Boronic Acid Compounds

Abstract

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

Description

[Technical Field]

[0001] The present invention claims the benefit of priority based on Korean Patent Application No. 10-2020-0171958, filed on December 10, 2020, and all contents disclosed in the documents of this Korean patent application are incorporated herein by reference.

[0002] The present invention relates to a boronic acid compound. [Background technology]

[0003] The proteasome is a part of the intracellular machinery that plays an important role in cell function and growth by degrading damaged or unnecessary proteins via the ubiquitin-proteasome pathway. Proteasome inhibitors inhibit the proteasome, thereby inducing the excessive accumulation of abnormal proteins in cancer cells and thereby inducing the death of cancer cells.

[0004] Cancer cells are more sensitive to proteasome inhibitors than normal cells, so inhibiting the hydrolytic activity of the proteasome is expected to have an anti-cancer effect. In particular, selectively binding to and inhibiting chymotrypsin-like activity rather than caspase-like activity in the proteasome can reduce side effects and effectively treat cancer.

[0005] The anti-cancer effect of such proteasome inhibitors against blood cancers has been confirmed, and a drug utilizing this has been marketed as Velcade, but side effects such as drug resistance have also been reported. Therefore, research is ongoing on a treatment method using this drug in combination with an epidermal growth factor receptor (EGFR) kinase inhibitor (Korean Patent Publication No. 10-2007-0083719) and a marker composition for diagnosing drug resistance (Korean Patent Registration No. 10-1471274), but there remains a need for the development of alternative substances with fewer side effects.

[0006] Carfilzomib, a proteasome inhibitor drug, selectively binds to chymotrypsin-like activity rather than caspase-like activity within the proteasome, but its irreversible binding limits its utility.

[0007] Therefore, the present inventors conducted extensive research into compounds that selectively and reversibly bind to and inhibit chymotrypsin-like activity, and as a result, they confirmed that a novel boronic acid compound selectively and reversibly binds to chymotrypsin-like activity, thereby completing the present invention. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Korean Patent Publication No. 10-2007-0083719 (2007.08.24.) [Patent Document 2] Korean Patent Registration No. 10-1471274 (2014.12.03.) Summary of the Invention [Problem to be solved by the invention]

[0009] An object of the present invention is to provide compounds that can selectively and reversibly bind to and inhibit chymotrypsin-like activity within the proteasome. [Means for solving the problem]

[0010] One aspect of the present invention provides a compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt or isomer thereof:

[0011] [ka]

[0012] In the above formula, R1 represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, or a fused bicyclo ring; R2 represents hydrogen or alkyl; R3 represents hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl, or R2 and R3 may be bonded together to form a 3- to 6-membered aliphatic ring, in which case L2 is absent; R4 represents alkyl, cycloalkyl, or aryl; L 1a is (CH2) l (l is an integer of 0 to 3) or C(CH2CH2); L 1b is a direct bond or (C=O)NH, NH(C=O), NH, (CH2) m O (m is an integer of 0 to 3), (C=O)N(CH3), or S(O2)NH; L 1c is (CH2) n (n is an integer of 0 to 3), CHR5 or CR6R7, where R5, R6, and R7 are each independently a C1-C4 heteroalkyl or a C1-C4 alkyl having 1 to 3 heteroatoms selected from the group consisting of O, N, and S; L2 is (CH2) o (o is an integer from 0 to 3), (CH2) p O (p is an integer of 1 to 3), CHR, CX, X, or C(CHCH), where R is OH, halogen, or C-C alkyl, and X and X are each independently halogen; L3 is (CH2) q (q is an integer of 0 to 3) or CHR9, where R9 is C1 to C3 alkyl; Z1 and Z2 each independently represent OH or OR 10 and R 10 represents alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, or Z1 and Z2 are OR 10 When the two R 10may together form a cyclic borate ester having a saturated, unsaturated, or optionally fused bicyclic ring of C2 to C20, and the cyclic borate ester may be substituted with hydroxy, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, aryloxy, heteroaryl, or heterocycloalkyl containing one or two heteroatoms selected from N, O, and S atoms in the ring.

[0013] Another aspect of the present invention provides a pharmaceutical composition for inhibiting chymotrypsin-like activity in the proteasome, comprising the compound of Chemical Formula 1, a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable carrier. [Effects of the Invention]

[0014] The boronic acid compounds of the present invention can selectively and reversibly bind to and inhibit chymotrypsin-like activity relative to caspase-like activity within the proteasome.

[0015] The boronic acid compounds of the present invention have excellent selectivity for the activity of proteasomes in target cancer cells, thereby minimizing serious side effects, and they bind reversibly, allowing them to later release and restore proteasome function, which has the advantage of being highly developable and highly applicable. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention will be described in more detail below for better understanding. In this regard, the terms and phrases used in the specification and claims should not be interpreted in a limited way to their ordinary or dictionary meanings, but should be interpreted in a way that is consistent with the technical concept of the present invention, based on the principle that the inventors can appropriately define the concepts of terms in order to best describe their inventions.

[0017] In the definition of the substituents of the compound of Formula 1 according to the present invention, the term "alkyl" refers to an aliphatic hydrocarbon radical. The alkyl can be a "saturated alkyl" that does not contain an alkenyl or alkynyl moiety, or an "unsaturated alkyl" that contains at least one alkenyl or alkynyl moiety. "Alkenyl" refers to a group that contains at least one carbon-carbon double bond, and "alkynyl" refers to a group that contains at least one carbon-carbon triple bond. The alkyl can be branched or linear.

[0018] Unless otherwise defined, alkyl may have 1 to 20 carbon atoms. Alkyl may be a medium size alkyl having 1 to 10 carbon atoms. Alkyl may be a lower alkyl having 1 to 6 carbon atoms. Typical alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like. For example, a C1-C4 alkyl has 1 to 4 carbon atoms in the alkyl chain and is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl.

[0019] The term "alkoxy," unless otherwise defined, means an alkyloxy having from 1 to 10 carbon atoms.

[0020] The term "cycloalkyl," unless otherwise defined, means a saturated aliphatic 3- to 10-membered ring. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0021] The term "aryl" includes at least one ring having a conjugated π-electron system, for example, a monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group. Thus, as used herein, unless otherwise defined, aryl refers to a 4- to 10-membered, preferably 6- to 10-membered, aromatic monocyclic or multicyclic ring, including phenyl, naphthyl, and the like.

[0022] The term "heteroaryl," unless otherwise defined, refers to an aromatic 3- to 10-membered ring, preferably a 4- to 8-membered ring, and more preferably a 5- to 6-membered ring, containing one to three heteroatoms selected from the group consisting of N, O, and S, and which may be fused with benzo or a C3-C8 cycloalkyl. Examples of monocyclic heteroaryls include, but are not limited to, thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, isothiazole, pyrazole, triazole, triazine, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like. Examples of bicyclic heteroaryls include, but are not limited to, indole, indoline, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine, furopyridine, and the like.

[0023] The term "heterocycloalkyl," unless otherwise defined, refers to a 3- to 10-membered, preferably 4- to 8-membered, more preferably 5- to 6-membered ring containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, which may be fused with benzo or C3-C8 cycloalkyl, and which is saturated or contains 1 or 2 double bonds. Examples of heterocycloalkyl include, but are not limited to, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, morpholine, thiomorpholine, piperazine, hydrofuran, and the like.

[0024] The term "fused bicyclo ring" refers to a cyclo ring in which two rings are fused, including bridged bicyclo rings, joined bicyclo rings, and spirocyclo rings. The term "fused bicyclo ring" can also refer to fused bicycloalkyl, fused bicycloaryl, and fused bicycloheteroaryl, where the same definitions as above apply to alkyl, aryl, and heteroaryl. Specifically, the fused bicyclo ring may be a substituted or unsubstituted 4- to 8-membered aliphatic ring or 5- to 6-membered aromatic ring having 0 to 4 heteroatoms selected from the group consisting of O, N, and S, fused to a substituted or unsubstituted 4- to 8-membered aliphatic ring or 5- to 6-membered aromatic ring having 0 to 4 heteroatoms selected from the group consisting of O, N, and S.

[0025] The term "direct bond" refers to the absence of a hydrocarbon-like functional group in the substituent, i.e., -(CH2) k -, where k may be 0.

[0026] The term "halogen" means one or more selected from the group consisting of F, Cl, Br, and I.

[0027] In the present invention, [ka] is used to denote a bond in which the stereochemical relationship between the substituents attached to the carbon or nitrogen atoms that form the double bond includes either the E or Z isomer. Specifically, [ka] can mean that the bond between the nitrogen and the OH group that is double-bonded to the carbon includes either the E or Z isomer.

[0028] Unless otherwise defined, all other terms and abbreviations used herein shall be interpreted as having the meanings commonly understood by those of ordinary skill in the art to which this invention pertains.

[0029] One aspect of the present invention provides a compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt or isomer thereof:

[0030] [ka]

[0031] In the above formula, R1 represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, or a fused bicyclo ring; R2 represents hydrogen or alkyl; R3 represents hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl, or R2 and R3 may be bonded together to form a 3- to 6-membered aliphatic ring, in which case L2 is absent; R4 represents alkyl, cycloalkyl, or aryl; L 1a is (CH2) l (l is an integer of 0 to 3) or C(CH2CH2); L 1b is a direct bond or (C=O)NH, NH(C=O), NH, (CH2) m O (m is an integer of 0 to 3), (C=O)N(CH3), or S(O2)NH; L 1c is (CH2) n (n is an integer of 0 to 3), CHR5 or CR6R7, where R5, R6, and R7 are each independently a C1-C4 heteroalkyl or a C1-C4 alkyl having 1 to 3 heteroatoms selected from the group consisting of O, N, and S; L2 is (CH2) o (o is an integer from 0 to 3), (CH2) pO (p is an integer of 1 to 3), CHR, CX, X, or C(CHCH), where R is OH, halogen, or C-C alkyl, and X and X are each independently halogen; L3 is (CH2) q (q is an integer of 0 to 3) or CHR9, where R9 is C1 to C3 alkyl; Z1 and Z2 each independently represent OH or OR 10 and R 10 represents alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, or Z1 and Z2 are OR 10 When the two R 10 may together form a cyclic borate ester having a saturated, unsaturated, or optionally fused bicyclic ring of C2 to C20, and the cyclic borate ester may be substituted with hydroxy, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, aryloxy, heteroaryl, or heterocycloalkyl containing one or two heteroatoms selected from N, O, and S atoms in the ring.

[0032] In one embodiment, R1 represents C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, 5-6 membered heteroaryl or heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, and S atoms, fused bicycloalkyl, fused bicycloaryl, or fused bicycloheteroaryl containing 1-4 heteroatoms selected from N, O, and S atoms; R2 represents hydrogen or C1-C6 alkyl; R3 represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, or 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S atoms, or R2 and R3 may be bonded to each other to form a 3-6 membered aliphatic ring, in which case L2 is absent; R4 represents C1-C6 alkyl, C3-C6 cycloalkyl, or phenyl; L1a is (CH2) l (l is an integer of 0 to 3) or C(CH2CH2); L 1b is a direct bond or (C=O)NH, NH(C=O), NH, (CH2) m O (m is an integer of 0 to 3), (C=O)N(CH3), or S(O2)NH; L 1c is (CH2) n (n is an integer of 0 to 3), CHR5 or CR6R7, where R5 is a C1-C4 heteroalkyl or a C1-C4 alkyl having 1 to 3 heteroatoms selected from the group consisting of O, N, and S, and R6 and R7 are each independently a C1-C4 alkyl; L2 is (CH2) o (o is an integer from 0 to 3), (CH2) p O (p is an integer of 1 to 3), CHR, CX, X, or C(CHCH), where R is OH, halogen, or C-C alkyl, and X and X are each independently halogen; L3 is (CH2) q (q is an integer of 0 to 3) or CHR9, where R9 is C1 to C3 alkyl; Z1 and Z2 may each independently be OH, or may together form a cyclic borate ester of the following structure: [ka]

[0033] where r is 0 or 1 and R 11 ~R 16 are each independently hydrogen, hydroxy, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, aryloxy, heteroaryl or heterocycloalkyl containing one or two heteroatoms in the ring selected from N, O, and S atoms; R 13 and R 15 is hydrogen and R 14 and R16 are joined together to form a substituted or unsubstituted cycloalkyl, or R 13 and R 15 does not exist and R 14 and R 16 are joined together to form a substituted or unsubstituted aryl, or R 11 and R 12 or R 13 and R 14 or R 15 and R 16 may be joined together to form a substituted or unsubstituted cycloalkyl.

[0034] In one embodiment, R1 may represent a 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from phenyl, N, O, and S atoms, a fused bicycloaryl, or a fused bicycloheteroaryl; R1 is a halogen, amine, nitro, nitrile, acetonitrile, ether, alkyl halide, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 heteroalkyl having 1 or 2 heteroatoms selected from N, O, and S atoms, C1-C6 alkoxy, phenyl, phenoxy, 5-6 membered heteroaryl or heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, and S atoms, or 5-6 membered heteroaryloxy or heterocycloalkyloxy containing 1 or 2 heteroatoms selected from N, O, and S atoms, and R 12 (C═O)NH; and R 12 is hydrogen or C1 to C3 alkyl, and the substituent may be substituted with one or more selected from the group consisting of halogen, C1 to C3 alkyl, and C1 to C3 alkoxy.

[0035] In one embodiment, R2 may represent hydrogen.

[0036] In one embodiment, R3 may represent hydrogen, C1-C3 alkyl, or phenyl; R3 may be substituted with halogen, halogenated methyl, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, or C1-C3 alkoxy, and the above substituents may be further substituted with halogen.

[0037] In one embodiment, R4 may represent C1-C6 alkyl, C3-C6 cycloalkyl or phenyl.

[0038] In one embodiment, L 1a is (CH2) l (l is an integer of 0 to 3) or C(CH2CH2).

[0039] In one embodiment, L 1b is a direct bond or (C=O)NH, NH(C=O), NH, (CH2) m It may represent O (m is an integer of 0 to 3), (C=O)N(CH3), or S(O2)NH.

[0040] In one embodiment, L 1c is (CH2) n (n is an integer of 0 to 3), CHR5 or CR6R7, where R5 is a C1-C3 heteroalkyl or a C1-C4 alkyl having 1 or 2 heteroatoms selected from the group consisting of O, N, and S, and R6 and R7 may each independently be a C1-C3 alkyl.

[0041] In one embodiment, L2 is (CH2) o (o is an integer from 0 to 3), (CH2) p O (p is an integer of 1 to 3), CHR8, CX1X2, or C(CH2CH2), where R8 is OH, halogen, or C1 to C3 alkyl, and X1 and X2 may each independently be halogen.

[0042] In one embodiment, L3 is (CH2) q(q is an integer of 0 to 3) or CHR9, where R9 may be a C1 to C3 alkyl.

[0043] In one embodiment, Z1 and Z2 are each independently OH or may together form a cyclic borate ester of the following structure:

[0044] [ka]

[0045] where r is 0 or 1 and R 11 ~R 16 are each independently hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C5-C6 aryl, C5-C6 aryloxy, heteroaryl or heterocycloalkyl containing one or two heteroatoms selected from N, O and S atoms in the ring, or in which the substituents may be hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C5-C6 aryl or C5-C6 aryloxy; R 13 and R 15 is hydrogen and R 14 and R 16 may be bonded together to form a substituted or unsubstituted 4-8 membered cycloalkyl, wherein the substituents may be hydroxy, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C5-C6 aryl, or C5-C6 aryloxy; R 13 and R 15 does not exist and R 14 and R 16may be bonded together to form a substituted or unsubstituted 5- or 6-membered aryl, wherein the substituents may be hydroxy, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C5-C6 aryl, or C5-C6 aryloxy, or R 11 and R 12 or R 13 and R 14 or R 15 and R 16 may be bonded together to form a substituted or unsubstituted 4- to 8-membered cycloalkyl, in which the substituents may be hydroxy, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C5-C6 aryl, or C5-C6 aryloxy.

[0046] In a preferred embodiment, R1 may be selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0047] Alternatively, R2 may represent hydrogen.

[0048] Additionally, R3 may represent hydrogen, C1-C3 alkyl, or phenyl, which may be substituted with halogen, C1-C3 alkyl, or C1-C3 alkoxy.

[0049] Furthermore, R4 may represent a C1 to C6 branched alkyl or a C3 to C6 cycloalkyl.

[0050] In one embodiment, L 1a is (CH2) l (l is an integer of 0 to 3) or C(CH2CH2).

[0051] In one embodiment, L 1b is a direct bond or (C=O)NH, NH(C=O), NH, (CH2) m It may represent O (m is an integer of 0 to 3), (C=O)N(CH3), or S(O2)NH.

[0052] In one embodiment, L 1c is (CH2) n (n is an integer of 0 to 3) or CHR5, where R5 may be a C1 to C3 heteroalkyl or a C1 to C4 alkyl having 1 or 2 heteroatoms selected from the group consisting of O, N, and S.

[0053] In one embodiment, L2 is (CH2) o (o is an integer from 0 to 3), (CH2) p O (p is an integer of 1 to 3), CHR8, CX1X2, or C(CH2CH2), where R8 is OH, halogen, or C1 to C3 alkyl, and X1 and X2 may each independently be halogen.

[0054] In one embodiment, L3 is (CH2) q (q is an integer of 0 to 3).

[0055] As an example, Z1 and Z2 may each independently be OH, or together form a cyclic borate ester containing one or more selected from the following structures: [ka]

[0056] In one embodiment, Z1 and Z2 can each be OH.

[0057] In one aspect, the present invention provides a compound represented by the following chemical formula 2, or a pharmaceutically acceptable salt or isomer thereof:

[0058] [ka]

[0059] In the above formula, R 1a , R 1b , and R 1c are each independently defined as above for R1, R 2a , R 2b , and R 2c are each independently defined as above for R2, R 3a , R 3b , and R 3c are each independently defined as above for R3, R 4a , R 4b , and R 4c are each independently defined as above for R4, L 1a1 , L 1a2 , and L 1a3 are each independently 1a The same definition applies as for L 1b1 , L 1b2 , and L 1b3 are each independently 1bThe same definition applies as for L 1c1 , L 1c2 , and L 1c3 are each independently 1c The same definition applies as for L 2a , L 2b , and L 2c are each independently subject to the same definition as for L2 above, L 3a , L 3b , and L 3c The same definition as for L3 above can be applied to each of these independently.

[0060] The compounds of formula 1 according to the present invention, their pharmaceutically acceptable salts or isomers inhibit chymotrypsin-like activity within the proteasome.

[0061] The present invention provides compounds, pharmaceutically acceptable salts or isomers thereof, for use as inhibitors of chymotrypsin-like activity within the proteasome.

[0062] The present invention provides compounds, pharmaceutically acceptable salts or isomers thereof, for use in the prevention or treatment of proteasome-mediated diseases.

[0063] The compounds of Chemical Formula 1 according to the present invention, their pharmaceutically acceptable salts or isomers are suitable for the prevention or treatment of proteasome-mediated diseases.

[0064] The present invention provides a pharmaceutical composition for inhibiting chymotrypsin-like activity in the proteasome, comprising a compound of Chemical Formula 1, a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable carrier.

[0065] Also included within the scope of the present invention are various forms of prodrugs that can be converted in vivo to the compound of Formula 1 as desired.

[0066] The pharmaceutical composition of the present invention can be used for the prevention or treatment of proteasome-mediated diseases, which may be, but are not limited to, cancer.

[0067] The cancers include brain tumors, benign astrocytomas, malignant astrocytomas, pituitary adenomas, brain meningiomas, brain lymphomas, oligodendroglioma, craniopharyngiomas, ependymoma, brain stem tumors, head and neck tumors, laryngeal cancer, oropharyngeal cancer, nasal cavity / paranasal sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, neuroblastoma, breast tumors, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumors, esophageal cancer, breast cancer, male breast cancer, abdominal tumors, gastric cancer, and liver cancer. , gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, colon cancer, anal cancer, bladder cancer, kidney cancer, male reproductive organ tumors, penile cancer, urethral cancer, prostate cancer, female reproductive organ tumors, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female external genital organ cancer, female urethral cancer, skin cancer, myeloma, leukemia, lymphoma, and malignant lymphoma, and preferably multiple myeloma.

[0068] The present invention also provides a use of the compound of Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof for the manufacture of a medicament for treating a proteasome-mediated disease. The proteasome-mediated disease may be cancer, specific examples of which are as described above.

[0069] A "pharmaceutical composition" may also contain a compound of the present invention and other chemical components, such as a diluent or carrier. Thus, the pharmaceutical composition may contain a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof, as needed. A pharmaceutical composition facilitates administration of a compound into an organism. There are various techniques for administering a compound, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration.

[0070] 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 cells or tissues of living organisms.

[0071] The term "diluent" is defined as a compound diluted with water that dissolves the compound as well as stabilizes the biologically active form of the compound of interest. Salts dissolved in buffers are used as diluents in the art. A commonly used buffer is phosphate buffered saline, which mimics the salt form of human body fluids. Because buffer salts can control the pH of the solution at low concentrations, buffer diluents rarely alter the biological activity of the compound.

[0072] The term "pharmaceutically acceptable" means a property that does not impair the biological activity and physical properties of a compound.

[0073] The compounds of the present invention can be formulated into various pharmaceutical dosage forms depending on the purpose. When preparing the pharmaceutical composition of the present invention, the active ingredient, specifically the compound of Chemical Formula 1, its pharmaceutically acceptable salt or isomer, is mixed with various pharmaceutically acceptable carriers that can be selected depending on the dosage form to be prepared. For example, the pharmaceutical composition of the present invention may be formulated into an injectable formulation, an oral formulation, etc. depending on the purpose.

