OH]

[1482] Example 42: ((1R)-3-methyl-1-(3-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydroisocyanuric acid Preparation of azole-5-carboxamido)butyl)boronic acid

[1483] The title compound was obtained through the processes of Examples 42-(1), (2), (3), (4), (5) and (6).

[1484] (1) Preparation of 3-(pyridin-2-yloxy)-benzaldehyde

[1485]

[1486] The title compound was obtained by the method described in Synlett, 2008, #2 pp. 221-224.

[1487] (2) Preparation of 3-(pyridin-2-yloxy)-benzaldehyde oxime

[1488]

[1489] The title compound (0.19 g, 98%) was obtained by the preparation method of Example 3-(1) using 3-(pyridin-2-yloxy)-benzaldehyde (0.18 g, 0.90 mmol) obtained in Example 42-(1).

[1490] MS (m / z): 215 [M+H]

[1491] (3) 3-[4-(pyridin-2-yloxy)phenyl]-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1492]

[1493] The title compound (0.23 g, 83%) was obtained by the preparation method of Example 2-(3) using 3-(pyridin-2-yloxy)-benzaldehyde oxime (0.19 g, 0.89 mmol) obtained in Example 42-(2).

[1494] NMR: 1 H-NMR (400MHz, CDCl3); δ 8.21-8.19 (m, 1H), 7.73-7.70 (m, 3H), 7.20-7.18 (m, 2H), 7.05-6.96 (m, 2H), 5.19-5.15 (m, 1H), 4.31-4.19 (q, 2H),3.70-3.58 (m, 2H), 1.35-1.31 (t, 3H)

[1495] MS (m / z): 313 [M+H]

[1496] (4) 3-[4-(pyridin-2-yloxy)phenyl]-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1497]

[1498] Using 3-[4-(pyridin-2-yloxy)phenyl]-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.23 g, 0.74 mmol) was used to prepare the title compound (0.2 g, 99%) by the method described in Examples 1-(2).

[1499] MS (m / z): 284 [M+H]

[1500] (5) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1501]

[1502] Using the 3-[4-(pyridin-2-yloxy)phenyl]-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.09 g, 0.32 mmol) was used to prepare the title compound (0.11 g, 65%) by the method described in Examples 1-(3).

[1503] MS (m / z): 532 [M+H]

[1504] (6) ((1R)-3-methyl-1-(3-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1505]

[1506] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydroisocyano The title compound (0.054 g, 65%) was obtained by the preparation method of Examples 1-(4) (0.11 g, 0.21 mmol).

[1507] NMR: 1H-NMR(500MHz, MeOD-d4); δ 8.15-8..14 (m, 1H), 7.87-7.83 (m, 1H), 7.77-7.75 (m, 2H), 7.17-7.14 (m, 3H), 7.02-7.00 (d, 1H), 5.38-5.35 (m, 1H),3.86-3.80 (m, 1H), 3.70-3.64 (m, 1H), 2.87-2.83 (m, 1H), 1.66-1.62 (m, 1H),1.39-1.33 (m, 2H), 0.90-0.88 (dd, 6H)

[1508] MS (m / z): 398[M+H], 380[M-OH]

[1509] Example 43: ((1R)-3-methyl-1-(3-(3-(pyridin-2-ylmethoxy)phenyl)-4,5-dihydroisocyanuric acid Preparation of azole-5-carboxamido)butyl)boronic acid

[1510] The title compound was obtained through the following processes (1), (2), (3), (4), (5) and (6).

[1511] (1) Preparation of 3-(pyridin-2-ylmethoxy)-benzaldehyde

[1512]

[1513] The title compound was obtained by the method described in WO2007105904A1.

[1514] (2) Preparation of 3-(pyridin-2-ylmethoxy)-benzaldehyde oxime

[1515]

[1516] The title compound (0.71 g, 99%) was obtained by the preparation method of Example 3-(1) using 3-(pyridin-2-ylmethoxy)-benzaldehyde (0.66 g, 3.10 mmol) obtained in (1) above.

[1517] MS (m / z): 229 [M+H]

[1518] (3) 3-{3-[(pyridin-2-yl)methoxy]phenyl}-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1519]

[1520] The title compound (0.9 g, 89%) was obtained by the preparation method of Examples 2-(3) using 3-(pyridin-2-ylmethoxy)-benzaldehyde oxime (0.71 g, 3.11 mmol) obtained in (2) above.

[1521] NMR: 1 H-NMR (400MHz, CDCl3); δ 8.62-8.61 (d, 1H), 7.74-7.50 (m, 1H), 7.36-7.35 (d, 1H), 7.33-7.24 (m, 4H), 7.07-7.05 (m, 1H), 5.30 (s, 2H), 5.23-5.14 (m, 1H), 4.31-4.24 (q, 2H), 3.67-3.56 (m, 2H), 1.35-1.31 (t, 3H)

[1522] MS (m / z): 327 [M+H]

[1523] (4) 3-{3-[(pyridin-2-yl)methoxy]phenyl}-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1524]

[1525] Using the 3-{3-[(pyridin-2-yl)methoxy]phenyl}-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.9 g, 2.76 mmol) was used to prepare the title compound (0.82 g, 99%) by the method described in Examples 1-(2).

[1526] MS (m / z): 299 [M+H]

[1527] (5) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(3-(pyridin-2-ylmethoxy)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1528]

[1529] Using the 3-{3-[(pyridin-2-yl)methoxy]phenyl}-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.08 g, 0.27 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.05 g, 34%).

[1530] MS (m / z): 546 [M+H]

[1531] (6) ((1R)-3-methyl-1-(3-(3-(pyridin-2-ylmethoxy)phenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1532]

[1533] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(3-(pyridin-2-ylmethoxy)phenyl)-4,5-dihydroisocyano The title compound (0.031 g, 82%) was obtained by the preparation method of Examples 1-(4) (0.05 g, 0.092 mmol).

[1534] NMR: 1 H-NMR(500MHz, MeOD-d4); δ 8.54-8.53 (m, 1H), 7.88-7.84 (m, 1H), 7.61-7.59 (d, 1H), 7.38-7.28 (m, 4H), 7.13-7.12 (m, 1H), 5.37-5.33 (m, 1H),5.21 (s, 2H), 3.83-3.77 (m, 1H), 3.67-3.61 (m, 1H), 2.85-2.82 (m, 1H), 1.65-1.62 (m, 1H), 1.39-1.32 (m, 2H), 0.90-0.87 (dd, 6H)

[1535] MS (m / z): 412[M+H], 394[M-OH]

[1536] Example 44: ((1R)-3-methyl-1-(3-(4-phenoxyphenyl)-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[1537] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1538] (1) Preparation of 4-phenoxy-benzaldehyde oxime

[1539]

[1540] The title compound (0.38 g, quantified) was obtained using 4-phenoxybenzaldehyde (0.35 g, 1.8 mmol) by the preparation method of Example 3-(1).

[1541] MS (m / z): 214 [M+H]

[1542] (2) 3-(4-phenoxyphenyl)-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[1543]

[1544] The title compound (0.38 g 69%) was obtained by the preparation method of Examples 2-(3) using 4-phenoxy-benzaldehyde oxime (0.38 g, 1.8 mmol) obtained in (1) above.

[1545] MS (m / z): 312 [M+H]

[1546] (3) 3-(4-phenoxyphenyl)-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[1547]

[1548] Using the 3-(4-phenoxyphenyl)-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.38 g, 1.2 mmol) was used to prepare the title compound (0.32 g, 94%) by the method described in Examples 1-(2).

[1549] MS (m / z): 284 [M+H]

[1550] (4) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(4-phenoxyphenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1551]

[1552] Using the 3-(4-phenoxyphenyl)-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.098 g, 0.35 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.079 g, 43%).

[1553] MS (m / z): 531 [M+H]

[1554] (5) ((1R)-3-methyl-1-(3-(4-phenoxyphenyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1555]

[1556] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridgedbenziro[d][1,3,2]dioxaborane-2-yl)butyl)-3-(4-phenoxyphenyl)-4,5-dihydroisocyano The title compound (0.018 g, 31%) was obtained by the preparation method of Examples 1-(4) (0.079 g, 0.15 mmol).

[1557] MS (m / z): 397[M+H], 379[M-OH]

[1558] Example 45: ((1R)-1-(5-phenylmethyl-3-(((2,5-dichlorophenylmethyl)oxy)methyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1559] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1560] (1) Preparation of 1,4-dichloro-2-((2,2-diethoxyethoxy)methyl)benzene

[1561]

[1562] 2,2-Diethoxyethanol (0.268 g, 2.0 mmol) was dissolved in tetrahydrofuran (8 ml), and sodium hydride (0.088 g, 2.2 mmol) was added at 0 °C, followed by stirring for 30 min. 2,5-Dichlorobenzyl bromide (0.48 g, 2.0 mmol) was added, followed by stirring at room temperature for 1 h. Water (20 ml) was added to quench the reaction, and the mixture was extracted twice with dichloromethane (20 ml). The resulting organic layer was dehydrated over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.416 g, 71%).

[1563] NMR: 1 H-NMR (500MHz, CDCl3); δ 7.52 (1H, d), 7.26-7.24 (1H, m), 7.19-7.17 (1H, m), 4.70 (1H, t), 4.63 (2H, s), 3.76-3.70 (2H, m), 3.62-3.56 (4H,m), 1.24 (6H, t)

[1564] (2) Preparation of 2-((2,5-dichlorobenzyl)oxy)acetaldehyde oxime

[1565]

[1566] The 1,4-dichloro-2-((2,2-diethoxyethoxy)methyl)benzene (0.409 g, 1.39 mmol) obtained in (1) above was dissolved in methanol (10 ml), to which 50% aqueous hydroxylamine solution (0.26 ml, 4.24 mmol) and 6 N hydrochloric acid solution (0.80 ml, 4.80 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The resulting solution was neutralized with aqueous sodium bicarbonate solution, methanol was removed by distillation under reduced pressure, and the residue was extracted three times with dichloromethane (20 ml). The resulting organic layer was dehydrated on anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.294 g, 90%).

[1567] MS (m / z): 234 [M+H]

[1568] (3) 5-Benzyl-3-(((2,5-dichlorobenzyl)oxy)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[1569]

[1570] Using ((2,5-dichloro-benzylmethyloxy)-acetaldehyde oxime (0.130 g, 0.56 mmol) obtained in process (2) above, the title compound (0.173 g, 76%) was obtained by the preparation method of Preparation Example 6-(2).

[1571] NMR: 1 H-NMR(500MHz, CDCl3); δ 7.31-7.17 (8H, m), 4.34-4.15 (4H, m), 3.79(3H, s), 3.41 (2H, dd), 3.09 (2H, dd)

[1572] MS (m / z): 408 [M+H]

[1573] (4) 5-Benzyl-3-(((2,5-dichlorobenzyl)oxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1574]

[1575] Using the 5-benzyl-3-(((2,5-dichlorobenzyl)oxy)methyl)-4,5-dihydroisocyanate obtained in (3) above Methyl 5-azole carboxylate (0.173 g, 0.424 mmol) was used to prepare the title compound (0.135 g, 79%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1576] MS (m / z): 641 [M+H]

[1577] (5) ((1R)-1-(5-benzyl-3-(((2,5-dichlorobenzyl)oxy)methyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1578]

[1579] Using the 5-benzyl-3-(((2,5-dichlorobenzyl)oxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.076 g, 71%) was obtained by the preparation method of Examples 1-(4) (0.135 g, 0.21 mmol).

[1580] NMR: 1 H-NMR (500MHz, CD3OD); δ 7.41-7.18 (8H, m), 4.48-4.23 (4H, m), 3.47-3.14 (4H, m), 2.77-2.70 (1H, m), 1.49-1.06 (3H, m), 0.83-0.78 (6H, m)

[1581] MS (m / z): 507[M+H], 489[M-OH]

[1582] Example 46: ((1R)-1-(5-phenylmethyl-3-(((2-methylthiazolyl-4-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1583] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1584] (1) Preparation of (2,2-diethoxy-ethoxymethyl)-2-methyl-thiazole

[1585]

[1586] The title compound (0.396 g, 81%) was obtained using the preparation method of Example 45-(1) with 4-chloromethyl-2-methyl-thiazole (0.296 g, 2.0 mmol).

[1587] NMR: 1 H-NMR (500MHz, CDCl3); δ 7.06 (1H, s), 4.67 (1H, t), 4.65 (2H, s), 3.72-3.66 (2H, m), 3.59-3.55 (m, 4H), 2.69 (3H, s), 1.22 (6H, t)

[1588] (2) Preparation of (2-methyl-thiazolyl-4-ylmethoxy)-acetaldehyde oxime

[1589]

[1590] The title compound (0.267 g, 89%) was obtained by the preparation method of Example 45-(2) using (2,2-diethoxy-ethoxymethyl)-2-methyl-thiazole (0.396 g, 1.61 mmol) obtained in (1) above.

[1591] (3) 5-Benzyl-3-(((2-methylthiazolyl-4-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[1592]

[1593] The title compound (0.104 g, 41%) was obtained by the preparation method of Preparation Example 6-(2) using (2-methyl-thiazolyl-4-ylmethoxy)-acetaldehyde oxime (0.131 g, 0.70 mmol) obtained in (2) above.

[1594] NMR: 1 H-NMR(500MHz, CDCl3); δ 7.28-7.22 (5H, m), 6.95 (1H, s), 4.32-4.26(2H, dd), 4.23-4.13 (2H, dd), 3.77 (3H, s), 3.44 (1H, d), 3.33 (1H, d), 3.13(1H, d), 3.05 (1H, d), 2.69 (3H, s)

[1595] MS (m / z): 361 [M+H]

[1596] (4) 5-Benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(((2-methylthiazolyl-4-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamide

[1597]

[1598] Using the 5-benzyl-3-(((2-methylthiazolyl)methoxy)methyl)-4,5-dihydroisocyanate obtained in (3) above Methyl 5-azole carboxylate (0.104 g, 0.289 mmol) was used to prepare the title compound (0.063 g, 41%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1599] MS (m / z): 594 [M+H]

[1600] (5) ((1R)-1-(5-benzyl-3-(((2-methylthiazo-4-yl)methoxy)methyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1601]

[1602] Using the 5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(((2-methylthiazolyl-4-yl)methoxy)methyl)-4,5-dihydroisocyanate obtained in the above process (4) The title compound (0.028 g, 58%) was obtained by the preparation method of Examples 1-(4) (0.063 g, 0.106 mmol).

[1603] NMR: 1 H-NMR(500MHz, CD3OD); δ 7.17-7.11 (6H, m), 4.42 (2H, dd), 4.22(2H, dd), 3.43 (1H, d), 3.33-3.22 (2H, m), 3.16 (1H, d), 1.41-1.03 (3H, m),0.79 (6H, dd)

[1604] MS (m / z): 460[M+H], 442[M-OH]

[1605] Example 47: ((1R)-1-(5-phenylmethyl-3-(((6-methylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1606] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1607] (1) Preparation of 2-(2,2-diethoxy-ethoxymethyl)-6-methylpyridine

[1608]

[1609] The title compound (0.292 g, 61%) was obtained using 2-chloromethyl-6-methyl-pyridine (0.283 g, 2.0 mmol) by the preparation method of Example 45-(1).

[1610] NMR: 1 H-NMR (500MHz, CDCl3); δ 7.57 (1H, t), 7.26 (1H, d), 7.03 (1H, d), 4.70 (1H, t), 4.66 (2H, s), 3.74-3.68 (2H, m), 3.60-3.55 (4H, m), 2.52 (3H, s), 1.22 (6H, t)

[1611] (2) Preparation of (6-methylpyridin-2-yl-methoxy)-acetaldehyde oxime

[1612]

[1613] The title compound (0.189 g, 86%) was obtained by the preparation method of Preparation Example 6-(2) using 2-(2,2-diethoxy-ethoxymethyl)-6-methyl-pyridine (0.29 g, 1.2 mmol) obtained in (1) above.

[1614] MS (m / z): 181 [M+H]

[1615] (3) 5-Benzyl-3-(((6-methylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[1616]

[1617] The title compound (0.073 g, 36%) was obtained by the preparation method of Examples 45-(3) using (6-methylpyridin-2-yl-methoxy)-acetaldehyde oxime (0.104 g, 0.58 mmol) obtained in (2) above.

[1618] NMR: 1H-NMR(500MHz, CDCl3); δ 7.54 (1H, t), 7.25-7.21 (5H, m), 7.06 (1H,m), 7.03 (1H, d), 4.37 (2H, dd), 4.20 (2H, dd), 3.75 (3H, s), 3.46 (1H, d),3.30 (1H, d), 3.13 (1H, d), 3.05 (1H, d), 2.51 (3H, s)

[1619] MS (m / z): 355 [M+H]

[1620] (4) 5-Benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(((6-methylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamide

[1621]

[1622] Using the 5-benzyl-3-(((6-methylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisocyanate obtained in (3) above Methyl 5-azole carboxylate (0.073 g, 0.21 mmol) was used to prepare the title compound (0.06 g, 56%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1623] MS (m / z): 588 [M+H]

[1624] (5) ((1R)-1-(5-benzyl-3-(((6-methylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1625]

[1626] Using the 5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(((6-methylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisocyano The title compound (0.014 g, 27%) was obtained by the preparation method of Examples 1-(4) (0.068 g, 0.116 mmol).

[1627] NMR: 1 H-NMR(500MHz, CD3OD); δ 7.74 (1H, dd), 7.29-7.22 (5H, m), 4.46(2H, dd), 4.32 (2H, dd), 3.50 (1H, d), 3.37-3.28 (2H, m), 3.20 (1H, d), 2.73(1H, t), 1.46-1.10 (3H, m), 0.83 (6H, dd)

[1628] MS (m / z): 454[M+H], 436[M-OH]

[1629] Example 48: ((1R)-1-(5-phenylmethyl-3-(((5-methylpyrazine-2-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1630] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1631] (1) Preparation of 2-(2,2-diethoxy-ethoxymethyl)-5-methylpyrazine

[1632]

[1633] The title compound (0.168 g, 70%) was obtained using the preparation method of Example 45-(1) with 2-chloromethyl-5-methyl-pyrazine (0.143 g, 1.0 mmol).

[1634] NMR: 1 H-NMR (500MHz, CDCl3); δ 8.59(1H, s), 8.38 (1H, s), 4.70 (2H, s), 4.69 (1H, t), 3.74-3.68 (2H, m), 3.62-3.54 (4H, m), 2.55 (3H, s), 1.22 (6H,t)

[1635] (2) Preparation of (5-methyl-pyrazin-2-yl-methoxy)-acetaldehyde oxime

[1636]

[1637] The title compound (0.112 g, 88%) was obtained by the preparation method of Example 45-(2) using 2-(2,2-diethoxy-ethoxymethyl)-5-methyl-pyrazine (0.168 g, 0.70 mmol) obtained in (1) above.

[1638] MS (m / z): 182 [M+H]

[1639] (3) 5-Benzyl-3-(((5-methylpyrazine-2-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[1640]

[1641] The title compound (0.079 g, 36%) was obtained by the preparation method of Preparation Example 6-(2) using (5-methyl-pyrazin-2-yl-methoxy)-acetaldehyde oxime (0.112 g, 0.62 mmol) obtained in (2) above.

[1642] NMR: 1 H-NMR(500MHz, CDCl3); δ 8.40 (1H, s), 8.38 (1H, s), 7.25-7.17 (5H,m), 4.37 (1H, d), 4.26 (2H, d), 4.18 (1H, d), 3.77 (3H, s), 3.44 (1H, d),3.33 (1H, d), 3.11 (1H, d), 3.04 (1H, d), 2.55 (3H, s)

[1643] MS (m / z): 356 [M+H]

[1644] (4) 5-Benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(((5-methylpyrazine-2-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamide

[1645]

[1646] Using the 5-benzyl-3-(((5-methylpyrazin-2-yl)methoxy)methyl)-4,5-dihydroisocyanate obtained in (3) above Methyl 5-azole carboxylate (0.079 g, 0.22 mmol) was used to prepare the title compound (0.071 g, 54%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1647] MS (m / z): 589 [M+H]

[1648] (5) ((1R)-1-(5-phenylmethyl-3-(((5-methylpyrazin-2-yl)methoxy)methyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1649]

[1650] Using the 5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(((5-methylpyrazin-2-yl)methoxy)methyl)-4,5-dihydroisocyano The title compound (0.014 g, 26%) was obtained by the preparation method of Examples 1-(4) (0.071 g, 0.121 mmol).

[1651] NMR: 1 H-NMR(500MHz, CD3OD); δ 8.47 (2H, s), 7.28-7.19 (5H, m), 4.50 (2H,dd), 4.31 (2H, dd), 3.46 (1H, d), 3.33-3.25 (2H, m), 3.17 (1H, d), 2.69 (1H,t), 1.43-1.05 (3H, m), 0.80 (6H, dd)

[1652] MS (m / z): 437 [M-OH]

[1653] Example 49: ((1R)-1-(5-phenylmethyl-3-((isoquinoline-1-ylmethoxy)methyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1654] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1655] (1) Preparation of chloroacetaldehyde oxime

[1656]

[1657] The title compound (0.650 g, 45%) was obtained by the preparation method of Preparation Example 1-(1) using 50% aqueous chloroacetaldehyde (2.4 g, 15.3 mmol) and 50% aqueous hydroxylamine (1.2 g, 18.2 mmol).

[1658] (2) 5-Benzyl-3-(chloromethyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[1659]

[1660] Using the chloroacetaldehyde oxime (0.281 g, 3.00 mmol) obtained in (1) above, the title compound (0.351 g, 66%) was obtained by the preparation method of Preparation Example 6-(2).

[1661] NMR: 1 H-NMR(500MHz, CDCl3); δ 7.29-7.22 (5H, m), 4.13 (2H, dd), 3.78(3H, s), 3.47 (1H, d), 3.32 (1H, d), 3.17 (1H, d), 3.07 (1H, d)

[1662] (3) 5-Benzyl-3-((isoquinoline-1-ylmethoxy)methyl)-4,5-dihydroisoquinoline Preparation of methyl 5-azole carboxylate

[1663]

[1664] Isoquinoline-1-yl-methanol (0.064 g, 0.40 mmol) was dissolved in tetrahydrofuran (4 ml), and sodium hydride (0.040 g, 1.00 mmol) was added. The mixture was then stirred at room temperature for 30 minutes. 5-phenylmethyl-3-(chloromethyl)-4,5-dihydroisoquinoline-1-yl-methanol obtained in (2) above was then added sequentially to the solution in tetrahydrofuran (2 ml). A solution of methyl 5-azole carboxylate (0.11 g, 0.44 mmol) and tetrabutylammonium iodide (0.030 g, 0.08 mmol) was prepared, and the mixture was stirred at room temperature for 4 hours. After adding water (10 ml) to the reaction product, the mixture was extracted three times with dichloromethane (10 ml). The resulting organic layer was dehydrated on anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.042 g, 27%).

[1665] NMR: 1 H-NMR (500MHz, CDCl3); δ 8.46 (1H, d), 8.18 (1H, d), 7.88 (1H, d), 7.76 (1H, t), 7.71 (1H, d), 7.66 (1H, t), 7.28-7.16 (5H, m), 5.01 (1H, d),4.90 (1H, d), 4.23 (2H, dd), 3.72 (3H, s), 3.38-3.02 (4H, m)

[1666] MS (m / z): 391 [M+H]

[1667] (4) 5-Benzyl-3-((isoquinoline-1-ylmethoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroiso Preparation of azole-5-carboxamide

[1668]

[1669] Using the 5-benzyl-3-((isoquinoline-1-ylmethoxy)methyl)-4,5-dihydroisoquinoline obtained in (3) above Methyl 5-azole carboxylate (0.042 g, 0.112 mmol) was used to prepare the title compound (0.043 g, 58%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1670] (5) ((1R)-1-(5-benzylmethyl-3-((isoquinoline-1-ylmethoxy)methyl)-4,5-dihydroisoquinoline ... Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1671]

[1672] Using the 5-benzyl-3-((isoquinoline-1-ylmethoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridgedbenziro[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroiso The title compound (0.023 g, 68%) was obtained by the preparation method of Examples 1-(4) (0.043 g, 0.069 mmol).

[1673] NMR: 1 H-NMR (500MHz, CD3OD); δ 8.38 (1H, d), 8.30 (1H, d), 7.95 (1H, d), 7.80-7.78 (2H, m), 7.70 (1H, t), 7.24-7.15 (5H, m), 5.08 (1H, d), 4.99 (1H,d), 4.34-4.28 (2H, m), 3.41-3.17 (3H, m), 3.08 (1H, d), 2.63 (1H, t), 1.38-1.03 (3H, m), 0.76 (6H, dd)

[1674] MS (m / z): 490[M+H], 472[M-OH]

[1675] Example 50: ((1R)-1-(5-phenylmethyl-3-(((5-chloro-2-methylthiazolyl-4-yl)methoxy)methyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1676] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1677] (1) Preparation of 5-chloro-4-(2,2-diethoxy-ethoxymethyl)-2-methyl-thiazole

[1678]

[1679] The title compound (0.352 g, 63%) was obtained using 5-chloro-4-chloromethyl-2-methylthiazole (0.362 g, 1.99 mmol) by the preparation method of Example 45-(1).