[0074] The compounds of the present invention may be formulated by known methods using known pharmaceutical carriers and excipients and placed in unit dose or multi-dose containers. The formulations may be in the form of solutions, suspensions, or emulsions in oily or aqueous media, and may contain conventional dispersing, suspending, or stabilizing agents. They may also be in the form of dry powders, for example, to be dissolved in sterile, pyrogen-free water before use. The compounds of the present invention may also be formulated in the form of suppositories using conventional suppository bases, such as cocoa butter or other glycerides. Solid dosage forms for oral administration may be capsules, tablets, pills, powders, and granules, with capsules and tablets being particularly useful. Tablets and pills are preferably prepared in enteric-coated form. Solid dosage forms may be prepared by mixing the compounds of the present invention with one or more inert diluents, such as sucrose, lactose, starch, and the like, and carriers such as lubricants, disintegrants, binders, and the like, such as magnesium stearate. If necessary, the compound of the present invention or a pharmaceutical composition containing it can be administered in combination with other drugs, for example, other antidiabetic drugs.

[0075] The present invention also provides a method for preventing or treating a proteasome disorder, comprising administering to a subject a compound of Chemical Formula 1, a pharmaceutically acceptable salt or isomer thereof, or a pharmaceutical composition containing the same.

[0076] The subject may be a human or non-human mammal in need of treatment or prevention of a proteasome-mediated disease, and the proteasome-mediated disease may be cancer.

[0077] As used herein, the term "treatment" means halting, delaying, or alleviating the progression of a disease when used in a subject who has developed the disease, and "prevention" means halting, delaying, or alleviating the symptoms of development when used in a subject who has not developed the disease but is at high risk of developing the disease.

[0078] The dosage of the compound of Formula 1, its pharmaceutically acceptable salts, or isomers of the present invention will be prescribed by a physician depending on factors such as the patient's weight, age, and the specific nature and severity of the disease. However, the dosage required for adult treatment is typically in the range of about 1 to 500 mg per day, depending on the frequency and intensity of administration. For intramuscular or intravenous administration to adults, a total daily dose of about 1 to 300 mg in divided doses is usually sufficient, although higher daily doses may be preferred for some patients.

[0079] The present invention also provides a method for preparing a compound of Chemical Formula 1. Hereinafter, a method for preparing a compound of Chemical Formula 1 will be described based on an exemplary reaction scheme to facilitate understanding of the present invention. However, a person skilled in the art to which the present invention pertains would be able to prepare a compound of Chemical Formula 1 by various methods based on the structure of Chemical Formula 1, and all such methods should be considered to be within the scope of the present invention. In other words, a compound of Chemical Formula 1 can be prepared by any combination of various synthetic methods disclosed in this specification or the prior art, and these should be considered to be within the scope of the present invention, and the method for preparing a compound of Chemical Formula 1 is not limited to the following description.

[0080] When producing the compound of the present invention, the reaction order can be changed as appropriate. That is, any step can be performed first, or any substituent change step can be inserted, and any reagent other than the exemplified reagents can be used as needed. The compound obtained in each step can be separated or purified by a conventional method such as recrystallization, distillation, or silica gel column. Also, the compound obtained in each step can be used in the next step without separating or purifying it.

[0081] In the following reaction schemes, all substituents are as defined above unless otherwise specified. Reagents and starting materials are readily commercially available. Otherwise, they can be prepared by the synthetic methods described in the Preparations and Examples below, including methods for synthesizing known structurally similar compounds. Unless the method is otherwise described, compounds used as starting materials are known compounds or compounds that can be synthesized from known compounds by known synthetic methods or methods analogous thereto.

[0082] The present invention will be described in more detail below with reference to Production Examples and Examples, but the scope of the present invention is not limited thereto.

[0083] Example Preparation Example 1: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1) and (2).

[0084] (1) Preparation of tert-butyl (2-(hydroxyimino)ethyl)carbamate [ka] tert-Butyl (2-oxoethyl)carbamate (10.7 g, 67.2 mmol) was dissolved in methanol (50 mL), and 50% aqueous hydroxylamine solution (14.23 mL, 168 mmol) was added at room temperature. 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 further purification.

[0085] (2) Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] 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 at room temperature. 4% aqueous sodium hypochlorite solution (21 mL, 13.5 mmol) was slowly added at 0°C, and the mixture was stirred for 18 hours while warming to room temperature. The solvent was distilled under reduced pressure, and aqueous sodium bicarbonate solution was added, followed by extraction twice with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.67 g, 39%). 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) MS (m / z): 273[M+H], 173[M-C5H7O2]

[0086] Preparation Example 2: Preparation of methyl 3-(((tert-butoxycarbonyl)amino)methyl)-4-methyl-4,5-dihydroisoxazole-5-carboxylate [ka] Using crotonic acid methyl ester (0.48 ml, 4.5 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.523 g, 3.00 mmol) obtained in Production Example 1-(1), the title compound (0.076 g, 9%) was obtained according to the production method of Production Example 1-(2). NMR: 1H-NMR(400MHz, CDCl3); δ 5.33 - 5.10 (1H, 2 s), 4.63 - 4.55 (1H, 2 d), 4.17~4.02 (3H, m), 3.81 - 3.79 (3H, 2 s), 1.47~1.40 (12H, m)

[0087] Preparation Example 3: Preparation of ethyl 3-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1), (2), and (3).

[0088] (1) Preparation of tert-butyl (S)-(3-methyl-1-oxobutan-2-yl)carbamate [ka] ((S)-1-Hydroxymethyl-2-methyl-propyl)-carbamic acid tert-butyl ester (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 extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.01 g, 68%). 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)

[0089] (2) Preparation of tert-butyl (S)-(1-(hydroxyimino)-3-methylbutan-2-yl)carbamate [ka] The title compound (1.09, 99%) was obtained by the method of Preparation Example 1-(1) using tert-butyl N-[(1S)-1-formyl-2-methyl-propyl]carbamate (1.01 g, 5.04 ml) obtained in (1) above and the method of Preparation Example 1-(1).

[0090] (3) Preparation of ethyl 3-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.72 g, 84%) was obtained by the production method of Production Example 1-(2) using tert-butyl N-[(1S)-1-hydroxyiminomethyl-2-methyl-propyl]carbamate (0.59 g, 2.73 mmol) obtained in (2) above and ethyl acrylate (0.36 ml, 3.27 mmol). 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) MS (m / z): 315[M+H]

[0091] Preparation Example 4: Preparation of ethyl 3-((S)-1-((tert-butoxycarbonyl)amino)-3-methylbutyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1) and (2).

[0092] (1) Preparation of tert-butyl (S)-(1-(hydroxyimino)-4-methylpentan-2-yl)carbamate [ka] Using ((S)-1-formyl-3-methyl-butyl)-carbamic acid tert-butyl ester (0.39 g, 1.84 mmol), the title compound (0.42 g, 99%) was obtained according to the production method of Production Example 1-(1).

[0093] (2) Preparation of ethyl 3-((S)-1-((tert-butoxycarbonyl)amino)-3-methylbutyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.3 g, 34%) was obtained by the production method of Production Example 1-(2) using tert-butyl N-[(1S)-1-hydroxyiminomethyl-3-methyl-butyl]carbamate (0.61 g, 2.65 mmol) obtained in (1) above and ethyl acrylate (0.35 ml, 3.18 mmol). 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) MS (m / z): 329[M+H]

[0094] Preparation Example 5: Preparation of 5-(ethoxycarbonyl)-4,5-dihydroisoxazole-3-carboxylic acid The title compound was obtained through the following steps (1), (2), and (3).

[0095] (1) Preparation of tert-butyl 2-chloro-2-(hydroxyimino)acetate [ka] The title compound was obtained by the method described in WO200633551A1.

[0096] (2) Preparation of 3-(tert-butyl) 5-ethyl 4,5-dihydroisoxazole-3,5-dicarboxylate [ka] The title compound (1.05 g, 62%) was obtained by the method of Preparation Example 1-(2) using tert-butyl 2-chloro-2-(hydroxyimino)acetate (1.25 g, 6.96 mmol) obtained in (1) above. 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) MS (m / z): 244[M+H]

[0097] (3) Preparation of 5-(ethoxycarbonyl)-4,5-dihydroisoxazole-3-carboxylic acid [ka] 3-tert-Butyl 5-ethyl 4,5-dihydro-1,2-oxazole-3,5-dicarboxylate (1.05 g, 4.32 mmol) obtained in (2) above was dissolved in dichloromethane (20 ml). 4N hydrochloric acid in 1,4-dioxane (8.6 ml, 34.53 mmol) was slowly added at 0°C, and the mixture was stirred for 5 hours while warming to room temperature. The solvent was distilled under reduced pressure, and the mixture was separated by column chromatography to obtain the title compound (0.87 g, 99%). MS (m / z): 188[M+H]

[0098] Preparation Example 6: Preparation of methyl 5-benzyl-3-(((tert-butoxycarbonyl)amino)methyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1) and (2).

[0099] (1) Production of methyl 2-benzyl acrylate [ka] 2-Benzylacrylic acid (15 g, 92.5 mmol) was dissolved in methanol (100 ml). Thionyl chloride (20.15 ml, 27.75 mmol) was slowly added at 0°C, and the mixture was stirred for 16 hours while warming to room temperature. The solvent was distilled under reduced pressure, and ethyl acetate was added and washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and then dried under reduced pressure to obtain the title compound (16.32 g, 99%). 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)

[0100] (2) Preparation of methyl 5-benzyl-3-(((tert-butoxycarbonyl)amino)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using methyl 2-benzyl acrylate (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 Production Example 1-(1), the racemic title compound (10.87 g, 56%) was obtained by the production method in Production Example 1-(2). After separation into isomer 1 with a short retention time and isomer 2 with a long retention time by HPLC using a CHIRALPAK IA chiral column manufactured by CHIRAL TECHNOLOGIES and an ethanol / hexane developing solvent, isomer 2 was used for the synthesis of the title compound. NMR: 1H-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) MS (m / z): 349[M+H], 249[M-C5H7O2]

[0101] Preparation Example 7: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.21 g, 31%) was obtained by the method of Preparation Example 1-(2) using tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.41 g, 2.35 mmol) obtained in Preparation Example 1-(1) and 2-methyl-acrylic acid ethyl ester (0.35 ml, 2.82 mmol). 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) MS (m / z): 287[M+H]

[0102] Preparation Example 8: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-ethyl-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.25 g, 34%) was obtained by the method of Production Example 1-(2) using tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.43 g, 2.47 mmol) obtained in Production Example 1-(1) and 2-methylene-butyric acid ethyl ester (0.51 g, 2.96 mmol). NMR: 1 H-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) MS (m / z): 301[M+H]

[0103] Preparation Example 9: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-propyl-4,5-dihydroisoxazole-5-carboxylate [ka] Using tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.4 g, 2.29 mmol) obtained in Production Example 1-(1) and 2-methylene-pentanoic acid ethyl ester (0.39 g, 2.75 mmol), the title compound (0.27 g, 37%) was obtained according to the production method of Production Example 1-(2). 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) MS (m / z): 315[M+H]

[0104] Preparation Example 10: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-isopropyl-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1) and (2).

[0105] (1) Production of ethyl 3-methyl-2-methylenebutanoate [ka] The title compound was obtained by the method described in Tetrahedron Letters, Vol. 24, No. 33, pp. 3477-3480.

[0106] (2) Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-isopropyl-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.21 g, 30%) was obtained by the 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-butanoate (0.44 g, 2.62 mmol) obtained in (1) above. 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) MS (m / z): 315[M+H]

[0107] Preparation Example 11: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-isobutyl-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through steps (1) and (2).

[0108] (1) Preparation of ethyl 4-methyl-2-methylenepentanoate [ka] The title compound was obtained by the method described in Journal of Medicinal Chemistry, 2000, vol. 43, pp. 1398-1408.

[0109] (2) Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-isobutyl-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.41 g, 32%) was obtained by the production method of Production Example 1-(2) using tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.67 g, 3.90 mmol) obtained in Production Example 1-(1) and ethyl 4-methyl-2-methylenepentanoate (0.67 g, 4.29 mmol) obtained in (1) above. 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) MS (m / z): 329[M+H]

[0110] Preparation Example 12: Preparation of methyl 5-benzyl-3-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1) and (2).

[0111] (1) Preparation of tert-butyl (2-(hydroxyimino)ethyl)(methyl)carbamate [ka] Using (2-hydroxyethyl)-methyl-carbamic acid tert-butyl ester (0.7 g, 3.99 mmol), methyl-(2-oxoethyl)-carbamic acid tert-butyl ester (0.17 g, 25%) was obtained according to the method of Preparation 3-(1). Using methyl-(2-oxoethyl)-carbamic acid tert-butyl ester (0.17 g, 0.98 mmol), the title compound (0.16 g, 99%) was obtained according to the method of Preparation 1-(1).

[0112] (2) Preparation of methyl 5-benzyl-3-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.24 g, 76%) was obtained by the method of Production 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 acrylate (0.18 g, 1.02 mmol) obtained in Production Example 1-(1). NMR: 1H-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) MS (m / z): 363[M+H]

[0113] Preparation Example 13: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(3-methoxybenzyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1) and (2).

[0114] (1) Preparation of ethyl 2-(3-methoxybenzyl)acrylate [ka] (Diethoxyphosphoryl)-acetic acid ethyl ester (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, and after 30 minutes, 3-methoxybenzyl bromide (0.94 ml, 6.69 mmol) was added and 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, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and used in the next reaction without further purification.

[0115] The product obtained above (2.3 g, 6.68 mmol) and 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) was added. The mixture was refluxed and stirred at 90°C for 16 hours, then water was added and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.78 g, 53%, 2 steps). 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)

[0116] (2) Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(3-methoxybenzyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.31 g, 44%) was obtained by the method of Production 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 Production Example 1-(1). 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) MS (m / z): 393[M+H]

[0117] Preparation Example 14: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(4-chlorobenzyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1) and (2).

[0118] (1) Preparation of ethyl 2-(4-chlorobenzyl)acrylate [ka] Under a nitrogen blanket, sodium (0.79 g, 34.34 mmol) was added to ethanol (40 mL). Malonic acid diethyl ester (5 g, 31.22 mmol) was slowly added and stirred for 10 minutes, after which 4-chlorobenzyl chloride (5.03 g, 31.22 mmol) dissolved in ethanol (10 mL) was slowly added. After stirring for 16 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give 2-(4-chlorobenzyl)-malonic acid diethyl ester (3.27 g, 37%). 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)

[0119] 2-(4-Chlorobenzyl)-malonic acid diethyl ester (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 and stirred for 48 hours. After titration to pH 2 with 1N hydrochloric acid, water was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain 2-(4-chlorobenzyl)-malonic acid monoethyl ester (2.10 g, 71%). NMR: 1 H-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)

[0120] The 2-(4-chlorobenzyl)-malonic acid monoethyl ester (2.1 g, 8.19 mmol) obtained above was dissolved in pyridine (15 mL). Paraformaldehyde (0.23 g, 7.78 mmol) and piperidine (0.081 mL, 0.82 mmol) were added in that order, and the mixture was refluxed and stirred at 120°C for 3 hours. After adding water and extracting with hexane, the organic layer was washed successively with water, 1N hydrochloric acid, water, aqueous sodium carbonate, and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.29 g, 70%). 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)

[0121] (2) Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(4-chlorobenzyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.17 g, 19%) was obtained by the method of Production 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 Production Example 1-(1). MS (m / z): 397[M+H]

[0122] Preparation Example 15: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(2-chlorobenzyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Ethyl 2-(2-chlorobenzyl)acrylate was obtained by the method described in WO2006134485A1. Using tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.31 g, 1.76 mmol) obtained in Production Example 1-(1) and ethyl 2-(2-chlorobenzyl)acrylate (0.36 g, 1.6 mmol), the title compound (0.4 g, 38%) was obtained by the production method described in Production Example 1-(2). MS (m / z): 397[M+H]

[0123] Preparation Example 16: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(3-chlorobenzyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using 3-chlorobenzyl bromide (1.17 ml, 8.92 mmol), ethyl 2-(3-chlorobenzyl)acrylate (0.96 g, 48%, two steps) was obtained according to the method of Preparation 13-(1). Using tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.47 g, 2.67 mmol) obtained in Preparation 1-(1), the title compound (0.4 g, 38%) was obtained according to the method of Preparation 1-(2). 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) MS (m / z): 397[M+H]

[0124] Preparation Example 17: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(fluoro(phenyl)methyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1) and (2).

[0125] (1) Preparation of ethyl 2-(fluoro(phenyl)methyl)acrylate [ka] 2-(Hydroxy-phenyl-methyl)-acrylic acid ethyl ester (0.412 g, 2.0 mmol) was dissolved in dichloromethane (10 ml), and then diethylaminosulfur trifluoride (0.32 ml, 2.4 mmol) was added at -78 °C and stirred for 2 hours. The reaction was quenched with aqueous sodium bicarbonate, followed by extraction twice with dichloromethane (20 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.320 g, 77%). 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)

[0126] (2) Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(fluoro(phenyl)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using ethyl 2-(fluoro(phenyl)methyl)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 Production Example 1-(1), two title compounds, less polar isomer 1 (0.089 g, 17%) and more polar isomer 2 (0.100 g, 19%), were obtained according to the production method of Production Example 1-(2). Isomer 1 NMR: 1 H-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) Isomer 2 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)

[0127] Preparation Example 18: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(3-methylbenzyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using 3-methylbenzyl bromide (0.93 ml, 6.69 mmol), 2-(3-methyl-benzyl)-acrylic acid ethyl ester (0.7 g, 52%, two steps) was obtained according to the production method of Production Example 13-(1). 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)

[0128] Using 2-(3-methyl-benzyl)-acrylic acid ethyl ester (0.37 g, 1.83 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.35 g, 2.01 mmol) obtained in Production Example 1-(1), the title compound (0.38 g, 50%) was obtained according to the production method of Production Example 1-(2). NMR: 1H-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) MS (m / z): 377[M+H]

[0129] Preparation Example 19: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(phenoxymethyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Ethyl 2-(phenoxymethyl)acrylate was obtained by the method described in US 6747050. Using tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.64 g, 3.67 mmol) obtained in Production Example 1-(1) and ethyl 2-(phenoxymethyl)acrylate (0.83 g, 4.04 mmol), the title compound (0.59 g, 42%) was obtained by the production method of Production Example 1-(2). 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) MS (m / z): 434[M+H]

[0130] Preparation Example 20: Preparation of ethyl 5-((1H-pyrazol-1-yl)methyl)-3-(((tert-butoxycarbonyl)amino)methyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1) and (2).

[0131] (1) Preparation of ethyl 2-((1H-pyrazol-1-yl)methyl)acrylate [ka] 2-Hydroxymethyl-acrylic acid ethyl ester (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 in that order, and the mixture was refluxed and stirred for 20 hours. Water was added and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfonate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.5 g, 18%). 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)

[0132] (2) Preparation of ethyl 5-((1H-pyrazol-1-yl)methyl)-3-(((tert-butoxycarbonyl)amino)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.58 g, 59%) was obtained by the method of Production Example 1-(2) using ethyl 2-((1H-pyrazol-1-yl)methyl)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 Production Example 1-(1). 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) MS (m / z): 353[M+H]

[0133] Preparation Example 21: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(hydroxy(phenyl)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using 2-(hydroxyphenyl-methyl)-acrylic acid ethyl ester (1.40 g, 8.0 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (2.31 g, 11.2 mmol) obtained in Production Example 1-(1), the title compound (1.95 g, 64%) was obtained according to the production method of Production Example 1-(2). NMR: 1 H-NMR(500MHz, CDCl3); δ 7.44~7.26 (5H, m), 5.22 - 5.16 (1H, 2 d), 4.70 - 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 - 2.80 (1H, 2 s), 1.45 - 1.44 (9H, 2 s), 1.29~1.24 (3H, m)

[0134] Preparation Example 22: Preparation of methyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(1-phenylethyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1) and (2).

[0135] (1) Production of methyl 2-methylene-3-phenylbutanoate [ka] 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 minutes. After adding 2-methylbut-2-enoic acid methyl ester (0.72 ml, 6.00 mmol) and phenylboronic acid (0.488 g, 4.0 mmol), the mixture was stirred at room temperature under an oxygen balloon for 16 hours. After adding diethyl ether (50 ml), the mixture was washed with aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to give the title compound (0.546 g, 72%). 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))

[0136] (2) Preparation of methyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(1-phenylethyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using methyl 2-methylene-3-phenylbutanoate (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 Production Example 1-(1), the title compound (0.389 g, 52%) was obtained according to the production method of Production Example 1-(2). NMR: 1H-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)

[0137] Preparation Example 23: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(thiazol-4-ylmethyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1) and (2).