[1680] NMR: 1 H-NMR (500MHz, CDCl3); δ 4.67 (1H, t), 4.60 (2H, s), 3.72-3.66(2H, m), 3.59-3.53 (4H, m), 2.63 (3H, s), 1.21 (6H, t)

[1681] (2) Preparation of (5-chloro-2-methyl-thiazolyl-5-yl-methoxy)-acetaldehyde oxime

[1682]

[1683] The title compound (0.209 g, 75%) was obtained by the preparation method of Example 45-(2) using 5-chloro-4-(2,2-diethoxy-ethoxymethyl)-2-methyl-thiazole (0.352 g, 1.26 mmol) obtained in (1) above.

[1684] (3) 5-Benzyl-3-(((5-chloro-2-methylthiazolyl-4-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[1685]

[1686] The title compound (0.264 g, 70%) was obtained by the preparation method of Preparation Example 6-(2) using (5-chloro-2-methyl-thiazolyl-5-yl-methoxy)-acetaldehyde oxime (0.209 g, 0.95 mmol) obtained in (2) above.

[1687] NMR: 1 H-NMR(500MHz, CDCl3); δ 7.25-7.18 (5H, m), 4.28 (2H, dd), 4.16(2H, dd), 3.72 (3H, s), 3.43 (1H, d), 3.27 (1H, d), 3.13 (1H, d), 3.05 (1H,d), 2.59 (3H, s)

[1688] (4) 5-Benzyl-3-(((5-chloro-2-methylthiazolyl-4-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1689]

[1690] Using the 5-benzyl-3-(((5-chloro-2-methylthiazolyl-4-yl)methoxy)methyl)-4,5-dihydroisocyanate obtained in (3) above Methyl 5-azole carboxylate (0.264 g, 0.67 mmol) was used to prepare the title compound (0.217 g, 64%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1691] MS (m / z): 628 [M+H]

[1692] (5) ((1R)-1-(5-phenylmethyl-3-(((5-chloro-2-methylthiazo-4-yl)methoxy)methyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1693]

[1694] Using the 5-benzyl-3-(((5-chloro-2-methylthiazo-4-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.057 g, 33%) was obtained by the preparation method of Examples 1-(4) (0.21 g, 0.34 mmol).

[1695] NMR: 1 H-NMR(500MHz, CD3OD); δ 7.28-7.21 (5H, m), 4.43 (2H, dd), 4.23(2H, dd), 3.42 (1H, d), 3.32-3.22 (2H, m), 3.16 (1H, d), 2.66 (1H, t), 2.62(3H, s), 1.41-1.03 (3H, m), 0.79 (6H, dd)

[1696] MS (m / z): 476 [M-OH]

[1697] Example 51: ((1R)-1-(5-phenylmethyl-3-(((2,4-dimethylthiazolyl-5-yl)methoxy)methyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1698] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1699] (1) Preparation of 5-(2,2-diethoxy-ethoxymethyl)-2,4-dimethyl-thiazole

[1700]

[1701] The title compound (0.162 g, 38%) was obtained using 5-chloromethyl-2,4-dimethyl-thiazole (0.264 g, 1.63 mmol) by the preparation method of Example 45-(1).

[1702] NMR: 1 H-NMR (500MHz, CDCl3); δ 4.60 (2H, s), 4.52 (1H, t), 3.75-3.66(2H, m), 3.56-3.51 (4H, m), 2.60 (3H, s), 2. 42, (3H, s), 1.20 (6H, t)

[1703] (2) Preparation of (2,4-dimethyl-thiazolyl-5-yl-methoxy)-acetaldehyde oxime

[1704]

[1705] The title compound (0.055 g, 44%) was obtained by the preparation method of Example 45-(2) using 5-(2,2-diethoxy-ethoxymethyl)-2,4-dimethyl-thiazole (0.162 g, 0.625 mmol) obtained in (1) above.

[1706] (3) 5-Benzyl-3-(((2,4-dimethylthiazolyl-5-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[1707]

[1708] The title compound (0.040 g, 36%) was obtained by the preparation method of Preparation Example 6-(2) using (2,4-dimethyl-thiazolyl-5-yl-methoxy)-acetaldehyde oxime (0.055 g, 0.275 mmol) obtained in (2) above.

[1709] NMR: 1 H-NMR(500MHz, CDCl3); δ 7.27-7.21 (5H, m), 4.24 (2H, s), 4.07 (2H, dd), 3.76 (3H, s), 3.39 (1H, d), 3.32 (1H, d), 3.11 (1H, d), 2.99 (1H, d),2.61 (3H, s), 2.27 (3H, s)

[1710] MS (m / z): 375 [M+H]

[1711] (4) 5-Benzyl-3-(((2,4-dimethylthiazolyl-5-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1712]

[1713] Using the 5-benzyl-3-(((2,4-dimethylthiazolyl-5-yl)methoxy)methyl)-4,5-dihydroisocyanate obtained in (3) above Methyl 5-azole carboxylate (0.040 g, 0.107 mmol) was used to prepare the title compound (0.055 g, 85%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1714] (5) 5-Benzyl-3-(2,4-dimethyl-thiazolyl-5-yl-methoxymethyl)-4,5-dihydro-iso Preparation of azole-5-carboxylic acid ((R)-1-boronic acid-3-methyl-butyl)-amide

[1715]

[1716] Using the 5-benzyl-3-(((2,4-dimethylthiazo-5-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.013 g, 30%) was obtained by the preparation method of Examples 1-(4) (0.055 g, 0.091 mmol).

[1717] NMR: 1 H-NMR(500MHz, CD3OD); δ 7.27-7.21 (5H, m), 4.47 (2H, s), 4.16 (2H,dd), 3.40 (1H, d), 3.32-3.20 (2H, m), 3.15 (1H, d), 2.68 (1H, t), 2.61 (3H, s), 2.27 (3H, s), 1.42-1.05 (3H, m), 0.80 (6H, dd)

[1718] MS (m / z): 456 [M-OH]

[1719] Example 52: ((1R)-1-(5-phenylmethyl-3-(((3-bromophenylmethyl)oxy)methyl)-4,5-dihydroisocyanate Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1720] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1721] (1) Preparation of 1-bromo-3-(2,2-diethoxy-ethoxymethyl)-benzene

[1722]

[1723] The title compound (0.841 g, 69%) was obtained using 3-bromo-benzylmethyl bromide (1.00 g, 4.0 mmol) by the preparation method of Example 45-(1).

[1724] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.55 (1H, s), 7.45 (1H, dd), 7.31-7.23(2H, m), 4.71 (1H, t), 4.60 (2H, s), 3.78-3.71 (2H, m), 3.65-3.55 (4H, m),1.25 (6H, t)

[1725] (2) Preparation of (3-bromo-phenylmethyloxy)-acetaldehyde oxime

[1726]

[1727] The title compound (0.647 g, 96%) was obtained by the preparation method of Example 45-(2) using 1-bromo-3-(2,2-diethoxy-ethoxymethyl)-benzene (0.841 g, 2.77 mmol) obtained in (1) above.

[1728] (3) 5-Benzyl-3-(((3-bromophenylmethyl)oxy)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[1729]

[1730] Using (3-bromo-benzylmethyloxy)-acetaldehyde oxime (0.647 g, 2.65 mmol) obtained in process (2) above, the title compound (0.641 g, 58%) was obtained by the preparation method of Preparation Example 6-(2).

[1731] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.42 (1H, d), 7.36 (1H, s), 7.29-7.19 (6H,m), 7.12 (1H, d), 4.18-4.07 (4H, m), 3.79 (3H, s), 3.39 (2H, dd), 3.07 (2H,dd)

[1732] (4) 5-Benzyl-3-(((3-bromophenylmethyl)oxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1733]

[1734] Using the 5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-4,5-dihydroisocyanate obtained in (3) above Methyl 5-azole carboxylate (0.059 g, 0.14 mmol) was used to prepare the title compound (0.050 g, 54%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1735] MS (m / z): 651, 653 [M+H]

[1736] (5) ((1R)-1-(5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1737]

[1738] Using the 5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.016 g, 40%) was obtained by the preparation method of Examples 1-(4) (0.050 g, 0.077 mmol) of azole-5-carboxamide (0.050 g, 0.077 mmol).

[1739] NMR: 1 H-NMR(400MHz, CD3OD); δ 7.44 (1H, s), 7.43 (1H, d), 7.28-7.19 (7H,m), 4.33 (2H, dd), 4.20 (2H, dd), 3.42 (1H, d), 3.33-3.28 (1H, m), 3.23 (1H,d), 3.16 (1H, d), 2.69 (1H, dd), 1.44-1.04 (3H, m), 0.80 (6H, dd)

[1740] MS (m / z): 540, 542 (M+Na), 499, 501 [M-OH]

[1741] Example 53: ((1R)-1-(5-phenylmethyl-3-(((6-bromopyridin-2-yl)methoxy)methyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1742] The title compound was obtained through the following processes (1), (2), (3), (4) and (5).

[1743] (1) Preparation of 2-bromo-6-(2,2-diethoxy-ethoxymethyl)-pyridine

[1744]

[1745] The title compound (0.196 g, 81%) was obtained using 2-bromo-6-chloromethyl-pyridine (0.191 g, 0.925 mmol) by the preparation method of Example 45-(1).

[1746] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.60-7.35 (3H, m), 4.72 (1H, t), 4.69(2H, s), 3.81-3.67 (2H, m), 3.64-3.56 (4H, m), 1.24 (6H, t)

[1747] (2) Preparation of (6-bromopyridin-2-ylmethoxy)-acetaldehyde oxime

[1748]

[1749] The title compound (0.125 g, 79%) was obtained by the preparation method of Example 45-(2) using 2-bromo-6-(2,2-diethoxy-ethoxymethyl)-pyridine (0.196 g, 0.644 mmol) obtained in (1) above.

[1750] (3) 5-Benzyl-3-(((6-bromopyridin-2-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[1751]

[1752] The title compound (0.125 g, 58%) was obtained by the preparation method of Preparation Example 6-(2) using (6-bromopyridin-2-ylmethoxy)-acetaldehyde oxime (0.125 g, 0.51 mmol) obtained in (2) above.

[1753] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.58 (1H, t), 7.43 (1H, d), 7.30-7.24 (6H,m), 4.39 (2H, dd), 4.25 (2H, dd), 3.83 (3H, s), 3.45 (2H, dd), 3.14 (2H,dd)

[1754] (4) 5-Benzyl-3-(((6-bromopyridin-2-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1755]

[1756] Using the 5-benzyl-3-(((6-bromopyridin-2-yl)methoxy)methyl)-4,5-dihydroisocyanate obtained in (3) above Methyl 5-azole carboxylate (0.052 g, 0.124 mmol) was used to prepare the title compound (0.039 g, 49%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1757] MS (m / z): 652, 654 [M+H]

[1758] (5) ((1R)-1-(5-benzylmethyl-3-(((6-bromopyridin-2-yl)methoxy)methyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1759]

[1760] Using the 5-benzyl-3-(((6-bromopyridin-2-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.014 g, 45%) was obtained by the preparation method of Examples 1-(4) (0.039 g, 0.06 mmol).

[1761] NMR: 1 H-NMR (400MHz, CD3OD); δ 7.73 (1H, t), 7.53 (1H, d), 7.44 (1H, d), 7.32-7.22 (5H, m), 4.46 (2H, q), 4.34 (2H, dd), 3.50 (1H, d), 3.37-3,33 (2H,m), 3.21 (1H, d), 2.73 (1H, t), 1.48-1.07 (3H, m), 0.84 (6H, dd)

[1762] MS (m / z): 540, 542 (M+Na), 500, 502 [M-OH]

[1763] Example 54: ((1R)-1-(3-(([1,1'-biphenyl]-3-ylmethoxy)methyl)-5-benzyl-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1764] The title compound was obtained through the following processes (1), (2) and (3).

[1765] (1) 3-(([1,1'-biphenyl]-3-ylmethoxy)methyl)-5-benzyl-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[1766]

[1767] The 5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-4,5-dihydroisocyanate obtained in Examples 52-(3) was used. Methyl 5-azole carboxylate (0.095 g, 0.227 mmol) and phenylboronic acid were used to prepare the title compound (0.064 g, 68%) by the method described in Example 35-(3).

[1768] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.65-7.19 (14H, m), 4.34-4.13 (4H, m), 3.83 (3H, s), 3.45 (2H, dd), 3.14 (2H, dd)

[1769] MS (m / z): 416 [M+H]

[1770] (2) 3-(([1,1'-biphenyl]-3-ylmethoxy)methyl)-5-benzylmethyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1771]

[1772] Using the 3-(([1,1'-biphenyl]-3-ylmethoxy)methyl)-5-benzyl-4,5-dihydroisocyanate obtained in (1) above Methyl 5-azole carboxylate (0.064 g, 0.154 mmol) was used to prepare the title compound (0.069 g, 68%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1773] MS (m / z): 649 [M+H]

[1774] (3) ((1R)-1-(3-(([1,1'-biphenyl]-3-ylmethoxy)methyl)-5-benzyl-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1775]

[1776] Using the 3-(([1,1'-biphenyl]-3-ylmethoxy)methyl)-5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.019 g, 35%) was obtained by the preparation method of Examples 1-(4) (0.069 g, 0.106 mmol).

[1777] NMR: 1 H-NMR(400MHz, CD3OD); δ 7.64-7.24 (14H, m), 4.48-4.22 (4H, m), 3.47 (1H, d), 3.37-3.27 (1H, m), 3.23-3.14 (2H, m), 2.72 (1H, t), 1.47-1.10(3H, m), 0.82 (6H, dd)

[1778] MS (m / z): 537 (M+Na), 497 [M-OH]

[1779] Example 55: [(1R)-1-[[5-phenylmethyl-3-[(6-phenyl-2-pyridyl)methoxymethyl]-4H-1,2- Preparation of [azole-5-carbonyl]amino]-3-methyl-butyl]boronic acid

[1780] The title compound was obtained through the following processes (1), (2) and (3).

[1781] (1) 5-Benzyl-3-(((6-phenylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[1782]

[1783] The 5-benzyl-3-(((6-bromopyridin-2-yl)methoxy)methyl)-4,5-dihydroisocyanate obtained in Examples 53-(3) was used. Methyl 5-azole carboxylate (0.076 g, 0.181 mmol) and phenylboronic acid were used to prepare the title compound (0.041 g, 54%) by the method described in Example 35-(3).

[1784] NMR: 1H-NMR (400MHz, CDCl3); δ 8.04 (2H, dd), 7.79 (1H, t), 7.68 (1H, d), 7.53-7.46 (3H, m), 7.30-7.13 (6H, m), 4.55 (2H, dd), 4.32 (2H, dd), 3.82 (3H,s), 3.55 (1H, d), 3.39 (1H, d), 3.18 (2H, dd)

[1785] MS (m / z): 417 [M+H]

[1786] (2) 5-Benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(((6-phenylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamide

[1787]

[1788] Using the 5-benzyl-3-(((6-phenylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisocyanate obtained in (1) above Methyl 5-azole carboxylate (0.041 g, 0.098 mmol) was used to prepare the title compound (0.036 g, 57%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1789] MS (m / z): 650 [M+H]

[1790] (3) ((1R)-1-(5-benzylmethyl-3-(((6-phenylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1791]

[1792] Using the 5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(((6-phenylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisocyano The title compound (0.015 g, 53%) was obtained by the preparation method of Examples 1-(4) (0.036 g, 0.055 mmol).

[1793] NMR: 1 H-NMR (400MHz, CD3OD); δ 7.99 (2H, dd), 7.89 (1H, t), 7.77 (1H, d), 7.51-7.39 (4H, m), 7.29-7.24 (5H, m), 4.60 (2H, dd), 4.38 (2H, dd), 3.52 (1H,d), 3.37-3.30 (2H, m), 3.20 (1H, d), 2.72 (1H, t), 1.46-1.06 (3H, m), 0.82(6H, dd)

[1794] MS (m / z): 498 [M-OH]

[1795] Example 56: ((1R)-1-(5-phenylmethyl-3-(((4'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1796] The title compound was obtained through the following processes (1), (2) and (3).

[1797] (1) 5-Benzyl-3-(((4'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[1798]

[1799] The 5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-4,5-dihydroisocyanate obtained in Examples 52-(3) was used. Methyl 5-azole carboxylate (0.076 g, 0.182 mmol) and 4-methoxyphenylboronic acid were used to prepare the title compound (0.047 g, 58%) by the method described in Example 35-(3).

[1800] NMR: 1H-NMR(400MHz, CDCl3); δ 7.59-7.41 (5H, m), 7.32-7.21 (6H, m), 7.03(2H, dd), 4.32 (2H, dd), 4.18 (2H, dd), 3.90 (3H, s), 3.83 (3H, s), 3.51 (1H,d), 3.41 (1H,d), 3.18 (1H,d), 3.10 (1H,d)

[1801] MS (m / z): 446 [M+H]

[1802] (2) 5-Benzyl-3-(((4'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1803]

[1804] Using the 5-benzyl-3-(((4'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisocyanate obtained in (1) above Methyl 5-azole carboxylate (0.047 g, 0.105 mmol) was used to prepare the title compound (0.043 g, 60%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1805] MS (m / z): 679 [M+H]

[1806] (3) ((1R)-1-(5-benzylmethyl-3-(((4'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1807]

[1808] Using the 5-benzyl-3-(((4'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.015 g, 44%) was obtained by the preparation method of Examples 1-(4) (0.043 g, 0.063 mmol).

[1809] NMR: 1 H-NMR(400MHz, CD3OD); δ 7.58-7.39 (5H, m), 7.31-7.23 (6H, m), 7.03(2H, dd), 4.46 (2H, dd), 4.26 (2H, dd), 3.85 (3H, s), 3.47 (1H, d), 3.37-3.27(2H, m), 3.20 (1H, d), 2.72 (1H, t), 1.45-1.09 (3H, m), 0.82 (6H, dd)

[1810] MS (m / z): 545 [M+H], 527 [M-OH]

[1811] Example 57: ((1R)-1-(5-phenylmethyl-3-(((3'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1812] The title compound was obtained through the following processes (1), (2) and (3).

[1813] (1) 5-Benzyl-3-(((3'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[1814]

[1815] The 5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-4,5-dihydroisocyanate obtained in Examples 52-(3) was used. Methyl 5-azole carboxylate (0.072 g, 0.172 mmol) and 3-methoxyphenylboronic acid were used to prepare the title compound (0.046 g, 60%) by the method described in Example 35-(3).

[1816] NMR: 1H-NMR(400MHz, CDCl3); δ 7.56-7.40 (4H, m), 7.32-7.17 (8H, m), 6.98(1H, d), 4.31 (2H, dd), 4.20 (2H, dd), 3.92 (3H, s), 3.83 (3H, s), 3.51 (1H,d), 3.39 (1H,d), 3.18 (1H,d), 3.10 (1H,d)

[1817] MS (m / z): 446 [M+H]

[1818] (2) 5-Benzyl-3-(((3'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1819]

[1820] Using the 5-benzyl-3-(((3'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisocyanate obtained in (1) above Methyl 5-azole carboxylate (0.046 g, 0.103 mmol) was used to prepare the title compound (0.035 g, 50%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1821] MS (m / z): 679 [M+H]

[1822] (3) ((1R)-1-(5-benzylmethyl-3-(((3'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1823]

[1824] Using the 5-benzyl-3-(((3'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridgedbenzi[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.013 g, 46%) was obtained by the preparation method of Examples 1-(4) (0.035 g, 0.052 mmol).

[1825] NMR: 1 H-NMR(400MHz, CD3OD); δ 7.56-7.15 (12H, m), 6.95 (1H, dd), 4.48(2H, dd), 4.27 (2H, dd), 3.87 (3H, s), 3.47 (1H, d), 3.37-3.23 (2H, m), 3.16(1H, d), 2.72 (1H, t), 1.45-1.09 (3H, m), 0.82 (6H, dd)

[1826] MS (m / z): 545 [M+H], 527 [M-OH]

[1827] Example 58: [(1R)-1-[[5-phenylmethyl-3-[[3-(2-methoxyphenyl)phenyl]methoxymethyl]-4H-1,2- Preparation of [azole-5-carbonyl]amino]-3-methyl-butyl]boronic acid

[1828] The title compound was obtained through the following processes (1), (2) and (3).

[1829] (1) 5-Benzyl-3-(((2'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisocyanate Preparation of methyl 5-azole carboxylate

[1830]

[1831] The 5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-4,5-dihydroisocyanate obtained in Preparation Example 9 was used. Methyl 5-azole carboxylate (0.064 g, 0.153 mmol) and 4-methoxyphenylboronic acid were used to prepare the title compound (0.052 g, 76%) by the method described in Example 35-(3).

[1832] NMR: 1H-NMR (400MHz, CDCl3); δ 7.52-7.25 (11H, m), 7.11-7.04 (2H, m), 4.34 (2H, dd), 4.23 (2H, dd), 3.86 (3H, s), 3.83 (3H, s), 3.51 (1H, d), 3.39(1H, d), 3.19 (1H, d), 3.11 (1H, d)

[1833] MS (m / z): 446 [M+H]

[1834] (2) 5-Benzyl-3-(((2'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1835]

[1836] Using the 5-benzyl-3-(((2'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisocyanate obtained in (1) above Methyl 5-azole carboxylate (0.052 g, 0.117 mmol) was used to prepare the title compound (0.042 g, 52%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1837] MS (m / z): 679 [M+H]

[1838] (3) 5-Benzyl-3-(2'-methoxy-biphenyl-3-ylmethoxymethyl)-4,5-dihydro-iso Preparation of azole-5-carboxylic acid ((R)-1-boronic acid-3-methyl-butyl)-amide

[1839]

[1840] Using the 5-benzyl-3-(((2'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.018 g, 53%) was obtained by the preparation method of Examples 1-(4) (0.042 g, 0.062 mmol).

[1841] NMR: 1 H-NMR (400MHz, CD3OD); δ 7.42-7.24 (11H, m), 7.10-7.03 (2H, m), 4.45 (2H, dd), 4.25 (2H, dd), 3.80 (3H, s), 3.46 (1H, d), 3.37-3.22 (2H, m),3.15 (1H, d), 2.71 (1H, t), 1.45-1.09 (3H, m), 0.82 (6H, dd)

[1842] MS (m / z): 545 [M+H], 527 [M-OH]

[1843] Example 59: ((1R)-1-(3-(benzamidomethyl)-4,5-dihydroisocyanate) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1844] The title compound was obtained through the following processes (1), (2), (3) and (4).

[1845] (1) 3-(aminomethyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate hydrochloride

[1846]

[1847] The 3-[(tert-butoxycarbonylamino)methyl]-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.67 g, 2.46 mmol) was dissolved in dichloromethane (10 ml). 4 N 1,4-dioxane hydrochloride was slowly added to the solution at 0 °C. The solution was prepared in alkyl (5 ml, 20 mmol) and stirred for 5 hours while being heated to room temperature. The solvent was distilled under reduced pressure, and the resulting product was cured with dichloromethane and hexane. The residual solvent was distilled under reduced pressure and dried under reduced pressure to give the title compound (0.48 g, 94%).

[1848] MS (m / z): 173 [M+H]

[1849] (2) 3-(benzamidomethyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[1850]

[1851] The 3-(aminomethyl)-4,5-dihydroisocyanate obtained in (1) above Ethyl 5-carboxylate hydrochloride (0.15 g, 0.72 mmol) was dissolved in dimethylformamide (3 ml). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.18 g, 0.94 mmol), hydroxybenzotriazole (0.13 g, 0.94 mmol), and benzoic acid (0.11 g, 0.79 mmol) were added sequentially. Diisopropylethylamine (0.38 ml, 2.16 mmol) was slowly added, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled under reduced pressure, and an aqueous sodium bicarbonate solution was added, followed by two extractions with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.07 g, 35%).

[1852] NMR: 1 H-NMR (400MHz, CDCl3); δ 7.82-7.75 (dd, 2H), 7.54-7.40 (m, 3H), 6.90 (m, 1H), 5.06-5.02 (dd, 1H), 4.42-4.41 (d, 2H), 4.29-4.21 (q, 2H), 3.48-3.30 (m, 2H), 1.31-1.28 (t, 3H)

[1853] MS (m / z): 277 [M+H]

[1854] (3) 3-(benzamidomethyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1855]

[1856] Using the 3-(benzamidomethyl)-4,5-dihydroisocyanate obtained in (2) above Ethyl 5-oxazolium carboxylate (0.07 g, 0.26 mmol) was used to prepare the title compound (0.08 g, 64%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1857] MS (m / z): 496 [M+H]

[1858] (4) ((1R)-1-(3-(benzamidomethyl)-4,5-dihydroisocyano) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1859]

[1860] Using the 3-(benzoamidomethyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.045 g, 78%) was obtained by the preparation method of Examples 1-(4) (0.08 g, 0.16 mmol).

[1861] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.81-7.39 (m, 5H), 7.19 (m, 1H), 5.09-5.01(m, 1H), 4.41-4.30 (m, 2H), 3.36-3.34 (m, 2H), 3.19-2.75 (m, 1H), 1.54-1.34(m, 3H), 0.89-0.85 (m, 6H)

[1862] MS (m / z): 362[M+H], 344[M-OH]

[1863] Example 60: ((1R)-3-methyl-1-(3-((pyridin-2-ylamino)methyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamido)butyl)boronic acid

[1864] The title compound was obtained through the following processes (1), (2) and (3).