[0138] (1) Preparation of ethyl 2-(thiazol-4-ylmethyl)acrylate [ka] Malonic acid diethyl ester (0.59 ml, 3.85 mmol) was dissolved in dimethylamide (10 ml). Sodium hydride (0.162 g, 4.05 mmol) and 4-chloromethyl-thiazole (0.52 g, 3.85 mmol) were added sequentially at 0°C, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled under reduced pressure, and water was added, followed by extraction twice with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain 2-thiazol-4-ylmethyl-malonic acid diethyl ester (0.55 g, 56%). 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)

[0139] The 2-thiazol-4-ylmethyl-malonic acid diethyl ester (0.55 g, 2.14 mmol) obtained above 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 stirred for 48 hours. After titration to pH 2 with 1N hydrochloric acid, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound, 2-thiazol-4-ylmethyl-malonic acid monoethyl ester (0.36 g, 73%). 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)

[0140] The 2-thiazol-4-ylmethyl-malonic acid monoethyl ester (0.36 g, 1.56 mmol) obtained above was dissolved in pyridine (10 mL). Paraformaldehyde (0.045 g, 1.48 mmol) and piperidine (0.015 mL, 0.16 mmol) were added, in that order, and the mixture was refluxed and stirred at 120°C for 3 hours. After adding water and extracting with hexane, the organic layer was washed successively with water, 1N hydrochloric acid, water, aqueous sodium carbonate, and brine, dried over 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%). 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)

[0141] (2) Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(thiazol-4-ylmethyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.30 g, 40%) was obtained by the method of Production 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 Production Example 1-(1). 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) MS (m / z): 370[M+H]

[0142] Preparation Example 24: Preparation of methyl 5-benzyl-3-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using (S)-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (0.5 g, 2.89 mmol), tert-butyl (S)-(1-(hydroxyimino)propan-2-yl)carbamate (0.54 g, 99%) was obtained according to the production method of Production Example 1-(1). Using tert-butyl (S)-(1-(hydroxyimino)propan-2-yl)carbamate (0.44 g, 2.31 mmol) and methyl 2-benzyl acrylate (0.45 g, 2.54 mmol) obtained in Production Example 6-(1), the title compound (0.36 g, 43%) was obtained according to the production method of Production Example 1-(2). NMR: 1 H-NMR(400MHz, CDCl3); δ 7.29-2.20 (m, 3H), 4.79 (m, 1H), 4.31 (br s, 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) MS (m / z): 363[M+H]

[0143] Preparation Example 25: Preparation of methyl 5-benzyl-3-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (1.62 g, 82%) was obtained by the method of Production Example 1-(2) using tert-butyl (S)-(1-(hydroxyimino)-3-methylbutan-2-yl)carbamate (1.09 g, 5.04 mmol) obtained in Production Example 3-(2) and methyl 2-benzyl acrylate (0.98 g, 5.54 mmol) obtained in Production Example 6-(1). NMR: 1 H-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) MS (m / z): 391[M+H]

[0144] Preparation Example 26: Preparation of methyl 5-benzyl-3-((S)-1-((tert-butoxycarbonyl)amino)-3-methylbutyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.51 g, 67%) was obtained by the method of Production Example 1-(2) using tert-butyl (S)-(1-(hydroxyimino)-4-methylpentan-2-yl)carbamate (0.42 g, 1.84 mmol) obtained in Production Example 4-(1) and methyl 2-benzyl acrylate (0.39 g, 2.21 mmol) obtained in Production Example 6-(1). 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) MS (m / z): 405[M+H]

[0145] Preparation Example 27: Preparation of methyl 5-benzyl-3-((R)-1-((tert-butoxycarbonyl)amino)-2-methoxyethyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1), (2), (3), and (4).

[0146] (1) Preparation of methyl N-(tert-butoxycarbonyl)-O-methyl-L-serinate [ka] (S)-2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid methyl ester (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 in that order. The mixture was stirred at room temperature and protected from light for 20 hours. After filtration through Celite, the mixture was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.58 g, 36%). NMR: 1H-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)

[0147] (2) Preparation of tert-butyl (S)-(1-methoxy-3-oxopropan-2-yl)carbamate [ka] Methyl N-(tert-butoxycarbonyl)-O-methyl-L-serinate (0.58 g, 2.49 mmol) obtained in (1) above was dissolved in toluene (10 ml) under a nitrogen atmosphere. A 1.5 M solution of diisobutylaluminum hydride in toluene (2.82 ml, 4.23 mmol) was added at -78°C, followed by stirring for 2 hours. After quenching with methanol (4 ml), 1 N aqueous hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and separated by column chromatography to obtain the title compound (0.42 g, 83%). 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)

[0148] (3) Preparation of tert-butyl (R)-(1-(hydroxyimino)-3-methoxypropan-2-yl)carbamate [ka] The title compound (0.45 g, 99%) was obtained by the method of Preparation Example 1-(1) using tert-butyl (S)-(1-methoxy-3-oxopropan-2-yl)carbamate (0.42 g, 2.07 mmol) obtained in (2) above.

[0149] (4) Preparation of methyl 5-benzyl-3-((R)-1-((tert-butoxycarbonyl)amino)-2-methoxyethyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.42 g, 52%) was obtained by the method of Production Example 1-(2) using tert-butyl (R)-(1-(hydroxyimino)-3-methoxypropan-2-yl)carbamate (0.45 g, 2.06 mmol) obtained in (3) above and methyl 2-benzyl acrylate (0.44 g, 2.47 mmol) obtained in Production Example 6-(1). 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) MS (m / z): 393[M+H]

[0150] Preparation Example 28: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(2-methylbenzyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using 2-methylbenzyl bromide (1.0 g, 5.4 mmol), 2-(2-methylbenzyl)-acrylic acid ethyl ester (0.84 g, 4.1 mmol) was obtained according to the production method of Production Example 13-(1). Using 2-(2-methylbenzyl)-acrylic acid ethyl ester (0.082 g, 0.40 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.14 g, 0.80 mmol) obtained in Production Example 1-(1), the title compound (0.10 g, 68%) was obtained according to the production method of Production Example 1-(2). MS (m / z): 377[M+H]

[0151] Preparation Example 29: Preparation of methyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(difluoro(phenyl)methyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0152] (1) Production of 2,2-difluoro-2-phenylethan-1-ol [ka] 2-Bromoacetophenone (1.50 g, 7.54 mmol) was dissolved in benzene (15 mL) and diethylaminosulfur trifluoride (2.0 mL, 15.1 mmol) was added at room temperature. The mixture was then stirred at 60°C for 48 hours. After cooling to room temperature, water was added and the mixture was extracted twice with diethyl ether (50 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain (2-bromo-1,1-difluoro-ethyl)-benzene (1.12 g, 67%). NMR: 1 H-NMR(400MHz, CDCl3); δ 7.57~7.31 (5H, m), 3.81 (2H, dt)

[0153] (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 mixture was cooled to room temperature, water was added, and the mixture was extracted twice with diethyl ether (50 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain acetic acid 2,2-difluoro-2-phenyl-ethyl ester (0.634 g, 62%). NMR: 1 H-NMR(400MHz, CDCl3); δ 7.57~7.47 (5H, m), 4.57 (2H, dt), 2.13 (3H, s)

[0154] Acetic acid 2,2-difluoro-2-phenyl-ethyl ester (0.634 g, 3.17 mmol) was dissolved in methanol (12 ml) and treated with 1N NaOH (3.2 ml) and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the methanol was removed under reduced pressure. The mixture was then extracted twice with dichloromethane (20 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to obtain the title compound (0.489 g, 98%). NMR: 1 H-NMR(400MHz, CDCl3); δ 7.58~7.47 (5H, m), 4.02 (2H, t)

[0155] (2) Production of 3,3-difluoro-2-hydroxy-3-phenylpropanenitrile [ka] Oxalyl chloride (0.29 ml, 3.38 mmol) was dissolved in dichloromethane (6 ml) and the temperature was adjusted to -78°C. Dimethyl sulfoxide (0.49 ml, 6.90 mmol) was slowly added. The reaction mixture was stirred for 30 minutes, and then a solution of 2,2-difluoro-2-phenylethan-1-ol (0.489 g, 3.09 mmol) obtained in (1) above in dichloromethane (2 ml) was added and stirred for 30 minutes. Triethylamine (1.90 ml, 13.6 mmol) was added to the reaction mixture, which was then gradually warmed to room temperature and stirred for 18 hours. Water was added, and the mixture was extracted twice with dichloromethane (30 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure to obtain the title compound, difluoro-phenyl-acetaldehyde (0.531 g).

[0156] The difluorophenylacetaldehyde (0.531 g) obtained above was dissolved in tetrahydrofuran (30 ml), and then p-toluenesulfonic acid monohydrate (0.705 g, 3.71 mmol) and potassium cyanide (0.242 g, 3.72 mmol) were added in that order. The mixture was then stirred at 40°C for 3 hours. The reaction mixture 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 aqueous sodium disulfite solution, dried over 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). NMR: 1 H-NMR(400MHz, CDCl3); δ 7.57~7.43 (5H, m), 4.80 (1H, t)

[0157] (3) Preparation of methyl 3,3-difluoro-2-hydroxy-3-phenylpropanoate [ka] 3,3-Difluoro-2-hydroxy-3-phenylpropanenitrile (0.327 g, 1.79 mmol) obtained in (2) above was dissolved in MeOH (8 ml), and 4N HCl (8.0 ml) was added. The mixture was stirred at 65°C for 48 hours. After cooling to room temperature, water was added, the methanol was removed under reduced pressure, and the mixture was extracted twice with dichloromethane (20 ml). The organic layer was dried over 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%). 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)

[0158] (4) Preparation of methyl 2-(difluoro(phenyl)methyl)acrylate [ka] Methyl 3,3-difluoro-2-hydroxy-3-phenylpropanoate (0.419 g, 1.94 mmol) obtained in (3) above was dissolved in dimethyl sulfoxide (15 ml), and 2-iodoxybenzoic acid (IBX, 1.29 g, 4.61 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the precipitated solid was removed under reduced pressure. The filtrate was then extracted twice with ethyl acetate (30 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain 3,3-difluoro-2-oxo-3-phenyl-propionic acid methyl ester (0.282 g, 68%).

[0159] Methyltriphenylphosphonium bromide (1.18 g, 3.30 mmol) and potassium t-butoxide (0.356 g, 3.17 mmol) were dissolved in tetrahydrofuran (10 mL) and stirred at room temperature for 1 hour. The temperature of the reaction mixture was adjusted to -30°C, and a solution of the above-obtained 3,3-difluoro-2-oxo-3-phenyl-propionic acid methyl ester (0.282 g, 1.32 mmol) dissolved in tetrahydrofuran (2 mL) was added. The reaction mixture was gradually warmed to room temperature and stirred at room temperature for 18 hours. Water was added, and the mixture was extracted twice with ethyl acetate (20 mL). It was then dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.114 g, 41%). 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)

[0160] (5) Preparation of methyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(difluoro(phenyl)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.173 g, 84%) was obtained by the method of Production Example 1-(2) using methyl 2-(difluoro(phenyl)methyl)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 Production Example 1-(1). 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)

[0161] Preparation Example 30: Preparation of methyl 5-benzyl-3-(2-((tert-butoxycarbonyl)amino)propan-2-yl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1) and (2).

[0162] (1) Preparation of tert-butyl (1-(hydroxyimino)-2-methylpropan-2-yl)carbamate [ka] (1,1-Dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester was obtained by the method described in EP2036896A1. Using (1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (1 g, 5.34 mmol), the title compound (1.07 g, 99%) was obtained by the method described in Preparation Example 1-(1).

[0163] (2) Preparation of methyl 5-benzyl-3-(2-((tert-butoxycarbonyl)amino)propan-2-yl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.37 g, 18%) was obtained by the method of Production Example 1-(2) using tert-butyl (1-(hydroxyimino)-2-methylpropan-2-yl)carbamate (0.69 g, 3.41 mmol) obtained in (1) above and methyl 2-benzyl acrylate (0.4 g, 2.27 mmol) obtained in Production Example 6-(1). 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) MS (m / z): 377[M+H]

[0164] Preparation Example 31: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-phenethyl-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1) and (2).

[0165] (1) Preparation of ethyl 2-methylene-4-phenylbutanoate [ka] (Diethoxyphosphoryl)-acetic acid ethyl ester (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-bromoethyl)-benzene (1.83 ml, 13.38 mmol) was added and 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, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and used in the next reaction without further purification.

[0166] The product obtained above (4.11 g, 12.50 mmol) and 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) was added. After refluxing and stirring at 90°C for 16 hours, water was added and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.39 g, 51%, 2 steps). 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)

[0167] (2) Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-phenethyl-4,5-dihydroisoxazole-5-carboxylate [ka] Using ethyl 2-methylene-4-phenylbutanoate (0.5 g) obtained in (1) above and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.36 g) obtained in Production Example 1-(1), the title compound (0.27 g, 30%) was obtained according to the production method of Production Example 1-(2). 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) MS (m / z): 377[M+H]

[0168] Preparation Example 32: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(2-(trifluoromethyl)benzyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using 2-(trifluoromethyl)benzyl chloride (0.47 g, 2.42 mmol), 2-(2-trifluoromethyl-benzyl)-acrylic acid ethyl ester (0.24 g, 0.93 mmol) was obtained according to the production method of Production Example 13-(1). Using 2-(2-trifluoromethyl-benzyl)-acrylic acid ethyl ester (0.24 g, 0.93 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.18 g, 1.02 mmol) obtained in Production Example 1-(1), the title compound (0.09 g, 22%) was obtained according to the production method of Production Example 1-(2). MS (m / z): 431[M+H]

[0169] Preparation Example 33: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(2-fluorobenzyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using 2-fluorobenzyl bromide (1.0 g, 5.3 mmol), 2-(2-fluorobenzyl)-acrylic acid ethyl ester (0.76 g, 3.65 mmol) was obtained according to the production method of Production Example 13-(1). Using 2-(2-fluorobenzyl)-acrylic acid ethyl ester (0.21 g, 1.0 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.17 g, 1.0 mmol) obtained in Production Example 1-(1), the title compound (0.11 g, 30%) was obtained according to the production method of Production Example 1-(2). MS (m / z): 381[M+H]

[0170] Preparation Example 34: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(2,6-difluorobenzyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using 2,6-difluorobenzyl bromide (1.0 g, 4.83 mmol), 2-(2,6-difluorobenzyl)-acrylic acid ethyl ester (0.79 g, 3.49 mmol) was obtained according to the production method of Production Example 13-(1). Using 2-(2,6-difluorobenzyl)-acrylic acid ethyl ester (0.79 g, 3.49 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (1.21 g, 6.38 mmol) obtained in Production Example 1-(1), the title compound (0.476 g, 34%) was obtained according to the production method of Production Example 1-(2). MS (m / z): 399[M+H]

[0171] Preparation Example 35: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(2,4-difluorobenzyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using 2,4-difluorobenzyl bromide (1 g, 4.8 mmol), 2-(2,4-difluorobenzyl)-acrylic acid ethyl ester (0.67 g, 3.0 mmol) was obtained according to the production method of Production Example 13-(1). Using 2-(2,4-difluorobenzyl)-acrylic acid ethyl ester (0.30 g, 1.33 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.28 g, 1.6 mmol) obtained in Production Example 1-(1), the title compound (0.20 g, 37%) was obtained according to the production method of Production Example 1-(2). MS (m / z): 399[M+H]

[0172] Preparation Example 36: Preparation of methyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(1-phenylcyclopropyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (2), (3), (4), and (5).

[0173] (1) Preparation of 1-phenylcyclopropane-1-carbonitrile [ka] 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 then 1,2-dibromoethane (6.90 ml, 80.0 mmol) was added at 50°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted twice with diethyl ether (100 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (3.61 g, 63%). 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)

[0174] (2) Preparation of 2-hydroxy-2-(1-phenylcyclopropyl)acetonitrile [ka] 1-Phenylcyclopropane-1-carbonitrile (3.61 g, 25.2 mmol) obtained in (1) above was dissolved in dichloromethane (40 ml), and then 1.5 M diisoaluminum hydride toluene solution (18.5 ml, 27.8 mmol) was slowly added at 0°C. The mixture was then stirred at room temperature for 2 hours. 1N HCl (150 ml) was slowly added to the reaction mixture at 0°C, followed by extraction with dichloromethane (100 ml) twice. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure to obtain 1-phenylcyclopropanecarbaldehyde (3.19 g, 87%). Using the 1-phenylcyclopropanecarbaldehyde (3.1 g, 21.8 mmol) obtained above, the title compound (2.69 g, 71%) was obtained according to the preparation method described in Preparation Example 29-(2). NMR: 1H-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)

[0175] (3) Preparation of methyl 2-hydroxy-2-(1-phenylcyclopropyl)acetate [ka] Using 2-hydroxy-2-(1-phenylcyclopropyl)acetonitrile (1.0 g, 5.77 mmol) obtained in (2) above, the title compound (0.986 g, 83%) was obtained according to the production method of Production Example 29-(3). 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)

[0176] (4) Preparation of methyl 2-(1-phenylcyclopropyl)acrylate [ka] The title compound (0.209 g, 40%) was obtained by the method of Preparation Example 29-(4) using methyl 2-hydroxy-2-(1-phenylcyclopropyl)acetate (0.486 g, 2.36 mmol) obtained in (3) above. 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)

[0177] (5) Preparation of methyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(1-phenylcyclopropyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.277 g, 72%) was obtained by the method of Production 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 Production Example 1-(1). NMR: 1 H-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)

[0178] Preparation Example 37: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(3,5-difluorobenzyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using 3,5-difluorobenzyl bromide (0.87 ml, 6.69 mmol), 2-(3,5-difluoro-benzyl)-acrylic acid ethyl ester (0.37 g, 24%, two steps) was obtained according to the production method of Production Example 13-(1). 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)

[0179] Using 2-(3,5-difluorobenzyl)-acrylic acid ethyl ester (0.36 g, 1.59 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.30 g, 1.75 mmol) obtained in Production Example 1-(1), the title compound (0.29, 41%) was obtained according to the production method of Production Example 1-(2). 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) MS (m / z): 399[M+H]

[0180] Preparation Example 38: Preparation of methyl 5-benzyl-3-((S)-1-((tert-butoxycarbonyl)amino)-2-methoxyethyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1) and (2).

[0181] (1) Preparation of tert-butyl (S)-(1-(hydroxyimino)-3-methoxypropan-2-yl)carbamate [ka] Using (R)-2-tert-butoxycarbonylamino-3-hydroxy-propionic acid methyl ester (2.26 g, 10.31 mmol), (R)-2-tert-butoxycarbonylamino-3-methoxy-propionic acid methyl ester (1.31 g, 54%) was obtained according to the production method of Production Example 27-(1). Using (R)-2-tert-butoxycarbonylamino-3-methoxy-propionic acid methyl ester (1.31 g, 5.62 mmol), the title compound ((R)-1-methoxymethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (0.89 g, 78%) was obtained according to the production method of Production Example 27-(2). The title compound (0.96 g, 99%) was obtained using ((R)-1-methoxymethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (0.89 g, 4.38 mmol) according to the method of Preparation Example 1-(1).

[0182] (2) Preparation of methyl 5-benzyl-3-((S)-1-((tert-butoxycarbonyl)amino)-2-methoxyethyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.93 g, 54%) was obtained by the method of Production Example 1-(2) using tert-butyl (S)-(1-(hydroxyimino)-3-methoxypropan-2-yl)carbamate (0.96 g, 4.39 mmol) obtained in (1) above and methyl 2-benzyl acrylate (0.85 g, 4.84 mmol) obtained in Production Example 6-(1). NMR: 1 H-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) MS (m / z): 393[M+H]

[0183] Preparation Example 39: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(3-fluorobenzyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using 3-fluorobenzyl bromide (1.0 g, 5.3 mmol), 2-(3-fluorobenzyl)-acrylic acid ethyl ester (0.49 g, 2.35 mmol) was obtained according to the production method of Production Example 13-(1). Using 2-(3-fluorobenzyl)-acrylic acid ethyl ester (0.49 g, 2.35 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.82 g, 4.7 mmol) obtained in Production Example 1-(1), the title compound (0.80 g, 80%) was obtained according to the production method of Production Example 1-(2). MS (m / z): 381[M+H]

[0184] Preparation Example 40: Preparation of methyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(methoxymethyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1), (2), (3), and (4).

[0185] (1) Preparation of methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)acrylate [ka] 2-Hydroxymethyl-acrylic acid methyl ester (0.5 g, 4.31 mmol) was dissolved in dimethylamide (10 ml). Imidazole (0.35 g, 5.17 mmol) and tert-butyl-chloro-dimethyl-silane (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, and water was added, followed by extraction with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.99 g, 99%). 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)

[0186] (2) Preparation of methyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.29 g, 31%) was obtained by the method of Production Example 1-(2) using methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)acrylate (0.59 g, 2.56 mmol) obtained in (1) above and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.36 g) obtained in Production Example 1-(1). 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) MS (m / z): 403[M+H]

[0187] (3) Preparation of methyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(hydroxymethyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Methyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.29 g, 0.72 mmol) obtained in (2) above 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 extracted organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the filtrate was distilled under reduced pressure. The residue was separated by column chromatography to obtain the title compound (0.13 g, 62%). MS (m / z): 289[M+H]

[0188] (4) Preparation of methyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(methoxymethyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Methyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(hydroxymethyl)-4,5-dihydroisoxazole-5-carboxylate (0.075 g, 0.26 mmol) obtained in (3) above 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 in that order. The mixture was stirred at room temperature in the dark for 20 hours. After filtration through Celite, the mixture was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.05 g, 64%). 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) MS (m / z): 303[M+H]

[0189] Preparation Example 41: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(ethoxymethyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1) and (2).

[0190] (1) Production of ethyl 2-(ethoxymethyl)acrylate [ka] To a solution of 2-hydroxymethyl-acrylic acid ethyl ester (1.30 g, 10.0 mmol) dissolved in dichloromethane (20 ml), phosphorus tribromide (0.47 ml, 5.0 mmol) was added at 0°C, and the mixture was then heated and stirred at room temperature for 2 hours. Dichloromethane (50 ml) was added to the reaction mixture, which was then washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain 2-bromomethyl-acrylic acid ethyl ester (1.71 g, 91%).