[1865] (1) 3-[(pyridine-2-carbonylamino)methyl]-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[1866]

[1867] Using 3-(aminomethyl)-4,5-dihydroisocyanate obtained in Example 59-(1) The title compound (0.09 g, 75%) was obtained by the preparation method of Example 59-(2) using ethyl 5-carboxylate hydrochloride (0.09 g, 0.43 mmol) and pyridine-2-carboxylic acid (0.059 g, 0.48 mmol).

[1868] MS (m / z): 278 [M+H]

[1869] (2) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-(pyridinamide methyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1870]

[1871] Using the 3-[(pyridine-2-carbonylamino)methyl]-4,5-dihydroisocyanate obtained in (1) above Ethyl 5-oxazolium carboxylate (0.09 g, 0.32 mmol) was prepared by the methods described in Examples 1-(2) and 1-(3) to obtain the title compound (0.052 g, 47%, 2 steps).

[1872] MS (m / z): 497 [M+H], 345 [MC] 10 H 15 O]

[1873] (3) ((1R)-3-methyl-1-(3-((pyridin-2-ylamino)methyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1874]

[1875] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-(pyridinamide methyl)-4,5-dihydroisocyano The title compound (0.042 g, 75%) was obtained by the preparation method of Examples 1-(4) (0.077 g, 0.16 mmol).

[1876] NMR: 1H-NMR (400MHz, CDCl3); δ 8.55-8.40 (m, 2H), 8.18-8.16 (t, 1H), 7.85-7.84 (m, 1H), 7.45-7.38 (m, 1H), 5.15-5.09 (m, 1H), 4.43-4.41 (m, 2H),3.41-3.38 (m, 2H), 2.99-2.87 (m, 1H), 1.54-1.25 (m, 3H), 0.87-0.84 (m, 6H)

[1877] MS (m / z): 363[M+H], 345[M-OH]

[1878] Example 61: ((1R)-1-(3-((isoquinoline-1-carbamate)methyl)-4,5-dihydroisoquinoline Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1879] The title compound was obtained through the following processes (1), (2) and (3).

[1880] (1) 3-[(isoquinoline-1-carbonylamino)methyl]-4,5-dihydroisoquinoline Preparation of ethyl 5-oxazolium carboxylate

[1881]

[1882] Using 3-(aminomethyl)-4,5-dihydroisocyanate obtained in Example 59-(1) Ethyl 5-carboxylate hydrochloride (0.1 g, 0.48 mmol) and isoquinoline-1-carboxylic acid (0.083 g, 0.53 mmol) were used to prepare the title compound (0.107 g, 68%) by the method described in Example 59-(2).

[1883] NMR: 1 H-NMR (500MHz, CDCl3); δ 9.54-9.53 (d, 1H), 8.65 (br s, 1H), 8.45-8.44 (d, 1H), 7.85-7.55 (m, 4H), 5.05-5.01 (m, 1H), 4.49-4.47 (m, 2H), 4.24-4.19 (q, 2H), 3.38-3.36 (m, 2H), 1.29-1.26 (t, 3H)

[1884] MS (m / z): 328 [M+H]

[1885] (2) 3-((isoquinoline-1-carbamate)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroiso Preparation of azole-5-carboxamide

[1886]

[1887] Using the 3-[(isoquinoline-1-carbonylamino)methyl]-4,5-dihydroisoquinoline obtained in (1) above Ethyl 5-oxazolium carboxylate (0.107 g, 0.33 mmol) was used to prepare the title compound (0.116 g, 66%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1888] MS (m / z): 547 [M+H]

[1889] (3) ((1R)-1-(3-((isoquinoline-1-carbamate)methyl)-4,5-dihydroisoquinoline) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1890]

[1891] Using the 3-((isoquinoline-1-carbamate)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisoquinoline obtained in (2) above. The title compound (0.065 g, 74%) was obtained by the preparation method of Examples 1-(4) (0.116 g, 0.21 mmol).

[1892] NMR: 1 H-NMR (400MHz, CDCl3); δ 9.51-9.46 (m, 1H), 8.68-8.50 (m, 1H), 8.47-8.38 (m, 1H), 7.83-7.60 (m, 4H), 7.50 (m, 1H), 5.12-5.06 (m, 1H), 4.49-4.41 (m, 2H), 3.49-3.39 (m, 2H), 2.98-2.87 (m, 1H), 1.59-1.27 (m, 3H), 0.88-0.82 (m, 6H)

[1893] MS (m / z): 413[M+H], 395[M-OH]

[1894] Example 62: ((1R)-3-methyl-1-(3-((quinoline-5-carbamate)methyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamido)butyl)boronic acid

[1895] The title compound was obtained through the following processes (1), (2) and (3).

[1896] (1) 3-((isoquinoline-1-formamido)methyl)-4,5-dihydroisoquinoline Preparation of ethyl 5-oxazolium carboxylate

[1897]

[1898] Using 3-(aminomethyl)-4,5-dihydroisocyanate obtained in Example 59-(1) The title compound (0.19 g, 45%) was obtained by the preparation method of Example 59-(2), consisting of ethyl 5-azole carboxylate hydrochloride (0.28 g, 1.3 mmol) and 5-quinolinecarboxylic acid (0.25 g, 1.5 mmol).

[1899] MS (m / z): 314 [M+H]

[1900] (2) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-((quinoline-5-carbamoyl)methyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1901]

[1902] Using the 3-[(isoquinoline-1-carbonylamino)methyl]-4,5-dihydroisoquinoline obtained in (1) above Ethyl 5-oxazolium carboxylate (0.19 g, 0.59 mmol) was used to prepare the title compound (0.092 g, 29%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1903] MS (m / z): 547 [M+H]

[1904] (3) ((1R)-3-methyl-1-(3-((quinoline-5-carbamoyl)methyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1905]

[1906] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-((quinoline-5-carbamoyl)methyl)-4,5-dihydroisocyano The title compound (0.054 g, 77%) was obtained by the preparation method of Examples 1-(4) (0.092 g, 0.17 mmol).

[1907] MS (m / z): 413[M+H], 395[M-OH]

[1908] Example 63: ((1R)-3-methyl-1-(3-((5,6,7,8-tetrahydronaphthalene-1-carbamate)methyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamido)butyl)boronic acid

[1909] The title compound was obtained through the following processes (1), (2) and (3).

[1910] (1) 3-[(tetrahydronaphthalene-5-carbonylamino)methyl]-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[1911]

[1912] Using 3-(aminomethyl)-4,5-dihydroisocyanate obtained in Example 59-(1) The title compound (0.114 g, 72%) was obtained by the preparation method of Example 59-(2) using ethyl 5-azole carboxylate hydrochloride (0.1 g, 0.48 mmol) and 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (0.085 g, 0.53 mmol).

[1913] MS (m / z): 331 [M+H]

[1914] (2) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-((5,6,7,8-tetrahydronaphthalene-1-carboxamido)methyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamide

[1915]

[1916] Using the 3-[(tetrahydronaphthalene-5-carbonylamino)methyl]-4,5-dihydroisocyanate obtained in (1) above Ethyl 5-oxazolium carboxylate (0.114 g, 0.35 mmol) was used to prepare the title compound (0.13 g, 69%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1917] MS (m / z): 550[M+H], 398[M+H]

[1918] (3) ((1R)-3-methyl-1-(3-((5,6,7,8-tetrahydronaphthalene-1-carbamoyl)methyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1919]

[1920] The N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-((5,6,7,8-tetrahydronaphthalene-1-carboxamido)methyl)-4,5-dihydroisocyanate obtained in (2) above is used. The title compound (0.067 g, 68%) was obtained by the preparation method of Examples 1-(4) (0.13 g, 0.24 mmol).

[1921] NMR: 1 H-NMR (500MHz, CD3OD); δ 7.14-7.11 (m, 3H), 5.26-5.22 (m, 1H), 4.30-4.23 (m, 2H), 3.52-3.46 (m, 1H), 3.33-3.30 (m, 1H), 2.81-2.78 (m, 5H),1.79-1.77 (m, 4H), 1.64-1.62 (m, 1H), 1.37-1.33 (m, 2H), 0.90-0.88 (m, 6H)

[1922] MS (m / z): 416[M+H], 398[M-OH]

[1923] Example 64: ((1R)-1-(3-((1-naphthamido)methyl)-4,5-dihydroisocyanate Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1924] The title compound was obtained through the following processes (1), (2) and (3).

[1925] (1) 3-[(naphthalene-1-carbonylamino)methyl]-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[1926]

[1927] Using 3-(aminomethyl)-4,5-dihydroisocyanate obtained in Example 59-(1) Ethyl 5-carboxylate hydrochloride (0.1 g, 0.48 mmol) and naphthalene-1-carboxylic acid (0.091 g, 0.53 mmol) were used to prepare the title compound (0.09 g, 57%) by the method described in Example 59-(2).

[1928] NMR: 1 H-NMR (400MHz, CDCl3); δ 8.28-8.27 (dd, 1H), 7.90-7.83 (m, 2H), 7.60-7.38 (m, 4H), 6.80-6.77 (m, 1H), 5.04-4.99 (t, 1H), 4.48-4.37 (m, 2H),4.25-4.16 (q, 2H), 3.42-3.29 (d, 2H), 1.30-1.26 (t, 3H)

[1929] MS (m / z): 327 [M+H]

[1930] (2) 3-((1-naphthamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1931]

[1932] Using the 3-[(naphthalene-1-carbonylamino)methyl]-4,5-dihydroisocyanate obtained in (1) above Ethyl 5-oxazolium carboxylate (0.09 g, 0.28 mmol) was used to prepare the title compound (0.114 g, 66%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1933] MS (m / z): 546[M+H], 394[M+H]

[1934] (3) ((1R)-1-(3-((1-naphthamido)methyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1935]

[1936] Using the 3-((1-naphthamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridgedbenzi[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.069 g, 80%) was obtained by the preparation method of Examples 1-(4) (0.114 g, 0.21 mmol).

[1937] NMR: 1 H-NMR(500MHz, CD3OD); δ 8.24-8.23 (d, 1H), 7.99-7.97 (d, 1H), 7.92-7.90 (m, 1H), 7.65-7.49 (m, 4H), 5.29-5.26 (m, 1H), 4.43-4.36 (m, 2H),3.61-3.53 (m, 1H), 3.39-3.34 (m, 1H), 2.82-2.80 (m, 1H), 1.65-1.60 (m, 1H),1.37-1.33 (m, 2H), 0.89-0.88 (dd, 6H)

[1938] MS (m / z): 412[M+H], 394[M+H]

[1939] Example 65: ((1R)-1-(3-((isoquinoline-1-carbamate)methyl)-4-methyl-4,5-dihydroisoquinoline) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1940] The title compound was obtained through the following processes (1), (2) and (3).

[1941] (1) 3-((isoquinoline-1-formamido)methyl)-4-methyl-4,5-dihydroisoquinoline Methyl 5-azole carboxylate

[1942]

[1943] The 3-(((tert-butoxycarbonyl)amino)methyl)-4-methyl-4,5-dihydroisocyanate obtained in Preparation Example 2 Methyl 5-oxazolium carboxylate (0.076 g, 0.28 mmol) was dissolved in dichloromethane (8 ml). 4 N 1,4-dioxane hydrochloride was slowly added to the solution at 0°C. An alkyl solution (4 ml, 16 mmol) was stirred for 5 hours while being heated to room temperature, and the solvent was distilled under reduced pressure. After dissolution with dimethylformamide (4 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.081 g, 0.42 mmol), hydroxybenzotriazole (0.057 g, 0.42 mmol), and isoquinoline-1-carboxylic acid (0.063 g, 0.36 mmol) were added sequentially. Diisopropylethylamine (0.25 ml, 1.4 mmol) was slowly added, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled under reduced pressure, an aqueous sodium bicarbonate solution was added, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.025 g, 27%, 2 steps).

[1944] MS (m / z): 342 [M+H]

[1945] (2) 3-((isoquinoline-1-carbamate)methyl)-4-methyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroiso Preparation of azole-5-carboxamide

[1946]

[1947] Using the 3-((isoquinoline-1-carbamate)methyl)-4-methyl-4,5-dihydroisoquinoline obtained in (1) above Ethyl 5-oxazolium carboxylate (0.025 g, 0.08 mmol) was used to prepare the title compound (0.019 g, 44%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1948] MS (m / z): 561 [M+H]

[1949] (3) ((1R)-1-(3-((isoquinoline-1-carbamoyl)methyl)-4-methyl-4,5-dihydroisoquinoline) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1950]

[1951] Using the 3-((isoquinoline-1-carbamate)methyl)-4-methyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisoquinoline obtained in (2) above. The title compound (0.003 g, 17%) was obtained by the preparation method of Examples 1-(4) (0.019 g, 0.03 mmol).

[1952] MS (m / z): 427[M+H], 409[M-OH]

[1953] Example 66: ((1R)-3-methyl-1-(3-((S)-2-methyl-1-(5,6,7,8-tetrahydronaphthalene-1-carbamoyl)propyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamido)butyl)boronic acid

[1954] The title compound was obtained through the following processes (1), (2) and (3).

[1955] (1) 3-((S)-2-methyl-1-(5,6,7,8-tetrahydronaphthalene-1-carbamoyl)propyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[1956]

[1957] Using 3-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-4,5-dihydroisocyanoacetate obtained in Preparation Example 3 Ethyl 5-carboxylate (0.13 g, 0.40 mmol) and 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (0.078, 0.44 mmol) were used to prepare the title compound (0.13 g, 88%, 2 steps) by the method described in Example 65-(1).

[1958] MS (m / z): 373 [M+H]

[1959] (2) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-((S)-2-methyl-1-(5,6,7,8-tetrahydronaphthalene-1-carbamoyl)propyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamide

[1960]

[1961] Using the 3-((S)-2-methyl-1-(5,6,7,8-tetrahydronaphthalene-1-carbamoyl)propyl)-4,5-dihydroisocyanate obtained in (1) above Ethyl 5-oxazolium carboxylate (0.13 g, 0.35 mmol) was used to prepare the title compound (0.15 g, 73%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1962] MS (m / z): 592 [M+H]

[1963] (3) ((1R)-3-methyl-1-(3-((S)-2-methyl-1-(5,6,7,8-tetrahydronaphthalene-1-carbamoyl)propyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[1964]

[1965] Using the 3-((S)-1-(isoquinoline-1-carbamate)-2-methylpropyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroiso The title compound (0.071 g, 61%) was obtained by the preparation method of Examples 1-(4) (0.15 g, 0.25 mmol).

[1966] MS (m / z): 458[M+H], 440[M-OH]

[1967] Example 67: ((1R)-1-(3-((S)-1-(isoquinoline-1-carbamate)-2-methylpropyl)-4,5-dihydroisoquinoline Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1968] The title compound was obtained through the following processes (1), (2) and (3).

[1969] (1) 3-((S)-1-(isoquinoline-1-formamido)-2-methylpropyl)-4,5-dihydroisoquinoline Preparation of ethyl 5-oxazolium carboxylate

[1970]

[1971] Using 3-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-4,5-dihydroisocyanoacetate obtained in Preparation Example 3 Ethyl 5-carboxylate (0.13 g, 0.40 mmol) and isoquinoline-1-carboxylic acid (0.076 g, 0.44 mmol) were used to prepare the title compound (0.12 g, 82%, 2 steps) by the method described in Example 65-(1).

[1972] MS (m / z): 370 [M+H]

[1973] (2) 3-((S)-1-(isoquinoline-1-carbamate)-2-methylpropyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroiso Preparation of azole-5-carboxamide

[1974]

[1975] Using the 3-((S)-1-(isoquinoline-1-carbamate)-2-methylpropyl)-4,5-dihydroisoquinoline obtained in (1) above Ethyl 5-oxazolium carboxylate (0.12 g, 0.32 mmol) was used to prepare the title compound (0.13 g, 68%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1976] MS (m / z): 589 [M+H]

[1977] (3) ((1R)-1-(3-((S)-1-(isoquinoline-1-carbamate)-2-methylpropyl)-4,5-dihydroisoquinoline Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1978]

[1979] The N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-((S)-2-methyl-1-(5,6,7,8-tetrahydronaphthalene-1-carbamoyl)propyl)-4,5-dihydroisocyanate obtained in (2) above is used. The title compound (0.070 g, 70%) was obtained by the preparation method of Examples 1-(4) (0.13 g, 0.22 mmol).

[1980] MS (m / z): 455[M+H], 437[M-OH]

[1981] Example 68: ((1R)-1-(3-((2,5-dichlorobenzamido)methyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1982] The title compound was obtained through the following processes (1), (2) and (3).

[1983] (1) 3-[[(2,5-dichlorobenzyl)amino]methyl]-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[1984]

[1985] Using 3-(aminomethyl)-4,5-dihydroisocyanate obtained in Example 59-(1) The title compound (0.1 g, 60%) was obtained by the preparation method of Example 59-(2) using ethyl 5-carboxylate hydrochloride (0.1 g, 0.48 mmol) and 2,5-dichlorobenzoic acid (0.1 g, 0.53 mmol).

[1986] MS (m / z): 345 [M+H]

[1987] (2) 3-((2,5-dichlorobenzamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[1988]

[1989] Using the 3-[[(2,5-dichlorobenzyl)amino]methyl]-4,5-dihydroisocyanate obtained in (1) above Ethyl 5-oxazolium carboxylate (0.1 g, 0.29 mmol) was used to prepare the title compound (0.09 g, 55%, 2 steps) by the methods described in Examples 1-(2) and (3).

[1990] MS (m / z): 564 [M+H]

[1991] (3) ((1R)-1-(3-((2,5-dichlorobenzamido)methyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[1992]

[1993] Using the 3-((2,5-dichlorobenzoamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.048 g, 70%) was obtained by the preparation method of Examples 1-(4) (0.09 g, 0.16 mmol).

[1994] NMR: 1 H-NMR(500MHz, CD3OD); δ 7.50-7.44 (m, 3H), 5.26-5.23 (m, 1H), 4.34-4.26 (m, 2H), 3.54-3.48 (m, 1H), 3.36-3.31 (m, 1H), 2.84-2.81 (m, 1H),1.65-1.62 (m, 1H), 1.37-1.33 (m, 1H), 0.90-0.89 (d, 6H)

[1995] MS (m / z): 430[M+H], 412[M-OH]

[1996] Example 69: [(1R)-3-methyl-1-[[3-[(naphthalene-2-carbonylamino)methyl]-4,5-dihydro-1,2- Preparation of azole-5-carbonyl]amino]butyl]boronic acid

[1997] The title compound was obtained through the following processes (1), (2) and (3).

[1998] (1) 3-((2-naphthamido)methyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[1999]

[2000] Using 3-(aminomethyl)-4,5-dihydroisocyanate obtained in Example 59-(1) The title compound (0.12 g, 57%) was obtained by the preparation method of Example 59-(2) using ethyl 5-carboxylate hydrochloride (0.13 g, 0.62 mmol) and 2-naphthoic acid (0.18 g, 0.93 mmol).

[2001] MS (m / z): 327 [M+H]

[2002] (2) 3-((2-naphthamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[2003]

[2004] Using the 3-((2-naphthamido)methyl)-4,5-dihydroisocyanate obtained in (1) above Ethyl 5-oxazolium carboxylate (0.12 g, 0.36 mmol) was used to prepare the title compound (0.074 g, 38%, 2 steps) by the methods described in Examples 1-(2) and (3).

[2005] MS (m / z): 546 [M+H]

[2006] (3) ((1R)-1-(3-((2-naphthamido)methyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[2007]

[2008] Using the 3-((2-naphthamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridgedbenzi[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.027 g, 49%) was obtained by the preparation method of Examples 1-(4) (0.074 g, 0.14 mmol).

[2009] MS (m / z): 412[M+H], 394[M-OH]

[2010] Example 70: ((1R)-1-(3-((4-(tert-butyl)benzamido)methyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[2011] The title compound was obtained through the following processes (1), (2) and (3).

[2012] (1) 3-((4-(tert-butyl)benzamido)methyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[2013]

[2014] Using 3-(aminomethyl)-4,5-dihydroisocyanate obtained in Example 59-(1) The title compound (0.23 g, 50%, 2 steps) was obtained by the preparation method of Example 59-(2) using ethyl 5-carboxylate hydrochloride (0.28 g, 1.4 mmol) and 4-(tert-butyl)benzoic acid (0.27 g, 1.5 mmol).

[2015] MS (m / z): 333 [M+H]

[2016] (2) 3-((4-(tert-butyl)benzamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[2017]

[2018] Using the 3-((4-(tert-butyl)benzamido)methyl)-4,5-dihydroisocyanate obtained in (1) above Ethyl 5-oxazolium carboxylate (0.11 g, 0.32 mmol) was used to prepare the title compound (0.030 g, 17%, 2 steps) by the methods described in Examples 1-(2) and (3).

[2019] MS (m / z): 552 [M+H]

[2020] (3) ((1R)-1-(3-((4-(tert-butyl)benzamido)methyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[2021]

[2022] Using the 3-((4-(tert-butyl)benzamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.007 g, 31%) was obtained by the preparation method of Examples 1-(4) (0.030 g, 0.05 mmol).

[2023] MS (m / z): 418[M+H], 400[M+H]

[2024] Example 71: ((1R)-3-methyl-1-(3-((3-phenoxybenzamido)methyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamido)butyl)boronic acid

[2025] The title compound was obtained through the following processes (1), (2) and (3).

[2026] (1) 3-[[(3-phenoxybenzyl)amino]methyl]-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[2027]

[2028] Using 3-(aminomethyl)-4,5-dihydroisocyanate obtained in Example 59-(1) The title compound (0.05 g, 28%) was obtained by the preparation method of Example 59-(2), consisting of ethyl 5-carboxylate hydrochloride (0.1 g, 0.48 mmol) and 3-phenoxybenzoic acid (0.114 g, 0.53 mmol).

[2029] NMR: 1H-NMR(400MHz, CDCl3); δ 7.50-7.33 (m, 5H), 7.16-7.00 (m, 4H), 6.84(t, 1H), 5.04-4.99 (m, 1H), 4.43-4.37 (d, 2H), 4.28-4.17 (q, 2H), 3.38-3.26(m, 2H), 1.31-1.27 (t, 3H)

[2030] MS (m / z): 369 [M+H]

[2031] (2) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-((3-phenoxybenzamido)methyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[2032]

[2033] The 3-[[(3-phenoxybenzyl)amino]methyl]-4,5-dihydroisocyanate obtained in Example 71-(1) was used. Ethyl 5-carboxylate (0.05 g, 0.14 mmol) was prepared by the methods described in Examples 1-(2) and 1-(3) to obtain the title compound (0.05 g, 69%, 2 steps).

[2034] MS (m / z): 588 [M+H]

[2035] (3) ((1R)-3-methyl-1-(3-((3-phenoxybenzamido)methyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[2036]

[2037] The N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-((3-phenoxybenzamido)methyl)-4,5-dihydroisocyano The title compound (0.025 g, 54%) was obtained by the preparation method of Examples 1-(4) (0.06 g, 0.10 mmol) of azole-5-carboxamide (0.06 g, 0.10 mmol).

[2038] NMR:1 H-NMR(500MHz, CD3OD); δ 7.57-7.55 (m, 1H), 7.46-7.42 (m, 2H), 7.38-7.35 (m, 2H), 7.16-7.12 (m, 2H), 7.01-7.00 (m, 2H), 5.23-5.20 (m, 1H),4.27 (s, 2H), 3.48-3.42 (m, 1H), 3.26-3.22 (m, 1H), 2.78 (m, 1H), 1.63-1.60(m, 1H), 1.35-1.31 (m, 2H), 0.89-0.87 (d, 6H)

[2039] MS (m / z): 454[M+H], 436[M-OH]

[2040] Example 72: ((1R)-1-(3-((S)-1-(2,5-dichlorobenzamido)-2-methylpropyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[2041] The title compound was obtained through the following processes (1), (2) and (3).

[2042] (1) 3-((S)-1-(2,5-dichlorobenzamido)-2-methylpropyl)-4,5-dihydroisocyanuric acid Preparation of ethyl 5-oxazolium carboxylate

[2043]

[2044] Using 3-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-4,5-dihydroisocyanoacetate obtained in Preparation Example 3 Ethyl 5-carboxylate (0.18 g, 0.57 mmol) and 2,5-dichlorobenzoic acid (0.14 g, 0.74 mmol) were used to prepare the title compound (0.087 g, 39%) by the method described in Example 65-(1).

[2045] MS (m / z): 387 [M+H]

[2046] (2) 3-((S)-1-(2,5-dichlorobenzamido)-2-methylpropyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[2047]

[2048] Using the 3-((S)-1-(2,5-dichlorobenzamido)-2-methylpropyl)-4,5-dihydroisocyanate obtained in (1) above Ethyl 5-oxazolium carboxylate (0.087 g, 0.22 mmol) was used to prepare the title compound (0.040 g, 29%, 2 steps) by the methods described in Examples 1-(2) and (3).

[2049] MS (m / z): 606 [M+H]

[2050] (3) ((1R)-1-(3-((S)-1-(2,5-dichlorobenzamido)-2-methylpropyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[2051]

[2052] Using the 3-((S)-1-(2,5-dichlorobenzoamido)-2-methylpropyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.004 g, 13%) was obtained by the preparation method of Examples 1-(4) (0.040 g, 0.07 mmol).

[2053] MS (m / z): 472[M+H], 454[M-OH]

[2054] Example 73: ((1R)-1-(3-((S)-1-(isoquinoline-1-carbamate)-3-methylbutyl)-4,5-dihydroisoquinoline Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[2055] The title compound was obtained through the following processes (1), (2), (3) and (4).