[0191] Ethanol (0.046 g, 1.0 mmol) was dissolved in tetrahydrofuran (6 mL), and then 0.5 M potassium bis(trimethylsilyl)amide (2.0 mL, 1.0 mmol) was slowly added and stirred at room temperature for 10 minutes. A solution of 2-bromomethyl-acrylic acid ethyl ester (0.193 g, 1.0 mmol) obtained in the above step dissolved in tetrahydrofuran (2 mL) was added to this solution, and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was extracted twice with dichloromethane (20 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.118 g, 75%). 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)

[0192] (2) Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(ethoxymethyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.051 g, 25%) was obtained by the method of Production 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 Production Example 1-(1). NMR: 1H-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) MS (m / z): 331[M+H]

[0193] Preparation Example 42: Preparation of methyl 3-(((tert-butoxycarbonyl)amino)methyl)-3a,4,5,6-tetrahydro-6aH-cyclopenta[d]isoxazole-6a-carboxylate [ka] Using 1-cyclopentenecarboxylic acid methyl ester (0.252 g, 2.00 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.523 g, 3.00 mmol) obtained in Production Example 1-(1), the title compound (0.148 g, 25%) was obtained according to the production method of Production Example 1-(2). 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)

[0194] Preparation Example 43: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(2,3-difluorobenzyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using 2,3-difluorobenzyl bromide (0.84 ml, 6.69 mmol), 2-(2,3-difluoro-benzyl)-acrylic acid ethyl ester (0.92 g, 61%, two steps) was obtained according to the production method of Production Example 13-(1). 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)

[0195] Using 2-(2,3-difluoro-benzyl)-acrylic acid ethyl ester (0.35 g, 1.57 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.3 g, 1.72 mmol) obtained in Production Example 1-(1), the title compound (0.23 g, 37%) was obtained according to the production method of Production Example 1-(2). 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) MS (m / z): 399[M+H]

[0196] Preparation Example 44: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-((cyclohexyloxy)methyl)-4,5-dihydroisoxazole-5-carboxylate The title compound was obtained through the following steps (1) and (2).

[0197] (1) Preparation of ethyl 2-((cyclohexyloxy)methyl)acrylate [ka] Using cyclohexanol (0.20 g, 2.0 mmol), the title compound (0.20 g, 47%) was obtained according to the production method of Production Example 41-(1). 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).

[0198] (2) Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-((cyclohexyloxy)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.200 g, 55%) was obtained by the 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)methyl)acrylate (0.200 g, 0.94 mmol) obtained in (1) above. 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)

[0199] Preparation Example 45: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(3-(trifluoromethyl)benzyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using 3-trifluoromethylbenzyl bromide (1.02 ml, 6.69 mmol), 2-(3-trifluoromethyl-benzyl)-acrylic acid ethyl ester (0.49 g, 28%, two steps) was obtained according to the production method of Production Example 13-(1). 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)

[0200] Using 2-(3-trifluoromethyl-benzyl)-acrylic acid ethyl ester (0.36 g, 1.38 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.24 g, 1.38 mmol) obtained in Production Example 1-(1), the title compound (0.25 g, 42%) was obtained according to the production method of Production Example 1-(2). 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) MS (m / z): 431[M+H]

[0201] Preparation Example 46: Preparation of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(3-(trifluoromethoxy)benzyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using 3-trifluoromethoxybenzyl bromide (0.64 ml, 3.92 ml), 2-(3-trifluoromethoxy-benzyl)-acrylic acid ethyl ester (0.33 g, 32%, two steps) was obtained according to the production method of Production Example 13-(1). NMR: 1 H-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)

[0202] Using 2-(3-trifluoromethoxy-benzyl)-acrylic acid ethyl ester (0.33 g, 1.19 mmol) and tert-butyl (2-(hydroxyimino)ethyl)carbamate (0.24 g, 1.38 mmol) obtained in Production Example 1-(1), the title compound (0.35 g, 67%) was obtained according to the production method of Production Example 1-(2). 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) MS (m / z): 447[M+H]

[0203] Example 1: Preparation of ((1R)-3-methyl-1-(3-phenyl-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), and (4).

[0204] (1) Preparation of ethyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate [ka] N-Hydroxybenzenecarbonimidoyl 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 warming to room temperature. The solvent was distilled under reduced pressure, and aqueous sodium bicarbonate solution was added, followed by extraction twice with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.78 g, 82%). MS (m / z): 220[M+H]

[0205] (2) Preparation of 3-phenyl-4,5-dihydroisoxazole-5-carboxylic acid [ka] Ethyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate (0.78 g, 3.6 mmol) obtained in (1) above was dissolved in methanol (5 ml), and 6 N aqueous sodium hydroxide solution (1.8 ml, 10.8 mmol) was added. The mixture was stirred at room temperature for 5 hours. The pH was adjusted to 1 with 1 N hydrochloric acid solution, and then extracted twice with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was distilled under reduced pressure to quantitatively obtain the title compound without further purification. MS (m / z): 192[M+H]

[0206] (3) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-phenyl-4,5-dihydroisoxazole-5-carboxamide [ka] 3-Phenyl-4,5-dihydroisoxazole-5-carboxylic acid (0.11 g, 0.59 mmol) obtained in (2) above, (R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butan-1-amine hydrochloride (0.18 g, 0.6 mmol), and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.21 g, 0.64 mmol) were dissolved in dimethylformamide (5 mL) at 0°C. Diisopropylethylamine (0.31 mL, 1.78 mmol) was slowly added while maintaining the temperature, and the mixture was stirred for 18 hours while warming to room temperature. The solvent was distilled under reduced pressure, and the resulting mixture was added with aqueous sodium bicarbonate and extracted twice with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.19 g, 76%). MS (m / z): 439[M+H]

[0207] (4) Preparation of ((1R)-3-methyl-1-(3-phenyl-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-phenyl-4,5-dihydroisoxazole-5-carboxamide (0.19 g, 0.44 mmol) obtained in (3) above was dissolved in methanol (5 mL) and hexane (5 mL). Isobutylboronic acid (0.23 g, 2.2 mmol) and 1N aqueous hydrochloric acid (1.1 mL, 1.1 mmol) were added sequentially, and 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 once with methanol (5 mL), and all the methanol layers were distilled under reduced pressure. The mixture was washed with aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to give the title compound (0.052 g, 38%). MS (m / z): 305[M+H], 287[M-OH]

[0208] Example 2: Preparation of ((1R)-3-methyl-1-(3-(pyrazin-2-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), (5), and (6).

[0209] (1) Production of pyrazine-2-carbaldehyde [ka] The title compound was obtained by the method described in WO200540159A1.

[0210] (2) Preparation of pyrazine-2-carbaldehyde oxime [ka] Pyrazine-2-carbaldehyde (0.53 g, 4.90 mmol) obtained in (1) above was dissolved in dichloromethane (10 ml). Triethylamine (0.7 ml, 5.00 mmol) and hydroxyamine hydrochloride (0.38 g, 5.39 mmol) were added sequentially at 0°C, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled under reduced pressure, and water was added, followed by extraction with diethyl ether. The mixture was dried over anhydrous magnesium sulfate and filtered. The filtrate was separated by column chromatography to obtain the title compound (0.48 g, 79%). 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)

[0211] (3) Preparation of ethyl 3-(pyrazin-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] Pyrazine-2-carbaldehyde oxime (0.12 g, 0.97 mmol) obtained in (2) above was dissolved in dichloromethane (10 ml) and acrylic acid ethyl ester (0.096 ml, 0.97 mmol) was added at room temperature. 4% aqueous sodium hypochlorite solution (2.97 ml, 1.75 mmol) was slowly added at 0°C, and the mixture was stirred for 18 hours while warming to room temperature. The solvent was distilled under reduced pressure, and aqueous sodium bicarbonate solution was added, followed by extraction twice with ethyl acetate. The extracted organic layer was washed with brine, dried over 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%). 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) MS (m / z): 222[M+H]

[0212] (4) Preparation of 3-(pyrazin-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.1 g, 82%) was obtained by the production method of Example 1-(2) using ethyl 3-(pyrazin-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.14 g, 0.63 mmol) obtained in (3) above and the production method of Example 1-(2). MS (m / z): 194[M+H]

[0213] (5) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(pyrazin-2-yl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.16 g, 70%) was obtained by the production method of Example 1-(3) using 3-(pyrazin-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.1 g, 0.52 mmol) obtained in (4) above and the production method of Example 1-(3). MS (m / z): 441[M+H]

[0214] (6) Preparation of ((1R)-3-methyl-1-(3-(pyrazin-2-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.067 g, 60%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(pyrazin-2-yl)-4,5-dihydroisoxazole-5-carboxamide (0.16 g, 0.36 mmol) obtained in (5) above. 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) MS (m / z): 307[M+H], 289[M-OH]

[0215] Example 3: Preparation of ((1R)-1-(3-(2,5-dichlorophenyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0216] (1) Production of 2,5-dichlorobenzaldehyde oxime [ka] 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 at room temperature, followed by stirring for 16 hours. The solvent was distilled under reduced pressure to give the title compound (0.32 g, 99%), which was used immediately in the next reaction without further purification. MS (m / z): 190[M+H]

[0217] (2) Preparation of ethyl 3-(2,5-dichlorophenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.42 g, 87%) was obtained by the production method of Example 2-(3) using 2,5-dichlorobenzaldehyde oxime (0.32 g, 1.68 mmol) obtained in (1) above. MS (m / z): 288[M+H]

[0218] (3) Preparation of 3-(2,5-dichlorophenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.37 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 3-(2,5-dichlorophenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.42 g, 1.46 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 260[M+H]

[0219] (4) Preparation of 3-(2,5-dichlorophenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.16 g, 82%) was obtained by the production method of Example 1-(3) using 3-(2,5-dichlorophenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.1 g, 0.38 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 507[M+H]

[0220] (5) Preparation of ((1R)-1-(3-(2,5-dichlorophenyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.1 g, 85%) was obtained by the production method of Example 1-(4) using 3-(2,5-dichlorophenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.16 g, 0.32 mmol) obtained in (4) above. 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) MS (m / z): 373[M+H], 355[M-OH]

[0221] Example 4: Preparation of ((1R)-1-(5-ethyl-3-phenyl-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), and (4).

[0222] (1) Preparation of ethyl 5-ethyl-3-phenyl-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] Using N-hydroxybenzenecarbonimidoyl chloride (0.71 g, 4.6 mmol) and 2-methylene-butyric acid ethyl ester (1.19 g, 9.28 mmol), the title compound (0.91 g, 80%) was obtained according to the production method of Example 1-(1). MS (m / z): 248[M+H]

[0223] (2) Preparation of 5-ethyl-3-phenyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.81 g, quant.) was obtained by the production method of Example 1-(2) using ethyl 5-ethyl-3-phenyl-4,5-dihydro-1,2-oxazole-5-carboxylate (0.91 g, 3.7 mmol) obtained in (1) above and the production method of Example 1-(2). MS (m / z): 220[M+H]

[0224] (3) Preparation of 5-ethyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-phenyl-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.21 g, 79%) was obtained by the production method of Example 1-(3) using 5-ethyl-3-phenyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.12 g, 0.57 mmol) obtained in (2) above and the production method of Example 1-(3). MS (m / z): 467[M+H]

[0225] (4) Preparation of ((1R)-1-(5-ethyl-3-phenyl-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.025 g, 57%) was obtained by the production method of Example 1-(4) using 5-ethyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-phenyl-4,5-dihydroisoxazole-5-carboxamide (0.062 g, 0.13 mmol) obtained in (3) above, according to the method of Example 1-(4). MS (m / z): 333[M+H], 315[M-OH]

[0226] Example 5: Preparation of ((1R)-3-methyl-1-(5-methyl-3-phenyl-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), and (4).

[0227] (1) Preparation of ethyl 5-methyl-3-phenyl-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (1.0 g, 78%) was obtained by the preparation method of Example 2-(3) using N-hydroxybenzenecarbonimidoyl chloride (0.89 g, 5.7 mmol) and 2-methylene-butyric acid ethyl ester (1.3 g, 11.5 mmol). MS (m / z): 234[M+H]

[0228] (2) Preparation of 5-methyl-3-phenyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.83 g, 91%) was obtained by the production method of Example 1-(2) using ethyl 5-methyl-3-phenyl-4,5-dihydro-1,2-oxazole-5-carboxylate (1.0 g, 4.45 mmol) obtained in (1) above and the production method of Example 1-(2). MS (m / z): 206[M+H]

[0229] (3) Preparation of 5-methyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-phenyl-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.19 g, 89%) was obtained by the production method of Example 1-(3) using 5-methyl-3-phenyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.099 g, 0.48 mmol) obtained in (2) above and the production method of Example 1-(3). MS (m / z): 453[M+H]

[0230] (4) Preparation of ((1R)-3-methyl-1-(5-methyl-3-phenyl-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.071 g, 52%) was obtained by the production method of Example 1-(4) using 5-methyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-phenyl-4,5-dihydroisoxazole-5-carboxamide (0.19 g, 0.43 mmol) obtained in (3) above, according to the method of Example 1-(4). MS (m / z): 319[M+H], 301[M-OH]

[0231] Example 6: Preparation of ((1R)-1-(5-ethyl-3-(pyrazin-2-yl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), and (4).

[0232] (1) Preparation of ethyl 5-ethyl-3-(pyrazin-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.16 g, 56%) was obtained by the production method of Example 2-(3) using pyrazine-2-carbaldehyde oxime (0.15 g, 1.22 mmol) obtained in Example 2-(2) and 2-methylene-butyric acid ethyl ester (0.19 g, 1.11 mmol). 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) MS (m / z): 250[M+H]

[0233] (2) Preparation of 5-ethyl-3-(pyrazin-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.14 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 5-ethyl-3-(pyrazin-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.16 g, 0.62 mmol) obtained in (1) above and the production method of Example 1-(2). MS (m / z): 222[M+H]

[0234] (3): Preparation of 5-ethyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(pyrazin-2-yl)-4,5-dihydroisoxazole-5-carboxamide [ka]

[0235] The title compound (0.23 g, 76%) was obtained by the production method of Example 1-(3) using 5-ethyl-3-(pyrazin-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.14 g, 0.63 mmol) obtained in Example 6-(2). MS (m / z): 469[M+H]

[0236] (4): Preparation of ((1R)-1-(5-ethyl-3-(pyrazin-2-yl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.098 g, 60%) was obtained by the production method of Example 1-(4) using 5-ethyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(pyrazin-2-yl)-4,5-dihydroisoxazole-5-carboxamide (0.23 g, 0.49 mmol) obtained in Example 6-(3). 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) MS (m / z): 335[M+H], 317[M-OH]

[0237] Example 7: Preparation of ((R)-1-((S)-5-benzyl-3-phenyl-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2) and (3).

[0238] (1) Preparation of methyl 5-benzyl-3-phenyl-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] N-Hydroxybenzenecarbonimidoyl chloride (0.58 g, 3.7 mmol) was dissolved in tetrahydrofuran (10 mL), and 2-benzylacrylic 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 while raising the temperature to room temperature, 10 mL of 1N hydrochloric acid solution was added and stirred for 10 minutes. After distilling the tetrahydrofuran solvent under reduced pressure, the aqueous layer was extracted twice with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.12 g, 13%). 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) MS (m / z): 296[M+H]

[0239] (2) Preparation of 5-benzyl-3-phenyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.12 g, quant.) was obtained by the production method of Example 1-(2) using methyl 5-benzyl-3-phenyl-4,5-dihydro-1,2-oxazole-5-carboxylate (0.126 g, 0.43 mmol) obtained in (1) above and the production method of Example 1-(2). MS (m / z): 282[M+H]

[0240] (3) Preparation of ((R)-1-((S)-5-benzyl-3-phenyl-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] 5-Benzyl-3-phenyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.12 g, 0.41 mmol) obtained in (2) above, (R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butan-1-amine hydrochloride (0.14 g, 0.45 mmol), and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.14 g, 0.45 mmol) were dissolved in dimethylformamide (5 mL) at 0°C. Diisopropylethylamine (0.21 mL, 1.3 mmol) was slowly added while maintaining the temperature, and the mixture was stirred for 18 hours while warming to room temperature. The solvent was distilled under reduced pressure, and aqueous sodium bicarbonate was added. The mixture was extracted twice with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to give 5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-phenyl-4,5-dihydroisoxazole-5-carboxamide. This 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 1N aqueous hydrochloric acid 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 further extracted once with methanol (3 mL), and the entire methanol layer was distilled under reduced pressure. Ethyl acetate was added, washed sequentially with aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give two title compounds: the less polar isomer 1 (0.060 g, 37%, two steps) and the more polar isomer 2 (0.070 g, 44%, two steps). Isomer 1 MS (m / z): 395[M+H], 377[M-OH] Isomer 2 MS (m / z): 395[M+H], 377[M-OH]

[0241] Example 8: Preparation of ((1R)-1-(3-benzyl-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0242] (1) Preparation of phenylacetaldehyde oxime [ka] Using phenylacetaldehyde (1.0 g, 8.3 mmol), the title compound (1.11 g, 99%) was obtained according to the production method of Example 3-(1).

[0243] (2) Preparation of ethyl 3-benzyl-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (1.09 g, 57%) was obtained by the production method of Example 2-(3) using phenyl-acetaldehyde oxime (1.11 g, 8.2 mmol) obtained in (1) above. MS (m / z): 234[M+H]

[0244] (3) Preparation of 3-benzyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.96 g, quant.) was obtained by the production method of Example 1-(2) using ethyl 3-benzyl-4,5-dihydro-1,2-oxazole-5-carboxylate (1.09 g, 4.7 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 206[M+H]

[0245] (4) Preparation of 3-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.586 g, 28%) was obtained by the production method of Example 1-(3) using 3-benzyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.96 g, 4.7 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 453[M+H]

[0246] (5) Preparation of ((1R)-1-(3-benzyl-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.031 g, 36%) was obtained by the production method of Example 1-(4) using 3-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.122 g, 0.27 mmol) obtained in (4) above, according to the method of Example 1-(4). MS (m / z): 319[M+H], 301[M-OH]

[0247] Example 9: Preparation of ((1R)-1-(3-cyclohexyl-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0248] (1) Preparation of cyclohexanecarbaldehyde oxime [ka] The title compound (1.38 g, 88%) was obtained using cyclohexanecarbaldehyde (1.5 ml, 12.4 mmol) according to the production method of Example 3-(1).

[0249] (2) Preparation of ethyl 3-cyclohexyl-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (1.17 g, 48%) was obtained by the method of Preparation Example 1-(2) using cyclohexanecarbaldehyde oxime (1.38 g, 10.9 mmol) obtained in (1) above. MS (m / z): 226[M+H]

[0250] (3) Preparation of 3-cyclohexyl-4,5-dihydroisoxazole-5-carboxylic acid [ka] The title compound (1.02 g, quant.) was obtained by the production method of Example 1-(2) using ethyl 3-cyclohexyl-4,5-dihydroisoxazole-5-carboxylate (1.17 g, 5.2 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 198[M+H]

[0251] (4) Preparation of 3-cyclohexyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.26 g, 81%) was obtained by the production method of Example 1-(3) using 3-cyclohexyl-4,5-dihydroisoxazole-5-carboxylic acid (0.14 g, 0.72 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 445[M+H]

[0252] (5) Preparation of ((1R)-1-(3-cyclohexyl-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.11 g, 62%) was obtained by the production method of Example 1-(4) using 3-cyclohexyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.26 g, 0.58 mmol) obtained in (4) above, according to the method of Example 1-(4). MS (m / z): 311[M+H], 293[M-OH]

[0253] Example 10: Preparation of ((1R)-1-(3-cyclopropyl-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0254] (1) Preparation of cyclopropanecarbaldehyde oxime [ka] The title compound (0.37 g, 61%) was obtained using cyclopropanecarbaldehyde (0.5 g, 7.13 mmol) according to the method of Preparation Example 6-(1). 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)

[0255] (2) Preparation of ethyl 3-cyclopropyl-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.33 g, 41%) was obtained by the production method of Example 2-(3) using cyclopropanecarbaldehyde oxime (0.37 g, 4.35 mmol) obtained in (1) above. 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) MS (m / z): 184[M+H]

[0256] (3) Preparation of 3-cyclopropyl-4,5-dihydroisoxazole-5-carboxylic acid [ka] The title compound (0.25 g, 90%) was obtained by the production method of Example 1-(2) using ethyl 3-cyclopropyl-4,5-dihydroisoxazole-5-carboxylate (0.33 g, 1.80 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 156[M+H]

[0257] (4) Preparation of 3-cyclopropyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.13 g, 72%) was obtained by the production method of Example 1-(3) using 3-cyclopropyl-4,5-dihydroisoxazole-5-carboxylic acid (0.07 g, 0.45 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 403[M+H]

[0258] (5) Preparation of ((1R)-1-(3-cyclopropyl-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.07 g, 81%) was obtained by the production method of Example 1-(4) using 3-cyclopropyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.13 g, 0.32 mmol) obtained in (4) above, according to the method of Example 1-(4). NMR: 1 H-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) MS (m / z): 269[M+H], 251[M-OH]

[0259] Example 11: Preparation of ((1R)-3-methyl-1-(3-phenethyl-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0260] (1) Preparation of 3-phenyl-propionaldehyde oxime [ka] The title compound (0.55 g, 99%) was obtained using 3-phenyl-propionaldehyde (0.5 g, 3.7 mmol) according to the production method of Example 3-(1).

[0261] (2) Preparation of ethyl 3-(2-phenylethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.45 g, 49%) was obtained by the production method of Example 2-(3) using 3-phenyl-propionaldehyde oxime (0.55 g, 3.7 mmol) obtained in the above Example 11-(1). MS (m / z): 248[M+H]

[0262] (3) Preparation of 3-(2-phenylethyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.39 g, 98%) was obtained by the production method of Example 1-(2) using ethyl 3-(2-phenylethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.45 g, 1.8 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 220[M+H]

[0263] (4) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-phenethyl-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.16 g, 19%) was obtained by the production method of Example 1-(3) using 3-(2-phenylethyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.39 g, 1.8 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 467[M+H]

[0264] (5) Preparation of ((1R)-3-methyl-1-(3-phenethyl-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.045 g, 37%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-phenethyl-4,5-dihydroisoxazole-5-carboxamide (0.16 g, 0.34 mmol) obtained in (4) above. MS (m / z): 333[M+H], 315[M+H]

[0265] Example 12: Preparation of ((1R)-1-(3-(isoquinolin-1-yl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0266] (1) Preparation of isoquinoline-1-carbaldehyde oxime [ka] The title compound was obtained by the method described in WO200521516A1.