[2056] (1) 3-((S)-1-amino-3-methylbutyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate hydrochloride

[2057]

[2058] Using the 3-((S)-1-((tert-butoxycarbonyl)amino)-3-methylbutyl)-4,5-dihydroisocyanoacetate obtained in Preparation Example 4 Ethyl 5-oxazolium carboxylate (0.51 g, 1.6 mmol) was used to prepare the title compound (0.41 g, quantified) by the method described in Example 59-(1).

[2059] (2) 3-((S)-1-(isoquinoline-1-carbamate)-3-methylbutyl)-4,5-dihydroisoquinoline Preparation of ethyl 5-oxazolium carboxylate

[2060]

[2061] Using the 3-((S)-1-amino-3-methylbutyl)-4,5-dihydroisocyanate obtained in (1) above The title compound (0.10 g, 49%) was obtained by the preparation method of Example 59-(2), consisting of ethyl 5-oxazolium hydrochloride (0.14 g, 0.53 mmol) and isoquinoline-1-carboxylic acid (0.092 g, 0.53 mmol).

[2062] MS (m / z): 384 [M+H]

[2063] (3) 3-((S)-1-(isoquinoline-1-carbamate)-3-methylbutyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroiso Preparation of azole-5-carboxamide

[2064]

[2065] Using the 3-((S)-1-(isoquinoline-1-carbamate)-3-methylbutyl)-4,5-dihydroisoquinoline obtained in (2) above Ethyl 5-oxazolium carboxylate (0.10 g, 0.26 mmol) was used to prepare the title compound (0.11 g, 63%, 2 steps) by the methods described in Examples 1-(2) and (3).

[2066] MS (m / z): 603 [M+H]

[2067] (4) ((1R)-1-(3-((S)-1-(isoquinoline-1-carbamate)-3-methylbutyl)-4,5-dihydroisoquinoline) Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[2068]

[2069] Using the 3-((S)-1-(isoquinoline-1-carbamate)-3-methylbutyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroiso The title compound (0.065 g, 76%) was obtained by the preparation method of Examples 1-(4) (0.11 g, 0.18 mmol).

[2070] MS (m / z): 469[M+H], 451[M-OH]

[2071] Example 74: ((1R)-1-(3-((S)-1-(2,5-dichlorobenzamido)-3-methylbutyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[2072] The title compound was obtained through the following processes (1), (2) and (3).

[2073] (1) 3-((S)-1-(2,5-dichlorobenzamido)-3-methylbutyl)-4,5-dihydroisocyanuric acid Preparation of ethyl 5-oxazolium carboxylate

[2074]

[2075] Using 3-((S)-1-amino-3-methylbutyl)-4,5-dihydroisocyanate obtained in Example 73-(1) The title compound (0.098 g, 54%) was obtained by the preparation method of Example 59-(2) using ethyl 5-azole hydrochloride (0.12 g, 0.45 mmol) and 2,5-dichlorobenzoic acid (0.096 g, 0.50 mmol).

[2076] MS (m / z): 401 [M+H]

[2077] (2) 3-((S)-1-(2,5-dichlorobenzamido)-3-methylbutyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[2078]

[2079] Using the 3-((S)-1-(2,5-dichlorobenzamido)-3-methylbutyl)-4,5-dihydroisocyanate obtained in (1) above Ethyl 5-oxazolium carboxylate (0.098 g, 0.24 mmol) was used to prepare the title compound (0.047 g, 31%, 2 steps) by the methods described in Examples 1-(2) and (3).

[2080] MS (m / z): 620 [M+H]

[2081] (3) ((1R)-1-(3-((S)-1-(2,5-dichlorobenzamido)-3-methylbutyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[2082]

[2083] Using the 3-((S)-1-(2,5-dichlorobenzoamido)-3-methylbutyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.006 g, 17%) was obtained by the preparation method of Examples 1-(4) (0.047 g, 0.08 mmol).

[2084] MS (m / z): 486[M+H], 488[M+H], 468[M-OH], 470[M-OH]

[2085] Example 75: ((1R)-1-(3-((2,5-dichlorobenzyl)carbamoyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[2086] The title compound was obtained through the following processes (1), (2), (3) and (4).

[2087] (1) 3-{[(2,5-dichlorophenyl)methyl]carbamoyl}-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[2088]

[2089] The 5-(ethoxycarbonyl)-4,5-dihydro-1,2- Azoxyl-3-carboxylic acid (0.15 g, 0.82 mmol) was dissolved in dimethylformamide (5 ml). O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylhexafluorophosphate urea (0.4 g, 4.06 mmol), 2,5-dichlorobenzylmethylamine (0.16 g, 0.90 mmol), and diisopropylethylamine (0.43 ml) were added sequentially, followed by stirring at room temperature for 16 hours. The solvent was distilled under reduced pressure, and an aqueous sodium bicarbonate solution was added, followed by two extractions with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.16 g, 57%).

[2090] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.53-7.21 (m, 3H), 7.11 (m, 1H), 5.19-5.15(m, 1H), 4.63-4.53 (m, 2H), 4.30-4.23 (q, 2H), 3.57-3.48 (m, 2H), 1.35-1.32(t, 3H)

[2091] MS (m / z): 345 [M+H]

[2092] (2) 3-{[(2,5-dichlorophenyl)methyl]carbamoyl}-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[2093]

[2094] Using the 3-{[(2,5-dichlorophenyl)methyl]carbamoyl}-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.16 g, 0.46 mmol) was used to prepare the title compound (0.15 g, 99%) by the method described in Examples 1-(2).

[2095] MS (m / z): 317 [M+H]

[2096] (3) N3-(2,5-dichlorobenzyl)-N5-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridgedbenziro[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano Preparation of azole-3,5-dicarboxamide

[2097]

[2098] Using the 3-{[(2,5-dichlorophenyl)methyl]carbamoyl}-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.15 g, 0.47 mmol) was prepared by the method described in Examples 1-(3) to obtain the title compound (0.18 g, 69%).

[2099] MS (m / z): 564 [M+H]

[2100] (4) ((1R)-1-(3-((2,5-dichlorophenylmethyl)carbamoyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[2101]

[2102] Using the N3-(2,5-dichlorobenzyl)-N5-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridgedbenziro[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.092 g, 65%) was obtained by the preparation method of Examples 1-(4) (0.18 g, 0.33 mmol) of azole-3,5-dicarboxamide (0.18 g, 0.33 mmol).

[2103] NMR: 1 H-NMR(500MHz, MeOD-d4); δ 7.38-7.23 (m, 3H), 5.38-5.34 (m, 1H), 4.52 (s, 2H), 3.65-3.59 (m, 1H), 3.49-3.42 (m, 1H), 2.91-2.88 (m, 1H), 1.65-1.60 (m, 1H), 1.39-1.36 (d, 6H)

[2104] MS (m / z): 430[M+H], 412[M-OH]

[2105] Example 76: ((1R)-3-methyl-1-(3-(naphth-1-ylcarbamoyl)-4,5-dihydroisocyanate) Preparation of azole-5-carboxamido)butyl)boronic acid

[2106] The title compound was obtained through the following processes (1), (2) and (3).

[2107] (1) 3-[(naphth-1-yl)carbamoyl]-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[2108]

[2109] Using the 5-(ethoxycarbonyl)-4,5-dihydro-1,2-dihydrogen obtained in Preparation Example 5 Azoxyl-3-carboxylic acid (0.16 g, 0.85 mmol) was prepared by the method described in Example 75-(1) to obtain the title compound (0.15 g, 56%).

[2110] NMR: 1 H-NMR (500MHz, CDCl3); δ 8.85 (br s, 1H), 8.07-8.05 (d, 1H), 7.90-7.88 (m, 2H), 7.74-7.72 (m, 1H), 7.58-7.48 (m, 3H), 5.29-5.27 (m, 1H), 4.33-4.30 (q, 2H), 3.67-3.65 (m, 2H), 1.36-1.33 (t, 3H)

[2111] MS (m / z): 313 [M+H]

[2112] (2) 3-[(naphth-1-yl)carbamoyl]-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[2113]

[2114] Using the 3-[(naphthyl-1-yl)carbamoyl]-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.15 g, 0.49 mmol) was used to prepare the title compound (0.14 g, 99%) by the method described in Examples 1-(2).

[2115] MS (m / z): 285 [M+H]

[2116] (3) ((1R)-3-methyl-1-(3-(naphth-1-ylcarbamoyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[2117]

[2118] Using the 3-[(naphthyl-1-yl)carbamoyl]-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.14 g, 0.50 mmol) was prepared by the methods described in Examples 75-(3) and (4) to obtain the title compound (0.076 g, 38%, 2 steps).

[2119] NMR: 1 H-NMR(500MHz, MeOD-d4); δ 7.97-7.95 (m, 1H), 7.92-7.90 (m, 1H), 7.83-7.81 (m, 1H), 7.64-7.63 (m, 1H), 7.55-7.48 (m, 3H), 5.46-5.43 (m, 1H),3.76-3.70 (m, 1H), 3.60-3.53 (m, 1H), 2.96-2.93 (m, 1H), 1.68-1.64 (m, 1H),1.42-1.39 (m, 2H), 0.94-0.90 (d, 6H)

[2120] MS (m / z): 398[M+H], 380[M-OH / ]

[2121] Example 77: ((1R)-1-(3-((3-chlorophenyl)carbamoyl)-4,5-dihydroisocyanuric acid Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[2122] The title compound was obtained through the following processes (1), (2) and (3).

[2123] (1) 3-[(3-chlorophenyl)carbamoyl]-4,5-dihydro-1,2- Preparation of ethyl 5-oxazolium carboxylate

[2124]

[2125] Using the 5-(ethoxycarbonyl)-4,5-dihydro-1,2-dihydrogen obtained in Preparation Example 5 Azoxyl-3-carboxylic acid (0.17 g, 0.91 mmol) was prepared by the method described in Example 75-(1) to obtain the title compound (0.16 g, 56%).

[2126] NMR: 1H-NMR (400MHz, CDCl3); δ 8.40 (br s, 1H), 7.72-7.71 (d, 1H), 7.41-7.38 (m, 1H), 7.29-7.25 (t, 1H), 7.15-7.03 (m, 1H), 5.26-5.21 (m, 1H), 4.35-4.25 (q, 2H), 3.64-3.52 (m, 2H), 1.35-1.31 (t, 3H)

[2127] MS (m / z): 297 [M+H]

[2128] (2) 3-[(3-chlorophenyl)carbamoyl]-4,5-dihydro-1,2- Preparation of 5-azole carboxylic acid

[2129]

[2130] Using the 3-[(3-chlorophenyl)carbamoyl]-4,5-dihydro-1,2- Ethyl 5-oxazolium carboxylate (0.16 g, 0.52 mmol) was used to prepare the title compound (0.14 g, 99%) by the method described in Examples 1-(2).

[2131] MS (m / z): 269 [M+H]

[2132] (3) ((1R)-1-(3-((3-chlorophenyl)carbamoyl)-4,5-dihydroisocyano Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[2133]

[2134] Using the 3-[(3-chlorophenyl)carbamoyl]-4,5-dihydro-1,2- Azoxyl-5-carboxylic acid (0.14 g, 0.51 mmol) was prepared by the methods described in Examples 75-(3) and (4) to obtain the title compound (0.081 g, 42%, 2 steps).

[2135] NMR: 1H-NMR(500MHz, MeOD-d4); δ 7.81-7.80 (m, 1H), 7.54-7.52 (m, 1H), 7.31-728 (t, 1H), 7.14-7.12 (m, 1H), 5.42-5.38 (m, 1H), 3.67-3.48 (m, 2H),2.92 (m, 1H), 1.65-1.63 (m, 1H), 1.40-1.36 (m, 2H), 0.92-0.90 (dd, 6H)

[2136] MS (m / z): 382[M+H], 364[M-OH]

[2137] Example 78: ((1R)-1-(3-((2,3-dihydro-1H-indene-2-carbamate)methyl)-4,5-dihydroisocyanate Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[2138] The title compound was obtained through the following processes (1), (2) and (3).

[2139] (1) 3-((2,3-dihydro-1H-inden-2-carbamate)methyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[2140]

[2141] Using 3-(aminomethyl)-4,5-dihydroisocyanate obtained in Example 59-(1) Ethyl 5-carboxylate hydrochloride (0.28 g, 1.4 mmol) and 2-indanic acid (0.24 g, 1.5 mmol) were used to prepare the title compound (0.15 g, 36%) by the method described in Example 59-(2).

[2142] MS (m / z): 317 [M+H]

[2143] (2) 3-((2,3-dihydro-1H-indene-2-carbamate)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamide

[2144]

[2145] Using the 3-((2,3-dihydro-1H-inden-2-carbamoyl)methyl)-4,5-dihydroisocyanate obtained in (1) above Ethyl 5-oxazolium carboxylate (0.15 g, 0.48 mmol) was used to prepare the title compound (0.10 g, 37%, 2 steps) by the methods described in Examples 1-(2) and (3).