[0267] (2) Preparation of ethyl 3-(isoquinolin-1-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] Using isoquinoline-1-carbaldehyde oxime (0.52 g, 3.0 mmol) obtained in (1) above and ethyl acrylate (0.39 g, 3.9 mmol), the title compound (0.74 g, 91%) was obtained according to the production method of Example 2-(3). 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) MS (m / z): 271[M+H]

[0268] (3) Preparation of 3-(isoquinolin-1-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.66 g, quant.) was obtained by the production method of Example 1-(2) using ethyl 3-(isoquinolin-1-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.74 g, 2.7 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 243[M+H]

[0269] (4) Preparation of 3-(isoquinolin-1-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.13 g, 81%) was obtained by the production method of Example 1-(3) using 3-(isoquinolin-1-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.08 g, 0.33 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 490[M+H]

[0270] (5) Preparation of ((1R)-1-(3-(isoquinolin-1-yl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.045 g, 47%) was obtained by the production method of Example 1-(4) using 3-(isoquinolin-1-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.13 g, 0.27 mmol) obtained in (4) above, according to the method of Example 1-(4). MS (m / z): 356[M+H], 338[M+H]

[0271] Example 13: Preparation of ((R)-1-((R)-5-isopropyl-3-(isoquinolin-1-yl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0272] (1) Preparation of 3-(isoquinolin-1-yl)-5-(propan-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound was obtained by the method described in WO2005021516A1.

[0273] (2) Preparation of 5-isopropyl-3-(isoquinolin-1-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] Using (R)-5-isopropyl-3-isoquinolin-1-yl-4,5-dihydro-isoxazole-5-carboxylic acid (0.073 g, 0.14 mmol) obtained in (1) above, the title compound (0.075 g, 61%) was obtained according to the production method of Example 1-(3). MS (m / z): 490[M+H]

[0274] (3) Preparation of ((R)-1-((R)-5-isopropyl-3-(isoquinolin-1-yl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.035 g, 63%) was obtained by the production method of Example 1-(4) using 5-isopropyl-3-(isoquinolin-1-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.074 g, 0.14 mmol) obtained in (2) above, according to the method of Example 1-(4). 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) MS (m / z): 398[M+H], 380[M-OH]

[0275] Example 14: Preparation of ((1R)-1-(3-(3-(tert-butyl)phenyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0276] (1) Preparation of 3-tert-butyl-benzaldehyde oxime [ka] The title compound (0.54 g, 99%) was obtained using 3-tert-butyl-benzaldehyde (0.5 g, 3.08 mmol) according to the production method of Example 3-(1).

[0277] (2) Preparation of ethyl 3-(3-tert-butylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.41 g, 98%) was obtained by the production method of Example 2-(3) using 3-tert-butyl-benzaldehyde oxime (0.27 g, 1.52 mmol) obtained in (1) above. MS (m / z): 276[M+H]

[0278] (3) Preparation of 3-(3-tert-butylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.37 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 3-(3-tert-butylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.41 g, 1.49 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 248[M+H]

[0279] (4) Preparation of 3-(3-(tert-butyl)phenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.13 g, 66%) was obtained by the production method of Example 1-(3) using 3-(3-tert-butylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.1 g, 0.40 mmol) obtained in Example 14-(3). MS (m / z): 495[M+H]

[0280] (5) Preparation of ((1R)-1-(3-(3-(tert-butyl)phenyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.06 g, 63%) was obtained by the production method of Example 1-(4) using 3-(3-(tert-butyl)phenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.13 g, 0.27 mmol) obtained in (4) above, according to the method of Example 1-(4). NMR: 1 H-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) MS (m / z): 361[M+H], 343[M-OH]

[0281] Example 15: Preparation of ((1R)-1-(3-(4-(tert-butyl)phenyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0282] (1) Preparation of 4-tert-butyl-benzaldehyde oxime [ka] The title compound (0.46 g, quant.) was obtained using 4-tert-butyl-benzaldehyde (0.42 g, 2.6 mmol) according to the production method of Example 3-(1).

[0283] (2) Preparation of ethyl 3-(4-tert-butylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.12 g, 17%) was obtained by the production method of Example 2-(3) using 4-tert-butyl-benzaldehyde oxime (0.46 g, 2.6 mmol) obtained in (1) above. MS (m / z): 276[M+H]

[0284] (3) Preparation of 3-(4-tert-butylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.11 g, quant.) was obtained by the production method of Example 1-(2) using ethyl 3-(4-tert-butylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.12 g, 0.44 mmol) obtained in (2) above, according to the production method of Example 1-(2). MS (m / z): 248[M+H]

[0285] (4) Preparation of 3-(4-(tert-butyl)phenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.15 g, 68%) was obtained by the production method of Example 1-(3) using 3-(4-tert-butylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.11 g, 0.44 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 495[M+H]

[0286] (5) Preparation of ((1R)-1-(3-(4-(tert-butyl)phenyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.047 g, 44%) was obtained by the production method of Example 1-(4) using 3-(4-(tert-butyl)phenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.15 g, 0.30 mmol) obtained in (4) above, according to the method of Example 1-(4). MS (m / z): 361[M+H], 343[M-OH]

[0287] Example 16: Preparation of ((1R)-1-(3-(4-acetamidophenyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0288] (1) Preparation of N-(4-formyl-phenyl)-acetamidoxime [ka] The title compound (0.99 g, quant.) was obtained using N-(4-formyl-phenyl)-acetamide (0.90 g, 5.5 mmol) according to the production method of Example 3-(1). MS (m / z): 179[M+H]

[0289] (2) Preparation of ethyl 3-(4-acetamidophenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.69 g, 45%) was obtained by the production method of Example 2-(3) using N-(4-formyl-phenyl)-acetamide oxime (0.99 g, 5.5 mmol) obtained in (1) above and the production method of Example 2-(3). MS (m / z): 277[M+H]

[0290] (3) Preparation of 3-(4-acetamidophenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.12 g, quant.) was obtained by the production method of Example 1-(2) using ethyl 3-(4-acetamidophenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.13 g, 0.46 mmol) obtained in (2) above, according to the production method of Example 1-(2). MS (m / z): 249[M+H]

[0291] (4) Preparation of 3-(4-acetamidophenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.05 g, 22%) was obtained by the production method of Example 1-(3) using 3-(4-acetamidophenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.11 g, 0.46 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 496[M+H]

[0292] (5) Preparation of ((1R)-1-(3-(4-acetamidophenyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.022 g, 59%) was obtained by the production method of Example 1-(4) using 3-(4-acetamidophenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.050 g, 0.1 mmol) obtained in (4) above, according to the method of Example 1-(4). MS (m / z): 362[M+H], 344[M-OH]

[0293] Example 17: Preparation of ((1R)-3-methyl-1-(3-(naphthalen-2-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0294] (1) Production of naphthalene-2-carbaldehyde oxime [ka] The title compound (1.70 g, 99%) was obtained using naphthalene-2-carbaldehyde (1.56 g, 9.99 mmol) according to the production method of Example 3-(1).

[0295] (2) Preparation of ethyl 3-(naphthalen-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.60 g, 95%) was obtained by the production method of Example 2-(3) using naphthalene-2-carbaldehyde oxime (0.40 g, 2.3 mmol) obtained in (1) above. NMR: 1H-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) MS (m / z): 270[M+H]

[0296] (3) Preparation of 3-(naphthalen-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] Using ethyl 3-(naphthalen-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.60 g, 2.2 mmol) obtained in (2) above, the title compound (0.53 g, 99%) was obtained according to the production method of Example 1-(2). MS (m / z): 242[M+H]

[0297] (4) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(naphthalen-2-yl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.185 g, 91%) was obtained by the production method of Example 1-(3) using 3-(naphthalen-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.10 g, 0.41 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 489[M+H]

[0298] (5) Preparation of ((1R)-3-methyl-1-(3-(naphthalen-2-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.083 g, 62%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(naphthalen-2-yl)-4,5-dihydroisoxazole-5-carboxamide (0.184 g, 0.38 mmol) obtained in (4) above. 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) MS (m / z): 355[M+H], 337[M-OH]

[0299] Example 18: Preparation of ((1R)-3-methyl-1-(3-(naphthalen-2-ylmethyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0300] (1) Preparation of naphthalen-2-yl-acetaldehyde oxime [ka] The title compound (0.24 g, quant.) was obtained using naphthalen-2-yl-acetaldehyde (0.22 g, 1.3 mmol) according to the production method of Example 3-(1).

[0301] (2) Preparation of ethyl 3-[(naphthalen-2-yl)methyl]-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.081 g, 22%) was obtained by the production method of Example 2-(3) using naphthalen-2-yl-acetaldehyde oxime (0.24 g, 1.3 mmol) obtained in (1) above. MS (m / z): 284 [M+H]

[0302] (3) Preparation of 3-[(naphthalen-2-yl)methyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.073 g, quant.) was obtained by the production method of Example 1-(2) using ethyl 3-[(naphthalen-2-yl)methyl]-4,5-dihydro-1,2-oxazole-5-carboxylate (0.081 g, 0.29 mmol) obtained in (2) above, according to the production method of Example 1-(2). MS (m / z): 256 [M+H]

[0303] (4) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(naphthalen-2-ylmethyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.038 g, 26%) was obtained by the production method of Example 1-(3) using 3-[(naphthalen-2-yl)methyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.073 g, 0.29 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 503 [M+H]

[0304] (5) Preparation of ((1R)-3-methyl-1-(3-(naphthalen-2-ylmethyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.008 g, 30%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(naphthalen-2-ylmethyl)-4,5-dihydroisoxazole-5-carboxamide (0.038 g, 0.08 mmol) obtained in (4) above. MS (m / z): 369 [M+H], 351 [M-OH]

[0305] Example 19: Preparation of ((1R)-3-methyl-1-(3-(naphthalen-1-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0306] (1) Production of naphthalene-1-carbaldehyde oxime [ka] The title compound (1.71 g, 99%) was obtained using naphthalene-1-carbaldehyde (1.56 g, 9.99 mmol) according to the production method of Example 3-(1). MS (m / z): 172[M+H]

[0307] (2) Preparation of ethyl 3-(naphthalen-1-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.53 g, 85%) was obtained by the production method of Example 2-(3) using naphthalene-1-carbaldehyde oxime (0.4 g, 2.34 mmol) obtained in (1) above. MS (m / z): 270[M+H]

[0308] (3) Preparation of 3-(naphthalen-1-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.47 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 3-(naphthalen-1-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.53 g, 1.98 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 242[M+H]

[0309] (4) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(naphthalen-1-yl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.15 g, 70%) was obtained by the production method of Example 1-(3) using 3-(naphthalen-1-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.1 g, 0.41 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 517[M+H]

[0310] (5) Preparation of ((1R)-3-methyl-1-(3-(naphthalen-1-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.07 g, 70%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(naphthalen-1-yl)-4,5-dihydroisoxazole-5-carboxamide (0.15 g, 0.29 mmol) obtained in (4) above. 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) MS (m / z): 355[M+H]

[0311] Example 20: Preparation of ((1R)-1-(3-([1,1'-biphenyl]-3-yl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0312] (1) Preparation of biphenyl-3-carbaldehyde oxime [ka] The title compound (0.54 g, 99%) was obtained using biphenyl-3-carbaldehyde (0.5 g, 2.74 mmol) according to the production method of Example 3-(1). MS (m / z): 198[M+H]

[0313] (2) Preparation of ethyl 3-(3-phenylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.26 g, 87%) was obtained by the production method of Example 2-(3) using biphenyl-3-carbaldehyde oxime (0.2 g, 1.01 mmol) obtained in (1) above. NMR: 1 H-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) MS (m / z): 296[M+H]

[0314] (3) Preparation of 3-(3-phenylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.23 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 3-(3-phenylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.26 g, 0.88 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 268[M+H]

[0315] (4) Preparation of 3-([1,1'-biphenyl]-3-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.17 g, 88%) was obtained by the production method of Example 1-(3) using 3-(3-phenylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.1 g, 0.37 mmol) obtained in Example 20-(3). MS (m / z): 515[M+H]

[0316] (5) Preparation of ((1R)-1-(3-([1,1'-biphenyl]-3-yl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.089 g, 71%) was obtained by the production method of Example 1-(4) using 3-([1,1'-biphenyl]-3-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.17 g, 0.33 mmol) obtained in (4) above. 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) MS (m / z): 381[M+H]

[0317] Example 21: Preparation of ((1R)-3-methyl-1-(3-(quinolin-2-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0318] (1) Preparation of quinoline-2-carbaldehyde oxime [ka] The title compound (1.72 g, quant.) was obtained using quinoline-2-carbaldehyde (1.57 g, 10.0 mmol) according to the production method of Example 3-(1).

[0319] (2) Preparation of ethyl 3-(quinolin-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.49 g, 78%) was obtained by the production method of Example 2-(3) using quinoline-2-carbaldehyde oxime (0.40 g, 2.3 mmol) obtained in (1) above and the production method of Example 2-(3). MS (m / z): 271[M+H]

[0320] (3) Preparation of 3-(quinolin-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.39 g, 89%) was obtained by the production method of Example 1-(2) using ethyl 3-(quinolin-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.49 g, 1.8 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 243[M+H]

[0321] (4) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(quinolin-2-yl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.13 g, 82%) was obtained by the production method of Example 1-(3) using 3-(quinolin-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.08 g, 0.33 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 490[M+H]

[0322] (5) Preparation of ((1R)-3-methyl-1-(3-(quinolin-2-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.045 g, 47%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(quinolin-2-yl)-4,5-dihydroisoxazole-5-carboxamide (0.13 g, 0.27 mmol) obtained in (4) above. MS (m / z): 356[M+H]

[0323] Example 22: Preparation of ((1R)-1-(3-(isoquinolin-3-yl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0324] (1) Preparation of isoquinoline-3-carbaldehyde oxime [ka] Using isoquinoline-3-carbaldehyde (0.36 g, 2.3 mmol), the title compound (0.39 g, 99%) was obtained according to the production method of Example 3-(1). MS (m / z): 173[M+H]

[0325] (2) Preparation of ethyl 3-(isoquinolin-3-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.38 g, 62%) was obtained by the production method of Example 2-(3) using isoquinoline-3-carbaldehyde oxime (0.39 g, 2.3 mmol) obtained in (1) above and the production method of Example 2-(3). MS (m / z): 271[M+H]

[0326] (3) Preparation of 3-(isoquinolin-3-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.34 g, quant.) was obtained by the production method of Example 1-(2) using ethyl 3-(isoquinolin-3-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.38 g, 1.41 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 243[M+H]

[0327] (4) Preparation of 3-(isoquinolin-3-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.09 g, 56%) was obtained by the production method of Example 1-(3) using 3-(isoquinolin-3-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.08 g, 0.33 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 490[M+H]

[0328] (5) Preparation of ((1R)-1-(3-(isoquinolin-3-yl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] Using 3-(isoquinolin-3-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.09 g, 0.18 mmol) obtained in (4) above, the title compound (0.043 g, 66%) was obtained according to the production method of Example 1-(4). MS (m / z): 356[M+H]

[0329] Example 23: Preparation of ((1R)-3-methyl-1-(3-(quinolin-4-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0330] (1) Preparation of quinoline-4-carbaldehyde oxime [ka] The title compound (0.82 g, 99%) was obtained using quinoline-4-carbaldehyde (0.76 g, 4.8 mmol) according to the production method of Example 3-(1).

[0331] (2) Preparation of ethyl 3-(quinolin-4-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.87 g, 67%) was obtained by the production method of Example 2-(3) using quinoline-4-carbaldehyde oxime (0.82 g, 4.8 mmol) obtained in (1) above and the production method of Example 2-(3). MS (m / z): 271[M+H]

[0332] (3) Preparation of 3-(quinolin-4-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.77 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 3-(quinolin-4-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.87 g, 3.2 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 243[M+H]

[0333] (4) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(quinolin-4-yl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.092 g, 50%) was obtained by the production method of Example 1-(3) using 3-(quinolin-4-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.091 g, 0.37 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 490[M+H]

[0334] (5) Preparation of ((1R)-3-methyl-1-(3-(quinolin-4-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.062 g, 93%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(quinolin-4-yl)-4,5-dihydroisoxazole-5-carboxamide (0.092 g, 0.19 mmol) obtained in (4) above. MS (m / z): 356[M+H]

[0335] Example 24: Preparation of ((R)-1-((S)-5-benzyl-3-(3-(tert-butyl)phenyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), and (4).

[0336] (1) Preparation of methyl 5-benzyl-3-(3-tert-butylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.37 g, 93%) was obtained by the preparation method of Example 2-(3) using 3-tert-butyl-benzaldehyde oxime (0.2 g, 1.13 mmol) obtained in Example 14-(1) and methyl 2-benzyl acrylate (0.37 g, 1.24 mmol) obtained in Preparation Example 6-(1). 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) MS (m / z): 352[M+H]

[0337] (2) Preparation of 5-benzyl-3-(3-tert-butylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.35 g, 99%) was obtained by the production method of Example 1-(2) using methyl 5-benzyl-3-(3-tert-butylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.37 g, 1.05 mmol) obtained in Example 24-(1). MS (m / z): 338[M+H]

[0338] (3) 5-benzyl-3-(3-tert-butylphenyl)-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0 2,6 ]decan-4-yl]butyl]-4,5-dihydro-1,2-oxazole-5-carboxamide [ka] The title compound (0.1 g, 58%) was obtained by the production method of Example 1-(3) using 5-benzyl-3-(3-tert-butylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.1 g, 0.30 mmol) obtained in (2) above and the production method of Example 1-(3). MS (m / z): 585[M+H], 433[MC 10 H 15 O]

[0339] (4) Preparation of ((R)-1-((S)-5-benzyl-3-(3-(tert-butyl)phenyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] 5-benzyl-3-(3-tert-butylphenyl)-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0 2,6 Using ]decan-4-yl]butyl]-4,5-dihydro-1,2-oxazole-5-carboxamide (0.05 g, 0.086 mmol), the title compound (0.03 g, 80%) was obtained according to the preparation method of Example 1-(4). 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) MS (m / z): 451[M+H], 433[M-OH]

[0340] Example 25: Preparation of ((1R)-3-methyl-1-(3-(6-phenylpyridin-2-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), (5), and (6).

[0341] (1) Preparation of 6-phenyl-pyridine-2-carbaldehyde [ka] The title compound was obtained by the method described in WO200982573A1.

[0342] (2) Preparation of 6-phenyl-pyridine-2-carbaldehyde oxime [ka] The title compound (0.36 g, 98%) was obtained by the production method of Example 3-(1) using 6-phenyl-pyridine-2-carbaldehyde (0.34 g, 1.86 mmol) obtained in (1) above and the production method of Example 3-(1).

[0343] (3) Preparation of ethyl 3-(6-phenylpyridin-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] Using 6-phenyl-pyridine-2-carbaldehyde oxime (0.36 g, 1.82 mmol) obtained in (2) above, the title compound (0.53 g, 99%) was obtained according to the production method of Example 2-(3). MS (m / z): 297[M+H]

[0344] (4) Preparation of 3-(6-phenylpyridin-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.48 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 3-(6-phenylpyridin-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.53 g, 1.79 mmol) obtained in (3) above and the production method of Example 1-(2). MS (m / z): 269[M+H]

[0345] (5) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(6-phenylpyridin-2-yl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.06 g, 52%) was obtained by the production method of Example 1-(3) using 3-(6-phenylpyridin-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.06 g, 0.22 mmol) obtained in (4) above and the production method of Example 1-(3). MS (m / z): 517[M+H]

[0346] (6) Preparation of ((1R)-3-methyl-1-(3-(6-phenylpyridin-2-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.03 g, 68%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(6-phenylpyridin-2-yl)-4,5-dihydroisoxazole-5-carboxamide (0.06 g, 0.12 mmol) obtained in Example 25-(5). 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) MS (m / z): 382[M+H], 365[M-OH]

[0347] Example 26: Preparation of ((1R)-3-methyl-1-(3-(4-(pyridin-2-yl)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), (5), and (6).

[0348] (1) Preparation of 4-pyridin-2-yl-benzaldehyde [ka] The title compound was obtained by the method described in European Journal of Organic Chemistry, 2008, #12, pp. 2049-2055.

[0349] (2) Preparation of 4-pyridin-2-yl-benzaldehyde oxime [ka] The title compound (0.39 g, 99%) was obtained by the production method of Example 3-(1) using 4-pyridin-2-yl-benzaldehyde (0.36 g, 1.97 mmol) obtained in (1) above and the production method of Example 3-(1). MS (m / z): 199[M+H]

[0350] (3) Preparation of ethyl 3-[4-(pyridin-2-yl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.42 g, 72%) was obtained by the production method of Example 2-(3) using 4-pyridin-2-yl-benzaldehyde oxime (0.39 g, 1.97 mmol) obtained in (2) above. MS (m / z): 297[M+H]

[0351] (4) Preparation of 3-[4-(pyridin-2-yl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.38 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 3-[4-(pyridin-2-yl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate (0.42 g, 1.41 mmol) obtained in (3) above and the production method of Example 1-(2). MS (m / z): 269[M+H]

[0352] (5) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(4-(pyridin-2-yl)phenyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.13 g, 56%) was obtained by the production method of Example 1-(3) using 3-[4-(pyridin-2-yl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.12 g, 0.45 mmol) obtained in (4) above and the production method of Example 1-(3). MS (m / z): 516[M+H], 364[MC 10 H 15 O]

[0353] (6) Preparation of ((1R)-3-methyl-1-(3-(4-(pyridin-2-yl)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.06 g, 62%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(4-(pyridin-2-yl)phenyl)-4,5-dihydroisoxazole-5-carboxamide (0.13 g, 0.25 mmol) obtained in (5) above, according to the method of Example 1-(4). NMR:1 H-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) MS (m / z): 382[M+H], 364[M-OH]

[0354] Example 27: Preparation of ((1R)-1-(3-([1,1'-biphenyl]-4-yl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0355] (1) Production of biphenyl-4-carbaldehyde oxime [ka] The title compound (0.55 g, quant.) was obtained using biphenyl-4-carbaldehyde (0.51 g, 2.8 mmol) according to the production method of Production Example 6-(1) in Example 3-(1).

[0356] (2) Preparation of ethyl 3-(4-phenylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.62 g, 75%) was obtained by the production method of Example 2-(3) using biphenyl-4-carbaldehyde oxime (0.55 g, 2.8 mmol) obtained in (1) above. MS (m / z): 297[M+H]

[0357] (3) Preparation of 3-(4-phenylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] Using ethyl 3-(4-phenylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.62 g, 2.1 mmol) obtained in (2) above, the title compound (0.43 g, 78%) was obtained according to the production method of Example 1-(2). MS (m / z): 269[M+H]

[0358] (4) Preparation of 3-([1,1'-biphenyl]-4-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.11 g, 68%) was obtained by the production method of Example 1-(3) using 3-(4-phenylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.083 g, 0.31 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 516[M+H]

[0359] (5) Preparation of ((1R)-1-(3-([1,1'-biphenyl]-4-yl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.041 g, 50%) was obtained by the production method of Example 1-(4) using 3-([1,1'-biphenyl]-4-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.11 g, 0.21 mmol) obtained in (4) above. MS (m / z): 381[M+H], 363[M-OH]

[0360] Example 28: Preparation of ((1R)-1-(3-(5-(3-fluorophenyl)pyridin-2-yl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), (5), and (6).

[0361] (1) Preparation of 5-(3-fluoro-phenyl)-pyridine-2-carbaldehyde [ka] The title compound was obtained by the method described in US2013 / 40981A1.

[0362] (2) Preparation of 5-(3-fluoro-phenyl)-pyridine-2-carbaldehyde oxime [ka] The title compound (0.17 g, 98%) was obtained by the production method of Example 3-(1) using 5-(3-fluoro-phenyl)-pyridine-2-carbaldehyde (0.16 g, 0.80 mmol) obtained in (1) above and the production method of Example 3-(1). MS (m / z): 217[M+H]

[0363] (3) Preparation of ethyl 3-[5-(3-fluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] Using 5-(3-fluoro-phenyl)-pyridine-2-carbaldehyde oxime (0.17 g, 0.80 mmol) obtained in (2) above, the title compound (0.16 g, 64%) was obtained according to the production method of Example 2-(3). NMR: 1 H-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) MS (m / z): 315[M+H]

[0364] (4) Preparation of 3-[5-(3-fluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.14 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 3-[5-(3-fluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazole-5-carboxylate (0.16 g, 0.51 mmol) obtained in (3) above. MS (m / z): 287[M+H]

[0365] (5) Preparation of 3-(5-(3-fluorophenyl)pyridin-2-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.09 g, 69%) was obtained by the production method of Example 1-(3) using 3-[5-(3-fluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.07 g, 0.24 mmol) obtained in (4) above and the production method of Example 1-(3). MS (m / z): 534[M+H]

[0366] (6) Preparation of ((1R)-1-(3-(5-(3-fluorophenyl)pyridin-2-yl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.045 g, 67%) was obtained by the production method of Example 1-(4) using 3-(5-(3-fluorophenyl)pyridin-2-yl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.09 g, 0.17 mmol) obtained in (5) above, according to the production method of Example 1-(4). 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) MS (m / z): 400[M+H], 382[M-OH]

[0367] Example 29: Preparation of ((1R)-3-methyl-1-(3-(quinolin-3-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0368] (1) Preparation of quinoline-3-carbaldehyde oxime [ka] The title compound (0.48 g, quant.) was obtained using quinoline-3-carbaldehyde (0.44 g, 2.8 mmol) according to the production method of Example 3-(1). MS (m / z): 173[M+H]

[0369] (2) Preparation of ethyl 3-(quinolin-3-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.53 g, 70%) was obtained by the production method of Example 2-(3) using quinoline-3-carbaldehyde oxime (0.48 g, 2.8 mmol) obtained in (1) above and the production method of Example 2-(3). 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) MS (m / z): 271[M+H]

[0370] (3) Preparation of 3-(quinolin-3-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] Using ethyl 3-(quinolin-3-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.53 g, 2.0 mmol) obtained in (2) above, the title compound (0.47 g, 99%) was obtained according to the production method of Example 1-(2). MS (m / z): 243[M+H]

[0371] (4) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(quinolin-3-yl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.099 g, 39%) was obtained by the production method of Example 1-(3) using 3-(quinolin-3-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.13 g, 0.52 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 490[M+H]

[0372] (5) Preparation of ((1R)-3-methyl-1-(3-(quinolin-3-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.039 g, 57%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(quinolin-3-yl)-4,5-dihydroisoxazole-5-carboxamide (0.094 g, 0.19 mmol) obtained in Example 29-(4). MS (m / z): 356[M+H], 338[M-OH]

[0373] Example 30: Preparation of ((1R)-3-methyl-1-(3-(quinolin-6-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0374] (1) Preparation of quinoline-6-carbaldehyde oxime [ka] The title compound (0.60 g, quant.) was obtained using quinoline-6-carbaldehyde (0.55 g, 3.5 mmol) according to the production method of Example 3-(1). MS (m / z): 173[M+H]

[0375] (2) Preparation of ethyl 3-(quinolin-6-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.35 g, 37%) was obtained by the production method of Example 2-(3) using quinoline-6-carbaldehyde oxime (0.60 g, 3.5 mmol) obtained in (1) above and the production method of Example 2-(3). MS (m / z): 271[M+H]

[0376] (3) Preparation of 3-(quinolin-6-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.27 g, 84%) was obtained by the production method of Example 1-(2) using ethyl 3-(quinolin-6-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.35 g, 1.3 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 243[M+H]

[0377] (4) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(quinolin-6-yl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.045 g, 22%) was obtained by the production method of Example 1-(3) using 3-(quinolin-6-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.10 g, 0.42 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 490[M+H]

[0378] (5) Preparation of ((1R)-3-methyl-1-(3-(quinolin-6-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.014 g, 43%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(quinolin-6-yl)-4,5-dihydroisoxazole-5-carboxamide (0.045 g, 0.09 mmol) obtained in (4) above. MS (m / z): 356[M+H], 338[M-OH]

[0379] Example 31: Preparation of ((1R)-3-methyl-1-(3-(4-(pyridin-3-yl)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), (5), and (6).

[0380] (1) Preparation of 4-pyridin-3-yl-benzaldehyde [ka] The title compound was obtained by the method described in Journal of Medicinal Chemistry, 2005, vol. 48, pp. 224-239.

[0381] (2) Preparation of 4-pyridin-3-yl-benzaldehyde oxime [ka] The title compound (0.46 g, 99%) was obtained by the production method of Example 3-(1) using 4-pyridin-3-yl-benzaldehyde (0.43 g, 2.34 mmol) obtained in (1) above and the production method of Example 3-(1). MS (m / z): 199[M+H]

[0382] (3) Preparation of ethyl 3-[4-(pyridin-3-yl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.42 g, 61%) was obtained by the production method of Example 2-(3) using 4-pyridin-3-yl-benzaldehyde oxime (0.46 g, 2.32 mmol) obtained in (2) above. MS (m / z): 297[M+H]

[0383] (4) Preparation of 3-[4-(pyridin-3-yl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.37 g, 98%) was obtained by the production method of Example 1-(2) using ethyl 3-[4-(pyridin-3-yl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate (0.42 g, 1.41 mmol) obtained in (3) above and the production method of Example 1-(2). MS (m / z): 269[M+H]

[0384] (5) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(4-(pyridin-3-yl)phenyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.13 g, 68%) was obtained by the production method of Example 1-(3) using 3-[4-(pyridin-3-yl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.1 g, 0.37 mmol) obtained in (4) above and the production method of Example 1-(3). MS (m / z): 516[M+H]

[0385] (6) Preparation of ((1R)-3-methyl-1-(3-(4-(pyridin-3-yl)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.07 g, 73%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(4-(pyridin-3-yl)phenyl)-4,5-dihydroisoxazole-5-carboxamide (0.13 g, 0.25 mmol) obtained in (5) above, according to the method of Example 1-(4). NMR: 1H-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) MS (m / z): 382[M+H], 364[M-OH]

[0386] Example 32: Preparation of ((1R)-3-methyl-1-(3-(6-phenylpyridin-3-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), (5), and (6).

[0387] (1) Preparation of 6-phenyl-pyridine-3-carbaldehyde [ka] The title compound was obtained by the method described in Journal of Organic Chemistry, 2006, vol. 71, pp. 9589-9594.

[0388] (2) Preparation of 6-phenyl-pyridine-3-carbaldehyde oxime [ka] Using 6-phenyl-pyridine-3-carbaldehyde (0.44 g, 2.40 mmol) obtained in (1) above, the title compound (0.48 g, 99%) was obtained according to the production method of Production Example 6-(1). MS (m / z): 199[M+H]

[0389] (3) Preparation of ethyl 3-(6-phenylpyridin-3-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] Using 6-phenyl-pyridine-3-carbaldehyde oxime (0.48 g, 2.42 mmol) obtained in (2) above, the title compound (0.5 g, 70%) was obtained according to the method of Preparation Example 1-(2). 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) MS (m / z): 297[M+H]

[0390] (4) Preparation of 3-(6-phenylpyridin-3-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.25 g, 92%) was obtained by the production method of Example 1-(2) using ethyl 3-(6-phenylpyridin-3-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.3 g, 1.01 mmol) obtained in (3) above. MS (m / z): 269[M+H]

[0391] (5) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(6-phenylpyridin-3-yl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.13 g, 85%) was obtained by the production method of Example 1-(3) using 3-(6-phenylpyridin-3-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.08 g, 0.30 mmol) obtained in (4) above and the production method of Example 1-(3). MS (m / z): 516[M+H]

[0392] (6) Preparation of ((1R)-3-methyl-1-(3-(6-phenylpyridin-3-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.063 g, 65%) was obtained by the production method of Example 1-(2) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(6-phenylpyridin-3-yl)-4,5-dihydroisoxazole-5-carboxamide (0.13 g, 0.25 mmol) obtained in (5) above, according to the method of Example 1-(2). 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) MS (m / z): 382[M+H], 364[M-OH]

[0393] Example 33: Preparation of ((1R)-3-methyl-1-(3-(5-phenylpyridin-3-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), (5), and (6).

[0394] (1) Preparation of 5-phenyl-pyridine-3-carbaldehyde [ka] The title compound was obtained by the method described in WO200770818A1.

[0395] (2) Preparation of 5-phenyl-pyridine-3-carbaldehyde oxime [ka] The title compound (0.51 g, 99%) was obtained by the production method of Example 3-(1) using 5-phenyl-pyridine-3-carbaldehyde (0.47 g, 2.56 mmol) obtained in (1) above and the production method of Example 3-(1). MS (m / z): 199[M+H]

[0396] (3) Preparation of ethyl 3-(5-phenylpyridin-3-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.57 g, 83%) was obtained by the production method of Example 2-(3) using 5-phenyl-pyridine-3-carbaldehyde oxime (0.51 g, 2.57 mmol) obtained in (2) above and the production method of Example 2-(3). MS (m / z): 297[M+H]

[0397] (4) Preparation of 3-(5-phenylpyridin-3-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.46 g, 89%) was obtained by the production method of Example 1-(2) using ethyl 3-(5-phenylpyridin-3-yl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.57 g, 1.92 mmol) obtained in (3) above and the production method of Example 1-(2). MS (m / z): 269[M+H]

[0398] (5) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(5-phenylpyridin-3-yl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.09 g, 59%) was obtained by the production method of Example 1-(3) using 3-(5-phenylpyridin-3-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.08 g, 0.30 mmol) obtained in (4) above and the production method of Example 1-(3). MS (m / z): 516[M+H]

[0399] (6) Preparation of ((1R)-3-methyl-1-(3-(5-phenylpyridin-3-yl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.054 g, 81%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(5-phenylpyridin-3-yl)-4,5-dihydroisoxazole-5-carboxamide (0.09 g, 0.17 mmol) obtained in (5) above, according to the method of Example 1-(4). 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) MS (m / z): 382[M+H], 364[M-OH]

[0400] Example 34: Preparation of ((1R)-3-methyl-1-(3-(3-(pyridin-2-yl)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), (5), and (6).

[0401] (1) Preparation of 3-pyridin-2-yl-benzaldehyde [ka] The title compound was obtained by the method described in WO20032202772A1.

[0402] (2) Preparation of 3-pyridin-2-yl-benzaldehyde oxime [ka] The title compound (0.55 g, 99%) was obtained by the production method of Example 3-(1) using 3-pyridin-2-yl-benzaldehyde (0.51 g, 2.78 mmol) obtained in (1) above. MS (m / z): 199[M+H]

[0403] (3) Preparation of ethyl 3-[3-(pyridin-2-yl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.58 g, 70%) was obtained by the production method of Example 2-(3) using 3-pyridin-2-yl-benzaldehyde oxime (0.55 g, 2.77 mmol) obtained in (2) above. 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) MS (m / z): 297[M+H]

[0404] (4) Preparation of 3-[3-(pyridin-2-yl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.52 g, 98%) was obtained by the production method of Example 1-(2) using ethyl 3-[3-(pyridin-2-yl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate (0.58 g, 1.95 mmol) obtained in (3) above and the production method of Example 1-(2). MS (m / z): 269[M+H]

[0405] (5) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(3-(pyridin-2-yl)phenyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.04 g, 26%) was obtained by the production method of Example 1-(3) using 3-[3-(pyridin-2-yl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.08 g, 0.30 mmol) obtained in Example 34-(4). MS (m / z): 516[M+H]

[0406] (6) Preparation of ((1R)-3-methyl-1-(3-(3-(pyridin-2-yl)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.021 g, 71%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(3-(pyridin-2-yl)phenyl)-4,5-dihydroisoxazole-5-carboxamide (0.04 g, 0.078 mmol) obtained in (5) above, according to the method of Example 1-(4). 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) MS (m / z): 382[M+H], 364[M-OH]

[0407] Example 35: Preparation of ((1R)-1-(5-benzyl-3-(5'-chloro-2'-methoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0408] (1) Preparation of 3-bromobenzaldehyde oxime [ka] Using 3-bromo-benzaldehyde (1.85 g, 10.0 mmol), the title compound (2.03 g, 100%) was obtained according to the production method of Example 3-(1). NMR: 1 H-NMR (400MHz, CDCl3); δ 8.08 (1H, s), 7.81 (1H, s), 7.56~7.24 (4H, m)

[0409] (2) Preparation of methyl 5-benzyl-3-(3-bromophenyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (1.01 g, 90%) was obtained by the production method of Example 2-(3) using 3-bromobenzaldehyde oxime (0.60 g, 3.0 mmol) obtained in (1) above and methyl 2-benzyl acrylate (0.58 g, 3.3 mmol) obtained in Production Example 6-(1). 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) MS (m / z): 374[M+H]

[0410] (3) Preparation of methyl 5-benzyl-3-(5'-chloro-2'-methoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydroisoxazole-5-carboxylate [ka] Methyl 5-benzyl-3-(3-bromophenyl)-4,5-dihydroisoxazole-5-carboxylate (0.154 g, 0.412 mmol) obtained in (2) above, 5-chloro-2-methoxyphenylboronic acid (0.093 g, 0.499 mmol), potassium carbonate (0.29 g, 2.06 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloro complex (0.034 g, 0.042 mmol) were mixed in 1,4-dioxane (10 mL) and water (1 mL) and stirred at 80°C for 3 hours. The solvent was distilled under reduced pressure, and the remaining filtrate was purified by column chromatography to obtain the title compound (0.189 g, 100%). 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) MS (m / z): 436[M+H]

[0411] (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-boratricyclo[6.1.1.0 2,6 ]decan-4-yl]butyl]-4,5-dihydro-1,2-oxazole-5-carboxamide [ka] The title compound (0.163 g, 49%, 2 steps) was obtained by the preparation methods of Example 1-(2) and Example 1-(3) using methyl 5-benzyl-3-(5'-chloro-2'-methoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydroisoxazole-5-carboxylate (0.189 g, 0.434 mmol) obtained in (3) above. MS (m / z): 669[M+H]

[0412] (5) Preparation of ((1R)-1-(5-benzyl-3-(5'-chloro-2'-methoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] 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-boratricyclo[6.1.1.0] obtained in (4) above 2,6 Using ]decan-4-yl]butyl]-4,5-dihydro-1,2-oxazole-5-carboxamide (0.119 g, 0.180 mmol), the title compound (0.069 g, 72%) was obtained according to the preparation method of Example 1-(4). 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) MS (m / z): 535[M+H]

[0413] Example 36: Preparation of ((1R)-1-(5-benzyl-3-(3-(isoquinolin-1-yl)phenyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), and (4).

[0414] (1) Preparation of methyl 5-benzyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate [ka]

[0415] Methyl 5-benzyl-3-(3-bromophenyl)-4,5-dihydroisoxazole-5-carboxylate (0.655 g, 1.75 mmol) obtained in (2), bis-pinacolate diborane (0.889 g, 3.50 mmol), potassium acetate (0.689 g, 7.02 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 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 filtrate was separated by column chromatography to obtain the title compound (0.733 g, 100%). 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)

[0416] (2) Preparation of methyl 5-benzyl-3-[3-(isoquinolin-1-yl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.101 g, 71%) was obtained by the production method of Example 35-(3) using methyl 5-benzyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate (0.142 g, 0.337 mmol) obtained in (1) above and 1-bromoisoquinoline. 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)

[0417] (3) Preparation of 5-benzyl-3-(3-(isoquinolin-1-yl)phenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.076 g, 48%, 2 steps) was obtained by the preparation methods of Example 1-(2) and Example 1-(3) using methyl 5-benzyl-3-[3-(isoquinolin-1-yl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate (0.101 g, 0.239 mmol) obtained in (2) above. MS (m / z): 656[M+H]

[0418] (4) Preparation of ((1R)-1-(5-benzyl-3-(3-(isoquinolin-1-yl)phenyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.040 g, 66%) was obtained by the production method of Example 1-(4) using 5-benzyl-3-(3-(isoquinolin-1-yl)phenyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.076 g, 0.239 mmol) obtained in (3) above, according to the method of Example 1-(4). 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) MS (m / z): 522[M+H]

[0419] Example 37: Preparation of ((1R)-3-methyl-1-(3-(3-(trifluoromethoxy)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0420] (1) Preparation of 3-trifluoromethoxy-benzaldehyde oxime [ka] The title compound (0.54 g, 99%) was obtained using 3-trifluoromethoxy-benzaldehyde (0.5 g, 2.63 mmol) according to the production method of Example 3-(1). MS (m / z): 206[M+H]

[0421] (2) Preparation of ethyl 3-[3-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.63 g, 79%) was obtained by the production method of Example 2-(3) using 3-trifluoromethoxy-benzaldehyde oxime (0.54 g, 2.63 mmol) obtained in (1) above. MS (m / z): 304[M+H]

[0422] (3) Preparation of 3-[3-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.57 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 3-[3-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate (0.63 g, 2.08 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 276[M+H]

[0423] (4) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(3-(trifluoromethoxy)phenyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.11 g, 83%) was obtained by the production method of Example 1-(3) using 3-[3-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.07 g, 0.25 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 523[M+H]

[0424] (5) Preparation of ((1R)-3-methyl-1-(3-(3-(trifluoromethoxy)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.065 g, 80%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(3-(trifluoromethoxy)phenyl)-4,5-dihydroisoxazole-5-carboxamide (0.11 g, 0.21 mmol) obtained in (4) above. 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) MS (m / z): 389[M+H], 371[M-OH]

[0425] Example 38: Preparation of ((1R)-3-methyl-1-(3-(4-(trifluoromethoxy)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0426] (1) Preparation of 4-trifluoromethoxy-benzaldehyde oxime [ka] The title compound (1.0 g, quant.) was obtained using 4-trifluoromethoxy-benzaldehyde (0.93 g, 4.9 mmol) according to the production method of Production Example 6-(1). MS (m / z): 206[M+H]

[0427] (2) Preparation of ethyl 3-[4-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.94 g, 64%) was obtained by the production method of Example 2-(3) using 4-trifluoromethoxy-benzaldehyde oxime (1.0 g, 4.9 mmol) obtained in (1) above. MS (m / z): 304[M+H]

[0428] (3) Preparation of 3-[4-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.77 g, 90%) was obtained by the production method of Example 1-(2) using ethyl 3-[4-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate (0.94 g, 3.1 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 276[M+H]

[0429] (4) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(4-(trifluoromethoxy)phenyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.10 g, 54%) was obtained by the production method of Example 1-(3) using 3-[4-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.099 g, 0.36 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 523[M+H]

[0430] (5) Preparation of ((1R)-3-methyl-1-(3-(4-(trifluoromethoxy)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.014 g, 19%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(4-(trifluoromethoxy)phenyl)-4,5-dihydroisoxazole-5-carboxamide (0.10 g, 0.19 mmol) obtained in (4) above. MS (m / z): 389[M+H], 371[M-OH]

[0431] Example 39: Preparation of ((1R)-3-methyl-1-(3-(2-(trifluoromethoxy)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0432] (1) Preparation of 2-trifluoromethoxy-benzaldehyde oxime [ka] The title compound (0.54 g, quant.) was obtained using 2-trifluoromethoxy-benzaldehyde (0.50 g, 2.6 mmol) according to the production method of Example 3-(1). MS (m / z): 206[M+H]

[0433] (2) Preparation of ethyl 3-[2-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.60 g, 75%) was obtained by the production method of Example 2-(3) using 2-trifluoromethoxy-benzaldehyde oxime (0.54 g, 2.6 mmol) obtained in (1) above. MS (m / z): 304[M+H]

[0434] (3) Preparation of 3-[2-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.55 g, quant.) was obtained by the production method of Example 1-(2) using ethyl 3-[2-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate (0.60 g, 2.0 mmol) obtained in (2) above, according to the production method of Example 1-(2). MS (m / z): 276[M+H]

[0435] (4) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(2-(trifluoromethoxy)phenyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.12 g, 69%) was obtained by the production method of Example 1-(3) using 3-[2-(trifluoromethoxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.091 g, 0.33 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 523[M+H]

[0436] (5) Preparation of ((1R)-3-methyl-1-(3-(2-(trifluoromethoxy)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.063 g, 71%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(2-(trifluoromethoxy)phenyl)-4,5-dihydroisoxazole-5-carboxamide (0.12 g, 0.23 mmol) obtained in (4) above. MS (m / z): 389[M+H], 371[M-OH]

[0437] Example 40: Preparation of ((1R)-3-methyl-1-(3-(3-phenoxyphenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0438] (1) Preparation of 3-phenoxy-benzaldehyde oxime [ka] The title compound (0.32 g, 99%) was obtained using 3-phenoxy-benzaldehyde (0.3 g, 1.51 mmol) according to the production method of Example 3-(1). MS (m / z): 214[M+H]

[0439] (2) Preparation of ethyl 3-(3-phenoxyphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.44 g, 93%) was obtained by the production method of Example 2-(3) using 3-phenoxy-benzaldehyde oxime (0.32 g, 1.51 mmol) obtained in (1) above. MS (m / z): 312[M+H]

[0440] (3) Preparation of 3-(3-phenoxyphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.4 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 3-(3-phenoxyphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.44 g, 1.41 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 284[M+H]

[0441] (4) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(3-phenoxyphenyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.12 g, 80%) was obtained by the production method of Example 1-(3) using 3-(3-phenoxyphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.08 g, 0.28 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 531[M+H]

[0442] (5) Preparation of ((1R)-3-methyl-1-(3-(3-phenoxyphenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.055 g, 61%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(3-phenoxyphenyl)-4,5-dihydroisoxazole-5-carboxamide (0.12 g, 0.23 mmol) obtained in (4) above. 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) MS (m / z): 397[M+H], 379[M-OH]

[0443] Example 41: Preparation of ((1R)-3-methyl-1-(3-(3-(pyridin-2-yloxy)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), (5), and (6).