[2146] MS (m / z): 536 [M+H]

[2147] (3) ((1R)-3-methyl-1-(3-((2-phenylacetamido)methyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[2148]

[2149] Using the 3-((2,3-dihydro-1H-indene-2-carboxamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.024 g, 32%) was obtained by the preparation method of Examples 1-(4) (0.10 g, 0.19 mmol).

[2150] MS (m / z): 402[M+H], 384[M-OH]

[2151] Example 79: ((1R)-3-methyl-1-(3-((2-phenylacetamido)methyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamido)butyl)boronic acid

[2152] The title compound was obtained through the following processes (1), (2) and (3).

[2153] (1) 3-((2-phenylacetamido)methyl)-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[2154]

[2155] Using 3-(aminomethyl)-4,5-dihydroisocyanate obtained in Example 59-(1) The title compound (0.19 g, 50%) was obtained by the preparation method of Example 59-(2), consisting of ethyl 5-azole hydrochloride (0.28 g, 1.3 mmol) and phenylacetic acid (0.2 g, 1.5 mmol).

[2156] MS (m / z): 333 [M+H]

[2157] (2) N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-3-((2-phenylacetamido)methyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamide

[2158]

[2159] Using the 3-((2-phenylacetamido)methyl)-4,5-dihydroisocyanate obtained in (1) above Ethyl 5-oxazolium carboxylate (0.19 g, 0.67 mmol) was used to prepare the title compound (0.042 g, 12%, 2 steps) by the methods described in Examples 1-(2) and (3).

[2160] MS (m / z): 552 [M+H]

[2161] (3) ((1R)-3-methyl-1-(3-((2-phenylacetamido)methyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[2162]

[2163] Using the N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborane-2-yl)butyl)-3-((2-phenylacetamido)methyl)-4,5-dihydroisocyano The title compound (0.011 g, 36%) was obtained by the preparation method of Examples 1-(4) (0.042 g, 0.08 mmol).

[2164] MS (m / z): 376[M+H], 358[M-OH]

[2165] Example 80: ((1R)-3-methyl-1-(3-((1,2,3,4-tetrahydronaphthyl-1-carbamoyl)methyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamido)butyl)boronic acid

[2166] The title compound was obtained through the following processes (1), (2) and (3).

[2167] (1) 3-[(1,2,3,4,4a,8a-hexahydronaphthalene-1-carbonylamino)methyl]-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[2168]

[2169] Using 3-(aminomethyl)-4,5-dihydroisocyanate obtained in Example 59-(1) Ethyl 5-carboxylate hydrochloride (0.17 g, 0.82 mmol) and 1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (0.14 g, 0.90 mmol) were used to prepare the title compound (0.11 g, 41%) by the method described in Example 59-(2).

[2170] NMR: 1 H-NMR(500MHz, CDCl3); δ 7.19-7.07 (m, 4H), 5.85 (m, 1H), 4.99-1.95(dd, 1H), 4.22-4.06 (m, 4H), 3.72-3.69 (m, 1H), 3.23-2.20 (m, 2H), 2.25-2.71(m, 2H), 2.27-2.24 (m, 1H), 1.98-1.95 (m, 1H), 1.79-1.76 (m, 2H), 1.30-1.27(t, 3H)

[2171] MS (m / z): 333 [M+H]

[2172] (2) 3-((1,2,3,4,4a,8a-hexahydronaphthyl-1-carbamate)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamide

[2173]

[2174] Using the 3-[(1,2,3,4,4a,8a-hexahydronaphthalene-1-carbonylamino)methyl]-4,5-dihydroisocyanate obtained in (1) above Ethyl 5-oxazolium carboxylate (0.11 g, 0.33 mmol) was used to prepare the title compound (0.073 g, 40%, 2 steps) by the methods described in Examples 1-(2) and (3).

[2175] MS (m / z): 550 [M+H]

[2176] (3) ((1R)-3-methyl-1-(3-((1,2,3,4-tetrahydronaphthyl-1-carbamoyl)methyl)-4,5-dihydroisocyano Preparation of azole-5-carboxamido)butyl)boronic acid

[2177]

[2178] Using the 3-((1,2,3,4,4a,8a-hexahydronaphthyl-1-carbamate)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridgedbenziro[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)-4,5-dihydroisocyano The title compound (0.025 g, 45%) was obtained by the preparation method of Examples 1-(4) (0.073 g, 0.13 mmol).

[2179] NMR: 1 H-NMR(500MHz, CD3OD); δ 7.11-7.05 (m, 4H), 5.21-5.19 (m, 1H), 4.18-4.10 (m, 2H), 3.73-3.70 (m, 1H), 3.43-3.36 (m, 1H), 3.24-3.18 (m, 1H),2.86-2.73 (m, 3H), 2.03-1.97 (m, 3H), 1.73-1.62 (m, 2H), 1.37-1.33 (m, 2H),0.90-0.89 (d, 6H)

[2180] MS (m / z): 416[M+H], 398[M-OH]

[2181] Example 81: ((1R)-3-methyl-1-(3-((5-methylisocyanate) (Z-3-carbamate)methyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamido)butyl)boronic acid

[2182] The title compound was obtained through the following processes (1), (2) and (3).

[2183] (1) 3-[[(5-methylisocyanate) [Azazole-3-carbonyl]amino]methyl]-4,5-dihydroisocyano] Preparation of ethyl 5-oxazolium carboxylate

[2184]

[2185] Using 3-(aminomethyl)-4,5-dihydroisocyanate obtained in Example 59-(1) Ethyl 5-oxazolium-5-carboxylate hydrochloride (0.18 g, 0.87 mmol) and 5-methyl-isocyanate Azoxyl-3-carboxylic acid (0.11 g, 0.87 mmol) was prepared by the method described in Example 59-(2) to obtain the title compound (0.07 g, 29%).

[2186] NMR: 1 H-NMR(400MHz, CDCl3); δ 7.54 (br s, 1H), 6.45 (s, 1H), 5.09-5.02(dd, 1H), 4.45-4.41 (d, 2H), 4.27-4.20 (q, 2H), 3.38-3.33 (m, 2H), 2.48 (s,3H), 1.29-1.26 (t, 3H)

[2187] MS (m / z): 282 [M+H]

[2188] (2) 5-Methyl-N-((5-(((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaboranecyclopentan-2-yl)butyl)carbamoyl)-4,5-dihydroisocyano (zol-3-yl)methyl)iso Preparation of azole-3-carboxamide

[2189]

[2190] Using the 3-[[(5-methylisocyanate) obtained in (1) above [Azazole-3-carbonyl]amino]methyl]-4,5-dihydroisocyano] Ethyl 5-oxazolium carboxylate (0.07 g, 0.25 mmol) was used to prepare the title compound (0.04 g, 34%, 2 steps) by the methods described in Examples 1-(2) and (3).

[2191] MS (m / z): 501 [M+H]

[2192] (3) ((1R)-3-methyl-1-(3-((5-methyliso) (Z-3-carbamate)methyl)-4,5-dihydroisocyanate Preparation of azole-5-carboxamido)butyl)boronic acid

[2193]

[2194] The 5-methyl-N-((5-((((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylbridged benzo[d][1,3,2]dioxaborone-2-yl)butyl)carbamoyl)-4,5-dihydroisocyano (zol-3-yl)methyl)iso The title compound (0.017 g, 59%) was obtained by the preparation method of Examples 1-(4) (0.04 g, 0.08 mmol).

[2195] NMR: 1 H-NMR (500MHz, CD3OD); δ 6.44 (s, 1H), 5.24-5.21 (m, 1H), 4.28 (s, 2H), 3.48-3.43 (m, 1H), 3.27-3.22 (m, 1H), 2.81-2.78 (m, 1H), 2.46 (s, 3H),1.66-1.60 (m, 1H), 1.36-1.32 (m, 2H), 0.89-0.88 (d, 6H)

[2196] MS (m / z): 367[M+H], 349[M-OH]

[2197] Example 82: ((1R)-1-(3-((5-fluoro-2-methylbenzamido)methyl)-4,5-dihydroisocyanate Preparation of (-5-carboxamido)-3-methylbutyl)boronic acid

[2198] The title compound was obtained through the following processes (1), (2) and (3).

[2199] (1) 3-[[(5-fluoro-2-methyl-phenylmethyl)amino]methyl]-4,5-dihydroisocyanate Preparation of ethyl 5-oxazolium carboxylate

[2200]

[2201] Using 3-(am...

Claims

1. A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1] In the above formula, R1 is selected from: R2 represents hydrogen; R3 represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, or a 5- to 6-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S atoms, or R2 and R3 combined to form a 3- to 6-membered aliphatic ring, wherein L2 is absent; R4 represents C1-C6 alkyl, C3-C6 cycloalkyl, or phenyl; L 1a (CH2) l Or C(CH2CH2), where l is an integer from 0 to 3; L 1b It represents a direct bond, or indicates (C=O)NH, NH(C=O), NH, (CH2). m O, (C=O)N(CH3) or S(O2)NH, where m is an integer from 0 to 3; L 1c (CH2) n , CHR5 or CR6R7, where n is an integer from 0 to 3, where R5 represents a C1-C3 heteroalkyl or C1-C4 alkyl having one or two heteroatoms selected from O, N and S, and R6 and R7 are each independently a C1-C3 alkyl; L2 represents (CH2) o (CH2) p O, CHR8, CX1X2 or C(CH2CH2), where o is an integer from 0 to 3, p is an integer from 1 to 3, R8 is OH, a halogen or a C1-C3 alkyl group, and X1 and X2 are each independently a halogen; L3 represents (CH2) q Or CHR9, where q is an integer from 0 to 3, and R9 is a C1-C3 alkyl group; and Z1 and Z2 are each independently OH, or together form a cyclic borate ester, said cyclic borate ester comprising one or more of the following structures: 。 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, R3 is substituted with halogen, methyl halide, C1-C3 alkyl, phenyl or C1-C3 alkoxy.

3. A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1] In the above formula, R1 is a phenyl group, a 5- to 6-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S atoms, or a fused bicyclic ring, wherein a substituted or unsubstituted 4- to 8-membered aliphatic ring or a 5- to 6-membered aromatic ring having 0 to 4 heteroatoms selected from O, N, and S is fused to a substituted or unsubstituted 4- to 8-membered aliphatic ring or a 5- to 6-membered aromatic ring having 0 to 4 heteroatoms selected from O, N, and S. Alternatively, R1 may be substituted with one or more substituents selected from the following: halogens, haloalkyls, C1-C6 alkyls, C3-C6 cycloalkyls, phenyls, and phenoxys, and said substituents may be substituted with one or more halogens. R2 represents hydrogen; R3 represents hydrogen or phenyl; Alternatively, R3 may be substituted with a halogen, a C1-C3 alkyl group, or a C1-C3 alkoxy group; R4 represents C1-C6 alkyl or phenyl; L 1a (CH2) l , where l is an integer from 0 to 3; L 1b This represents (C=O)NH and (CH2). m O or S(O2)NH, where m is an integer from 0 to 3; L 1c (CH2) n Or CHR5, where n is an integer from 0 to 3, and R5 represents a C1-C3 heteroalkyl or C1-C4 alkyl with one O heteroatom; L2 represents (CH2) o Or (CH2) p O, where o is an integer from 0 to 3, and p is an integer from 1 to 3; L3 represents (CH2) q Or CHR9, where q is an integer from 0 to 3, and R9 is a C1-C3 alkyl group; and Z1 and Z2 can be OH independently, or they can form together. .

4. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to claim 4, which is used to inhibit chymotrypsin-like activity in the protease.

6. The pharmaceutical composition according to claim 4, for the prevention or treatment of proteasome-mediated diseases.

7. The pharmaceutical composition according to claim 6, wherein the proteasome-mediated disease is cancer.

8. The pharmaceutical composition according to claim 7, wherein the cancer is selected from brain tumors, thoracic tumors, abdominal tumors, male reproductive system tumors, female reproductive system tumors, and lymphoma.

9. The pharmaceutical composition according to claim 7, wherein the cancer is selected from brain lymphoma, gallbladder cancer, urethral cancer, head and neck tumors, breast cancer, and female external genital cancer.

10. The pharmaceutical composition according to claim 7, wherein the cancer is selected from benign astrocytoma, malignant astrocytoma, pituitary adenoma, intracranial meningioma, oligodendroglioma, craniopharyngioma, ependymoma, brainstem tumor, laryngeal cancer, oropharyngeal cancer, nasal cavity / sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, neuroblastoma, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumor, esophageal cancer, male breast cancer, gastric cancer, liver cancer, biliary tract cancer, pancreatic cancer, small bowel cancer, colorectal cancer, anal cancer, bladder cancer, kidney cancer, penile cancer, prostate cancer, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female urethral cancer, skin cancer, myeloma, leukemia, and malignant lymphoma.

Images