[0444] (1) Preparation of 3-(pyridin-2-yloxy)-benzaldehyde [ka] The title compound was obtained by the method described in EP1688138A1.

[0445] (2) Preparation of 3-(pyridin-2-yloxy)-benzaldehyde oxime [ka] The title compound (0.23 g, 99%) was obtained by the production method of Example 3-(1) using 3-(pyridin-2-yloxy)-benzaldehyde (0.21 g, 1.05 mmol) obtained in (1) above and the production method of Example 3-(1). MS (m / z): 215[M+H]

[0446] (3) Ethyl 3-[3-(pyridin-2-yloxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.3 g, 89%) was obtained by the production method of Example 2-(3) using 3-(pyridin-2-yloxy)-benzaldehyde oxime (0.23 g, 1.07 mmol) obtained in (2) above. MS (m / z): 313[M+H]

[0447] (4) 3-[3-(pyridin-2-yloxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.27 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 3-[3-(pyridin-2-yloxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate (0.3 g, 0.96 mmol) obtained in (3) above and the production method of Example 1-(2). MS (m / z): 285[M+H]

[0448] (5) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(3-(pyridin-2-yloxy)phenyl)-4,5-dihydroisoxazole-5-carboxamide The title compound (0.1 g, 59%) was obtained by the production method of Example 1-(3) using 3-[3-(pyridin-2-yloxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.09 g, 0.32 mmol) obtained in (4) above and the production method of Example 1-(3). MS (m / z): 532[M+H]

[0449] (6) Preparation of ((1R)-3-methyl-1-(3-(3-(pyridin-2-yloxy)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.046 g, 62%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(3-(pyridin-2-yloxy)phenyl)-4,5-dihydroisoxazole-5-carboxamide (0.1 g, 0.19 mmol) obtained in (5) above, according to the method of Example 1-(4). 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) MS (m / z): 398[M+H], 380[M-OH]

[0450] Example 42: Preparation of ((1R)-3-methyl-1-(3-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the steps of Example 42-(1), (2), (3), (4), (5) and (6) below.

[0451] (1) Preparation of 3-(pyridin-2-yloxy)-benzaldehyde [ka] The title compound was obtained by the method described in Synlett, 2008, #2 pp. 221-224.

[0452] (2) Preparation of 3-(pyridin-2-yloxy)-benzaldehyde oxime [ka] The title compound (0.19 g, 98%) was obtained by the production method of Example 3-(1) using 3-(pyridin-2-yloxy)-benzaldehyde (0.18 g, 0.90 mmol) obtained in the above Example 42-(1). MS (m / z): 215[M+H]

[0453] (3) Preparation of ethyl 3-[4-(pyridin-2-yloxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.23 g, 83%) was obtained by the production method of Example 2-(3) using 3-(pyridin-2-yloxy)-benzaldehyde oxime (0.19 g, 0.89 mmol) obtained in the above Example 42-(2). 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) MS (m / z): 313[M+H]

[0454] (4) Preparation of 3-[4-(pyridin-2-yloxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.2 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 3-[4-(pyridin-2-yloxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate (0.23 g, 0.74 mmol) obtained in Example 42-(3). MS (m / z): 284[M+H]

[0455] (5) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.11 g, 65%) was obtained by the production method of Example 1-(3) using 3-[4-(pyridin-2-yloxy)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.09 g, 0.32 mmol) obtained in (4) above and the production method of Example 1-(3). MS (m / z): 532[M+H]

[0456] (6) Preparation of ((1R)-3-methyl-1-(3-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.054 g, 65%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydroisoxazole-5-carboxamide (0.11 g, 0.21 mmol) obtained in (5) above, according to the method of Example 1-(4). NMR: 1 H-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) MS (m / z): 398[M+H], 380[M-OH]

[0457] Example 43: Preparation of ((1R)-3-methyl-1-(3-(3-(pyridin-2-ylmethoxy)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), (5), and (6).

[0458] (1) Preparation of 3-(pyridin-2-ylmethoxy)-benzaldehyde [ka] The title compound was obtained by the method described in WO2007105904A1.

[0459] (2) Preparation of 3-(pyridin-2-ylmethoxy)-benzaldehyde oxime [ka] The title compound (0.71 g, 99%) was obtained by the production method of Example 3-(1) using 3-(pyridin-2-ylmethoxy)-benzaldehyde (0.66 g, 3.10 mmol) obtained in (1) above and the production method of Example 3-(1). MS (m / z): 229[M+H]

[0460] (3) Preparation of ethyl 3-{3-[(pyridin-2-yl)methoxy]phenyl}-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.9 g, 89%) was obtained by the production method of Example 2-(3) using 3-(pyridin-2-ylmethoxy)-benzaldehyde oxime (0.71 g, 3.11 mmol) obtained in (2) above and the method of preparation of Example 2-(3). 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) MS (m / z): 327[M+H]

[0461] (4) Preparation of 3-{3-[(pyridin-2-yl)methoxy]phenyl}-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.82 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 3-{3-[(pyridin-2-yl)methoxy]phenyl}-4,5-dihydro-1,2-oxazole-5-carboxylate (0.9 g, 2.76 mmol) obtained in (3) above, according to the method of Example 1-(2). MS (m / z): 299[M+H]

[0462] (5) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(3-(pyridin-2-ylmethoxy)phenyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.05 g, 34%) was obtained by the production method of Example 1-(3) using 3-{3-[(pyridin-2-yl)methoxy]phenyl}-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.08 g, 0.27 mmol) obtained in (4) above and the production method of Example 1-(3). MS (m / z): 546[M+H]

[0463] (6) Preparation of ((1R)-3-methyl-1-(3-(3-(pyridin-2-ylmethoxy)phenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.031 g, 82%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(3-(pyridin-2-ylmethoxy)phenyl)-4,5-dihydroisoxazole-5-carboxamide (0.05 g, 0.092 mmol) obtained in (5) above, according to the method of Example 1-(4). NMR: 1H-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) MS (m / z): 412[M+H], 394[M-OH]

[0464] Example 44: Preparation of ((1R)-3-methyl-1-(3-(4-phenoxyphenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0465] (1) Preparation of 4-phenoxy-benzaldehyde oxime [ka] The title compound (0.38 g, quant.) was obtained using 4-phenoxy-benzaldehyde (0.35 g, 1.8 mmol) according to the production method of Example 3-(1). MS (m / z): 214[M+H]

[0466] (2) Preparation of ethyl 3-(4-phenoxyphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] The title compound (0.38 g, 69%) was obtained by the production method of Example 2-(3) using 4-phenoxy-benzaldehyde oxime (0.38 g, 1.8 mmol) obtained in (1) above. MS (m / z): 312[M+H]

[0467] (3) Preparation of 3-(4-phenoxyphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.32 g, 94%) was obtained by the production method of Example 1-(2) using ethyl 3-(4-phenoxyphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (0.38 g, 1.2 mmol) obtained in (2) above and the production method of Example 1-(2). MS (m / z): 284[M+H]

[0468] (4) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(4-phenoxyphenyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.079 g, 43%) was obtained by the production method of Example 1-(3) using 3-(4-phenoxyphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.098 g, 0.35 mmol) obtained in (3) above and the production method of Example 1-(3). MS (m / z): 531[M+H]

[0469] (5) Preparation of ((1R)-3-methyl-1-(3-(4-phenoxyphenyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.018 g, 31%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(4-phenoxyphenyl)-4,5-dihydroisoxazole-5-carboxamide (0.079 g, 0.15 mmol) obtained in (4) above. MS (m / z): 397[M+H], 379[M-OH]

[0470] Example 45: Preparation of ((1R)-1-(5-benzyl-3-(((2,5-dichlorobenzyl)oxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0471] (1) Production of 1,4-dichloro-2-((2,2-diethoxyethoxy)methyl)benzene [ka] 2,2-Diethoxyethanol (0.268 g, 2.0 mmol) was dissolved in tetrahydrofuran (8 ml) and then sodium hydride (0.088 g, 2.2 mmol) was added at 0°C. The mixture was stirred for 30 minutes, followed by the addition of 2,5-dichlorobenzyl bromide (0.48 g, 2.0 mmol) and stirring at room temperature for 1 hour. Water (20 ml) was added to terminate the reaction, and the mixture was extracted twice with dichloromethane (20 ml). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.416 g, 71%). NMR: 1H-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)

[0472] (2) Preparation of 2-((2,5-dichlorobenzyl)oxy)acetaldehyde oxime [ka] 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), and 50% aqueous hydroxylamine solution (0.26 ml, 4.24 mmol) and 6N hydrochloric acid solution (0.80 ml, 4.80 mmol) were added, followed by stirring at room temperature for 18 hours. The solution was neutralized with aqueous sodium bicarbonate solution, and the methanol was removed by distillation under reduced pressure. The filtrate was extracted three times with dichloromethane (20 ml). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.294 g, 90%). MS (m / z): 234[M+H]

[0473] (3) Preparation of methyl 5-benzyl-3-(((2,5-dichlorobenzyl)oxy)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.173 g, 76%) was obtained by the method of Preparation Example 6-(2) using ((2,5-dichloro-benzyloxy)-acetaldehyde oxime (0.130 g, 0.56 mmol) obtained in the above step (2). NMR: 1H-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) MS (m / z): 408[M+H]

[0474] (4) Preparation of 5-benzyl-3-(((2,5-dichlorobenzyl)oxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.135 g, 79%, two steps) was obtained by the preparation method of Example 1-(2) and (3) using methyl 5-benzyl-3-(((2,5-dichlorobenzyl)oxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.173 g, 0.424 mmol) obtained in (3) above. MS (m / z): 641[M+H]

[0475] (5) Preparation of ((1R)-1-(5-benzyl-3-(((2,5-dichlorobenzyl)oxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.076 g, 71%) was obtained by the production method of Example 1-(4) using 5-benzyl-3-(((2,5-dichlorobenzyl)oxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.135 g, 0.21 mmol) obtained in (4) above, according to the method of Example 1-(4). 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) MS (m / z): 507[M+H], 489[M-OH]

[0476] Example 46: Preparation of ((1R)-1-(5-benzyl-3-(((2-methylthiazol-4-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0477] (1) Preparation of (2,2-diethoxy-ethoxymethyl)-2-methyl-thiazole [ka] Using 4-chloromethyl-2-methyl-thiazole (0.296 g, 2.0 mmol), the title compound (0.396 g, 81%) was obtained according to the preparation method of Example 45-(1). 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)

[0478] (2) Preparation of (2-methyl-thiazol-4-ylmethoxy)-acetaldehyde oxime [ka] Using (2,2-diethoxy-ethoxymethyl)-2-methyl-thiazole (0.396 g, 1.61 mmol) obtained in (1) above, the title compound (0.267 g, 89%) was obtained according to the production method of Example 45-(2).

[0479] (3) Preparation of methyl 5-benzyl-3-(((2-methylthiazol-4-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using (2-methyl-thiazol-4-ylmethoxy)-acetaldehyde oxime (0.131 g, 0.70 mmol) obtained in (2) above, the title compound (0.104 g, 41%) was obtained according to the method of Preparation Example 6-(2). 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) MS (m / z): 361[M+H]

[0480] (4) Preparation of 5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(((2-methylthiazol-4-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.063 g, 41%, two steps) was obtained by the preparation method of Example 1-(2) and (3) using methyl 5-benzyl-3-(((2-methylthiazol-4-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.104 g, 0.289 mmol) obtained in (3) above. MS (m / z): 594[M+H]

[0481] (5) Preparation of ((1R)-1-(5-benzyl-3-(((2-methylthiazol-4-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.028 g, 58%) was obtained by the production method of Example 1-(4) using 5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(((2-methylthiazol-4-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamide (0.063 g, 0.106 mmol) obtained in the above step (4). 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) MS (m / z): 460[M+H], 442[M-OH]

[0482] Example 47: Preparation of ((1R)-1-(5-benzyl-3-(((6-methylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0483] (1) Preparation of 2-(2,2-diethoxy-ethoxymethyl)-6-methyl-pyridine [ka] Using 2-chloromethyl-6-methyl-pyridine (0.283 g, 2.0 mmol), the title compound (0.292 g, 61%) was obtained according to the preparation method of Example 45-(1). 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)

[0484] (2) Preparation of (6-methyl-pyridin-2-yl-methoxy)-acetaldehyde oxime [ka] Using 2-(2,2-diethoxy-ethoxymethyl)-6-methyl-pyridine (0.29 g, 1.2 mmol) obtained in (1) above, the title compound (0.189 g, 86%) was obtained according to the production method of Production Example 6-(2). MS (m / z): 181[M+H]

[0485] (3) Preparation of methyl 5-benzyl-3-(((6-methylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using (6-methyl-pyridin-2-yl-methoxy)-acetaldehyde oxime (0.104 g, 0.58 mmol) obtained in (2) above, the title compound (0.073 g, 36%) was obtained according to the production method of Example 45-(3). NMR: 1 H-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) MS (m / z): 355[M+H]

[0486] (4) Preparation of 5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(((6-methylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.06 g, 56%, 2 steps) was obtained by the preparation method of Example 1-(2) and (3) using methyl 5-benzyl-3-(((6-methylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.073 g, 0.21 mmol) obtained in (3) above. MS (m / z): 588[M+H]

[0487] (5) Preparation of ((1R)-1-(5-benzyl-3-(((6-methylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.014 g, 27%) was obtained by the production method of Example 1-(4) using 5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(((6-methylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamide (0.068 g, 0.116 mmol) obtained in (4) above. 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) MS (m / z): 454[M+H], 436[M-OH]

[0488] Example 48: Preparation of ((1R)-1-(5-benzyl-3-(((5-methylpyrazin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0489] (1) Preparation of 2-(2,2-diethoxy-ethoxymethyl)-5-methyl-pyrazine [ka] Using 2-chloromethyl-5-methyl-pyrazine (0.143 g, 1.0 mmol), the title compound (0.168 g, 70%) was obtained according to the preparation method of Example 45-(1). NMR: 1H-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)

[0490] (2) Preparation of (5-methyl-pyrazin-2-yl-methoxy)-acetaldehyde oxime [ka] Using 2-(2,2-diethoxy-ethoxymethyl)-5-methyl-pyrazine (0.168 g, 0.70 mmol) obtained in (1) above, the title compound (0.112 g, 88%) was obtained according to the production method of Example 45-(2). MS (m / z): 182[M+H]

[0491] (3) Preparation of methyl 5-benzyl-3-(((5-methylpyrazin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using (5-methyl-pyrazin-2-yl-methoxy)-acetaldehyde oxime (0.112 g, 0.62 mmol) obtained in (2) above, the title compound (0.079 g, 36%) was obtained according to the method of Preparation Example 6-(2). 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) MS (m / z): 356[M+H]

[0492] (4) Preparation of 5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(((5-methylpyrazin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.071 g, 54%, two steps) was obtained by the production method of Example 1-(2) and (3) using methyl 5-benzyl-3-(((5-methylpyrazin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.079 g, 0.22 mmol) obtained in (3) above. MS (m / z): 589[M+H]

[0493] (5) Preparation of ((1R)-1-(5-benzyl-3-(((5-methylpyrazin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.014 g, 26%) was obtained by the production method of Example 1-(4) using 5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(((5-methylpyrazin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamide (0.071 g, 0.121 mmol) obtained in (4) above. NMR: 1H-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) MS (m / z): 437 [M-OH]

[0494] Example 49: Preparation of ((1R)-1-(5-benzyl-3-((isoquinolin-1-ylmethoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0495] (1) Preparation of chloroacetaldehyde oxime [ka] The title compound (0.650 g, 45%) was obtained by the production method of Production Example 1-(1) using 50% aqueous chloroacetaldehyde solution (2.4 g, 15.3 mmol) and 50% aqueous hydroxyamine solution (1.2 g, 18.2 mmol).

[0496] (2) Preparation of methyl 5-benzyl-3-(chloromethyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.351 g, 66%) was obtained by the production method of Production Example 6-(2) using chloroacetaldehyde oxime (0.281 g, 3.00 mmol) obtained in (1) above. NMR: 1H-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)

[0497] (3) Preparation of methyl 5-benzyl-3-((isoquinolin-1-ylmethoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Isoquinolin-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 stirred at room temperature for 30 minutes. To this solution, a solution of methyl 5-benzyl-3-(chloromethyl)-4,5-dihydroisoxazole-5-carboxylate (0.11 g, 0.44 mmol) obtained in (2) above in tetrahydrofuran (2 mL) and tetrabutylammonium iodide (0.030 g, 0.08 mmol) were added, in that order, and the mixture was stirred at room temperature for 4 hours. Water (10 mL) was added to the reaction mixture, which was then extracted three times with dichloromethane (10 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.042 g, 27%). 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) MS (m / z): 391[M+H]

[0498] (4) Preparation of 5-benzyl-3-((isoquinolin-1-ylmethoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.043 g, 58%, two steps) was obtained by the preparation method of Example 1-(2) and (3) using methyl 5-benzyl-3-((isoquinolin-1-ylmethoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.042 g, 0.112 mmol) obtained in (3) above.

[0499] (5) Preparation of ((1R)-1-(5-benzyl-3-((isoquinolin-1-ylmethoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.023 g, 68%) was obtained by the production method of Example 1-(4) using 5-benzyl-3-((isoquinolin-1-ylmethoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.043 g, 0.069 mmol) obtained in (4) above, according to the method of Example 1-(4). NMR: 1H-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) MS (m / z): 490[M+H], 472[M-OH]

[0500] Example 50: Preparation of ((1R)-1-(5-benzyl-3-(((5-chloro-2-methylthiazol-4-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0501] (1) Preparation of 5-chloro-4-(2,2-diethoxy-ethoxymethyl)-2-methyl-thiazole [ka] The title compound (0.352 g, 63%) was obtained using 5-chloro-4-chloromethyl-2-methylthiazole (0.362 g, 1.99 mmol) according to the preparation method of Example 45-(1). 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)

[0502] (2) Preparation of (5-chloro-2-methyl-thiazol-5-yl-methoxy)-acetaldehyde oxime [ka] The title compound (0.209 g, 75%) was obtained by the production 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 and the production method of Example 45-(2).

[0503] (3) Preparation of methyl 5-benzyl-3-(((5-chloro-2-methylthiazol-4-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using (5-chloro-2-methyl-thiazol-5-yl-methoxy)-acetaldehyde oxime (0.209 g, 0.95 mmol) obtained in (2) above, the title compound (0.264 g, 70%) was obtained according to the method of Preparation Example 6-(2). 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)

[0504] (4) Preparation of 5-benzyl-3-(((5-chloro-2-methylthiazol-4-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.217 g, 64%, two steps) was obtained by the preparation methods of Example 1-(2) and (3) using methyl 5-benzyl-3-(((5-chloro-2-methylthiazol-4-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.264 g, 0.67 mmol) obtained in (3) above. MS (m / z): 628[M+H]

[0505] (5) Preparation of ((1R)-1-(5-benzyl-3-(((5-chloro-2-methylthiazol-4-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.057 g, 33%) was obtained by the production method of Example 1-(4) using 5-benzyl-3-(((5-chloro-2-methylthiazol-4-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.21 g, 0.34 mmol) obtained in (4) above, according to the method of Example 1-(4). 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) MS (m / z): 476[M-OH]

[0506] Example 51: Preparation of ((1R)-1-(5-benzyl-3-(((2,4-dimethylthiazol-5-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0507] (1) Preparation of 5-(2,2-diethoxy-ethoxymethyl)-2,4-dimethyl-thiazole [ka] Using 5-chloromethyl-2,4-dimethyl-thiazole (0.264 g, 1.63 mmol), the title compound (0.162 g, 38%) was obtained according to the preparation method of Example 45-(1). 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)

[0508] (2) Preparation of (2,4-dimethyl-thiazol-5-yl-methoxy)-acetaldehyde oxime [ka] The title compound (0.055 g, 44%) was obtained by the production 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 and the production method of Example 45-(2).

[0509] (3) Preparation of methyl 5-benzyl-3-(((2,4-dimethylthiazol-5-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using (2,4-dimethyl-thiazol-5-yl-methoxy)-acetaldehyde oxime (0.055 g, 0.275 mmol) obtained in (2) above, the title compound (0.040 g, 36%) was obtained according to the method of Preparation Example 6-(2). 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) MS (m / z): 375[M+H]

[0510] (4) Preparation of 5-benzyl-3-(((2,4-dimethylthiazol-5-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.055 g, 85%, 2 steps) was obtained by the production methods described in Example 1-(2) and (3) using methyl 5-benzyl-3-(((2,4-dimethylthiazol-5-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.040 g, 0.107 mmol) obtained in (3) above.

[0511] (5) Preparation of 5-benzyl-3-(2,4-dimethyl-thiazol-5-yl-methoxymethyl)-4,5-dihydro-isoxazole-5-carboxylic acid ((R)-1-boronic acid-3-methyl-butyl)-amide [ka] The title compound (0.013 g, 30%) was obtained by the production method of Example 1-(4) using 5-benzyl-3-(((2,4-dimethylthiazol-5-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.055 g, 0.091 mmol) obtained in (4) above, according to the method of Example 1-(4). 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) MS (m / z): 456[M-OH]

[0512] Example 52: Preparation of ((1R)-1-(5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0513] (1) Preparation of 1-bromo-3-(2,2-diethoxy-ethoxymethyl)-benzene [ka] Using 3-bromo-benzyl bromide (1.00 g, 4.0 mmol), the title compound (0.841 g, 69%) was obtained according to the preparation method of Example 45-(1). NMR: 1H-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)

[0514] (2) Preparation of (3-bromo-benzyloxy)-acetaldehyde oxime [ka] The title compound (0.647 g, 96%) was obtained by the production method of Example 45-(2) using 1-bromo-3-(2,2-diethoxy-ethoxymethyl)-benzene (0.841 g, 2.77 mmol) obtained in (1) above and the production method of Example 45-(2).

[0515] (3) Preparation of methyl 5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using (3-bromo-benzyloxy)-acetaldehyde oxime (0.647 g, 2.65 mmol) obtained in the above step (2), the title compound (0.641 g, 58%) was obtained according to the production method of Production Example 6-(2). 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)

[0516] (4) Preparation of 5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.050 g, 54%, two steps) was obtained by the preparation method of Example 1-(2) and (3) using methyl 5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.059 g, 0.14 mmol) obtained in (3) above. MS (m / z): 651, 653 [M+H]

[0517] (5) Preparation of ((1R)-1-(5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.016 g, 40%) was obtained by the production method of Example 1-(4) using 5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.050 g, 0.077 mmol) obtained in (4) above, according to the method of Example 1-(4). NMR: 1H-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), MS (m / z): 540, 542 (M+Na), 499, 501 [M-OH]

[0518] Example 53: Preparation of ((1R)-1-(5-benzyl-3-(((6-bromopyridin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0519] (1) Preparation of 2-bromo-6-(2,2-diethoxy-ethoxymethyl)-pyridine [ka] Using 2-bromo-6-chloromethyl-pyridine (0.191 g, 0.925 mmol), the title compound (0.196 g, 81%) was obtained according to the preparation method of Example 45-(1). 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)

[0520] (2) Preparation of (6-bromo-pyridin-2-ylmethoxy)-acetaldehyde oxime [ka] Using 2-bromo-6-(2,2-diethoxy-ethoxymethyl)-pyridine (0.196 g, 0.644 mmol) obtained in (1) above, the title compound (0.125 g, 79%) was obtained according to the production method of Example 45-(2).

[0521] (3) Preparation of methyl 5-benzyl-3-(((6-bromopyridin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using (6-bromo-pyridin-2-ylmethoxy)-acetaldehyde oxime (0.125 g, 0.51 mmol) obtained in (2) above, the title compound (0.125 g, 58%) was obtained according to the production method of Production Example 6-(2). 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)

[0522] (4) Preparation of 5-benzyl-3-(((6-bromopyridin-2-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.039 g, 49%, two steps) was obtained by the preparation method of Example 1-(2) and (3) using methyl 5-benzyl-3-(((6-bromopyridin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.052 g, 0.124 mmol) obtained in (3) above. MS (m / z): 652, 654 [M+H]

[0523] (5) Preparation of ((1R)-1-(5-benzyl-3-(((6-bromopyridin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.014 g, 45%) was obtained by the production method of Example 1-(4) using 5-benzyl-3-(((6-bromopyridin-2-yl)methoxy)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.039 g, 0.06 mmol) obtained in (4) above, according to the method of Example 1-(4). 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), MS (m / z): 540, 542 (M+Na), 500, 502 [M-OH]

[0524] Example 54: Preparation of ((1R)-1-(3-(([1,1'-biphenyl]-3-ylmethoxy)methyl)-5-benzyl-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0525] (1) Preparation of methyl 3-(([1,1'-biphenyl]-3-ylmethoxy)methyl)-5-benzyl-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.064 g, 68%) was obtained by the preparation method of Example 35-(3) using methyl 5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.095 g, 0.227 mmol) obtained in Example 52-(3) and phenylboronic acid. 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). MS (m / z): 416 [M+H]

[0526] (2) Preparation of 3-(([1,1'-biphenyl]-3-ylmethoxy)methyl)-5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.069 g, 68%, two steps) was obtained by the preparation methods of Example 1-(2) and (3) using methyl 3-(([1,1'-biphenyl]-3-ylmethoxy)methyl)-5-benzyl-4,5-dihydroisoxazole-5-carboxylate (0.064 g, 0.154 mmol) obtained in (1) above. MS (m / z): 649 [M+H]

[0527] (3) Preparation of ((1R)-1-(3-(([1,1'-biphenyl]-3-ylmethoxy)methyl)-5-benzyl-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.019 g, 35%) was obtained by the production method of Example 1-(4) using 3-(([1,1'-biphenyl]-3-ylmethoxy)methyl)-5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.069 g, 0.106 mmol) obtained in (2) above, according to the method of Example 1-(4). 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), MS (m / z): 537 (M+Na), 497 [M-OH]

[0528] Example 55: Preparation of [(1R)-1-[[5-benzyl-3-[(6-phenyl-2-pyridyl)methoxymethyl]-4H-1,2-oxazole-5-carbonyl]amino]-3-methyl-butyl]boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0529] (1) Preparation of methyl 5-benzyl-3-(((6-phenylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.041 g, 54%) was obtained by the preparation method of Example 35-(3) using methyl 5-benzyl-3-(((6-bromopyridin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.076 g, 0.181 mmol) obtained in Example 53-(3) and phenylboronic acid. NMR: 1 H-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) MS (m / z): 417 [M+H]

[0530] (2) Preparation of 5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(((6-phenylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.036 g, 57%, 2 steps) was obtained by the preparation methods of Example 1-(2) and (3) using methyl 5-benzyl-3-(((6-phenylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.041 g, 0.098 mmol) obtained in (1) above. MS (m / z): 650 [M+H]

[0531] (3) Preparation of ((1R)-1-(5-benzyl-3-(((6-phenylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.015 g, 53%) was obtained by the production method of Example 1-(4) using 5-benzyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(((6-phenylpyridin-2-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamide (0.036 g, 0.055 mmol) obtained in (2) above, according to the method of Example 1-(4). 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), MS (m / z): 498 [M-OH]

[0532] Example 56: Preparation of ((1R)-1-(5-benzyl-3-(((4'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0533] (1) Preparation of methyl 5-benzyl-3-(((4'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.047 g, 58%) was obtained by the preparation method of Example 35-(3) using methyl 5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.076 g, 0.182 mmol) obtained in Example 52-(3) and 4-methoxyphenylboronic acid. NMR: 1 H-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) MS (m / z): 446 [M+H]

[0534] (2) Preparation of 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-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.043 g, 60%, two steps) was obtained by the production methods of Example 1-(2) and (3) using methyl 5-benzyl-3-(((4'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.047 g, 0.105 mmol) obtained in (1) above. MS (m / z): 679 [M+H]

[0535] (3) Preparation of ((1R)-1-(5-benzyl-3-(((4'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.015 g, 44%) was obtained by the production method of Example 1-(4) using 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-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.043 g, 0.063 mmol) obtained in (2) above, according to the method of Example 1-(4). 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) MS (m / z): 545 [M+H], 527 [M-OH]

[0536] Example 57: Preparation of ((1R)-1-(5-benzyl-3-(((3'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0537] (1) Preparation of methyl 5-benzyl-3-(((3'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.046 g, 60%) was obtained by the preparation method of Example 35-(3) using methyl 5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.072 g, 0.172 mmol) obtained in Example 52-(3) and 3-methoxyphenylboronic acid. NMR: 1 H-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) MS (m / z): 446 [M+H]

[0538] (2) Preparation of 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-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.035 g, 50%, two steps) was obtained by the production methods of Example 1-(2) and (3) using methyl 5-benzyl-3-(((3'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.046 g, 0.103 mmol) obtained in (1) above and the preparation methods of Example 1-(2) and (3). MS (m / z): 679 [M+H]

[0539] (3) Preparation of ((1R)-1-(5-benzyl-3-(((3'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.013 g, 46%) was obtained by the production method of Example 1-(4) using 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-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.035 g, 0.052 mmol) obtained in (2) above, according to the method of Example 1-(4). 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) MS (m / z): 545 [M+H], 527 [M-OH]

[0540] Example 58: Preparation of [(1R)-1-[[5-benzyl-3-[[3-(2-methoxyphenyl)phenyl]methoxymethyl]-4H-1,2-oxazole-5-carbonyl]amino]-3-methyl-butyl]boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0541] (1) Preparation of methyl 5-benzyl-3-(((2'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.052 g, 76%) was obtained by the preparation method of Example 35-(3) using methyl 5-benzyl-3-(((3-bromobenzyl)oxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.064 g, 0.153 mmol) obtained in Preparation Example 9 and 4-methoxyphenylboronic acid. NMR: 1 H-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) MS (m / z): 446 [M+H]

[0542] (2) Preparation of 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-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.042 g, 52%, two steps) was obtained by the preparation methods of Example 1-(2) and (3) using methyl 5-benzyl-3-(((2'-methoxy-[1,1'-biphenyl]-3-yl)methoxy)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.052 g, 0.117 mmol) obtained in (1) above. MS (m / z): 679 [M+H]

[0543] (3) Preparation of 5-benzyl-3-(2'-methoxy-biphenyl-3-ylmethoxymethyl)-4,5-dihydro-isoxazole-5-carboxylic acid ((R)-1-boronic acid-3-methyl-butyl)-amide [ka] The title compound (0.018 g, 53%) was obtained by the production method of Example 1-(4) using 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-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.042 g, 0.062 mmol) obtained in (2) above, according to the method of Example 1-(4). 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) MS (m / z): 545 [M+H], 527 [M-OH]

[0544] Example 59: Preparation of ((1R)-1-(3-(benzamidomethyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), and (4).

[0545] (1) Preparation of ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride [ka] Ethyl 3-[(tert-butoxycarbonylamino)methyl]-4,5-dihydro-1,2-oxazole-5-carboxylate (0.67 g, 2.46 mmol) obtained in Preparation Example 1 was dissolved in dichloromethane (10 ml). 4N hydrochloric acid in 1,4-dioxane (5 ml, 20 mmol) was slowly added at 0°C, and the mixture was stirred for 5 hours while warming to room temperature. The solvent was distilled under reduced pressure, and then solidified with dichloromethane and hexane. The remaining solvent was distilled under reduced pressure and dried under reduced pressure to obtain the title compound (0.48 g, 94%). MS (m / z): 173 [M+H]

[0546] (2) Preparation of ethyl 3-(benzamidomethyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.15 g, 0.72 mmol) obtained in (1) above 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, followed by stirring at room temperature for 18 hours. The solvent was distilled under reduced pressure, and the resulting mixture was added with aqueous sodium bicarbonate and extracted twice with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to obtain the title compound (0.07 g, 35%). NMR: 1H-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) MS (m / z): 277[M+H]

[0547] (3) Preparation of 3-(benzamidomethyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] Using ethyl 3-(benzamidomethyl)-4,5-dihydroisoxazole-5-carboxylate (0.07 g, 0.26 mmol) obtained in (2) above, the title compound (0.08 g, 64%, two steps) was obtained according to the production methods of Example 1-(2) and (3). MS (m / z): 496[M+H]

[0548] (4) Preparation of ((1R)-1-(3-(benzamidomethyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.045 g, 78%) was obtained by the production method of Example 1-(4) using 3-(benzamidomethyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.08 g, 0.16 mmol) obtained in (3) above, according to the method of Example 1-(4). NMR: 1H-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) MS (m / z): 362[M+H], 344[M-OH]

[0549] Example 60: Preparation of ((1R)-3-methyl-1-(3-((pyridin-2-ylamino)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0550] (1) Preparation of ethyl 3-[(pyridine-2-carbonylamino)methyl]-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.09 g, 75%) was obtained by the preparation method of Example 59-(2) using ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.09 g, 0.43 mmol) obtained in Example 59-(1) and pyridine-2-carboxylic acid (0.059 g, 0.48 mmol). MS (m / z): 278[M+H]

[0551] (2) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(picolinamidomethyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.052 g, 47%, 2 steps) was obtained by the preparation methods of Example 1-(2) and Example 1-(3) using ethyl 3-[(pyridine-2-carbonylamino)methyl]-4,5-dihydroisoxazole-5-carboxylate (0.09 g, 0.32 mmol) obtained in (1) above. MS (m / z): 497[M+H], 345[MC 10 H 15 O]

[0552] (3) Preparation of ((1R)-3-methyl-1-(3-((pyridin-2-ylamino)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.042 g, 75%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-(picolinamidomethyl)-4,5-dihydroisoxazole-5-carboxamide (0.077 g, 0.16 mmol) obtained in (2) above. NMR: 1 H-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) MS (m / z): 363[M+H], 345[M-OH]

[0553] Example 61: Preparation of ((1R)-1-(3-((isoquinoline-1-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0554] (1) Preparation of ethyl 3-[(isoquinoline-1-carbonylamino)methyl]-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.107 g, 68%) was obtained by the preparation method of Example 59-(2) using ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.1 g, 0.48 mmol) obtained in Example 59-(1) and isoquinoline-1-carboxylic acid (0.083 g, 0.53 mmol). 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) MS (m / z): 328[M+H]

[0555] (2) Preparation of 3-((isoquinoline-1-carboxamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.116 g, 66%, 2 steps) was obtained by the preparation methods of Example 1-(2) and (3) using ethyl 3-[(isoquinoline-1-carbonylamino)methyl]-4,5-dihydroisoxazole-5-carboxylate (0.107 g, 0.33 mmol) obtained in (1) above. MS (m / z): 547[M+H]

[0556] (3) Preparation of ((1R)-1-(3-((isoquinoline-1-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.065 g, 74%) was obtained by the production method of Example 1-(4) using 3-((isoquinoline-1-carboxamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.116 g, 0.21 mmol) obtained in (2) above, according to the production method of Example 1-(4). 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) MS (m / z): 413[M+H], 395[M-OH]

[0557] Example 62: Preparation of ((1R)-3-methyl-1-(3-((quinoline-5-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0558] (1) Preparation of ethyl 3-((isoquinoline-1-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.19 g, 45%) was obtained by the preparation method of Example 59-(2) using ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.28 g, 1.3 mmol) obtained in Example 59-(1) and 5-quinolinecarboxylic acid (0.25 g, 1.5 mmol). MS (m / z): 314[M+H]

[0559] (2) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-((quinoline-5-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.092 g, 29%, two steps) was obtained by the preparation methods of Example 1-(2) and (3) using ethyl 3-[(isoquinoline-1-carbonylamino)methyl]-4,5-dihydroisoxazole-5-carboxylate (0.19 g, 0.59 mmol) obtained in (1) above. MS (m / z): 547[M+H]

[0560] (3) Preparation of ((1R)-3-methyl-1-(3-((quinoline-5-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.054 g, 77%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-((quinoline-5-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamide (0.092 g, 0.17 mmol) obtained in (2) above. MS (m / z): 413[M+H], 395[M-OH]

[0561] Example 63: Preparation of ((1R)-3-methyl-1-(3-((5,6,7,8-tetrahydronaphthalene-1-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0562] (1) Preparation of ethyl 3-[(tetralin-5-carbonylamino)methyl]-4,5-dihydroisoxazole-5-carboxylate [ka] Using ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.1 g, 0.48 mmol) obtained in Example 59-(1) and 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (0.085 g, 0.53 mmol), the title compound (0.114 g, 72%) was obtained by the preparation method of Example 59-(2). MS (m / z): 331[M+H]

[0563] (2) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-((5,6,7,8-tetrahydronaphthalene-1-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.13 g, 69%, two steps) was obtained by the production methods of Example 1-(2) and (3) using ethyl 3-[(tetralin-5-carbonylamino)methyl]-4,5-dihydroisoxazole-5-carboxylate (0.114 g, 0.35 mmol) obtained in (1) above. MS (m / z): 550[M+H], 398[M+H]

[0564] (3) Preparation of ((1R)-3-methyl-1-(3-((5,6,7,8-tetrahydronaphthalene-1-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.067 g, 68%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-((5,6,7,8-tetrahydronaphthalene-1-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamide (0.13 g, 0.24 mmol) obtained in (2) above. 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) MS (m / z): 416[M+H], 398[M-OH]

[0565] Example 64: Preparation of ((1R)-1-(3-((1-naphthamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0566] (1) Preparation of ethyl 3-[(naphthalene-1-carbonylamino)methyl]-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.09 g, 57%) was obtained by the preparation method of Example 59-(2) using ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.1 g, 0.48 mmol) obtained in Example 59-(1) and naphthalene-1-carboxylic acid (0.091 g, 0.53 mmol). 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) MS (m / z): 327[M+H]

[0567] (2) Preparation of 3-((1-naphthamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] Using ethyl 3-[(naphthalene-1-carbonylamino)methyl]-4,5-dihydroisoxazole-5-carboxylate (0.09 g, 0.28 mmol) obtained in (1) above, the title compound (0.114 g, 66%, two steps) was obtained according to the production methods of Example 1-(2) and (3). MS (m / z): 546[M+H], 394[M+H]

[0568] (3) Preparation of ((1R)-1-(3-((1-naphthamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.069 g, 80%) was obtained by the production method of Example 1-(4) using 3-((1-naphthamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.114 g, 0.21 mmol) obtained in (2) above, according to the method of Example 1-(4). 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) MS (m / z): 412[M+H], 394[M+H]

[0569] Example 65: Preparation of ((1R)-1-(3-((isoquinoline-1-carboxamido)methyl)-4-methyl-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0570] (1) Preparation of methyl 3-((isoquinoline-1-carboxamido)methyl)-4-methyl-4,5-dihydroisoxazole-5-carboxylate [ka] Methyl 3-(((tert-butoxycarbonyl)amino)methyl)-4-methyl-4,5-dihydroisoxazole-5-carboxylate (0.076 g, 0.28 mmol) obtained in Preparation Example 2 was dissolved in dichloromethane (8 mL). 4 N hydrochloric acid in 1,4-dioxane (4 mL, 16 mmol) was slowly added at 0°C, and the mixture was stirred for 5 hours while warming to room temperature, after which the solvent was distilled off under reduced pressure. Dimethylformamide (4 mL) was added to dissolve the mixture, and then 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 in that order. 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, and aqueous sodium bicarbonate solution was added and extracted twice with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (0.025 g, 27%, 2 steps). MS (m / z): 342[M+H]

[0571] (2) Preparation of 3-((isoquinoline-1-carboxamido)methyl)-4-methyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.019 g, 44%, two steps) was obtained by the production method of Example 1-(2) and (3) using ethyl 3-((isoquinoline-1-carboxamido)methyl)-4-methyl-4,5-dihydroisoxazole-5-carboxylate (0.025 g, 0.08 mmol) obtained in (1) above. MS (m / z): 561[M+H]

[0572] (3) Preparation of ((1R)-1-(3-((isoquinoline-1-carboxamido)methyl)-4-methyl-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.003 g, 17%) was obtained by the production method of Example 1-(4) using 3-((isoquinoline-1-carboxamido)methyl)-4-methyl-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.019 g, 0.03 mmol) obtained in (2) above, according to the production method of Example 1-(4). MS (m / z): 427[M+H], 409[M-OH]

[0573] Example 66: Preparation of ((1R)-3-methyl-1-(3-((S)-2-methyl-1-(5,6,7,8-tetrahydronaphthalene-1-carboxamido)propyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0574] (1) Preparation of ethyl 3-((S)-2-methyl-1-(5,6,7,8-tetrahydronaphthalene-1-carboxamido)propyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using ethyl 3-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-4,5-dihydroisoxazole-5-carboxylate (0.13 g, 0.40 mmol) obtained in Preparation Example 3 and 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (0.078, 0.44 mmol), the title compound (0.13 g, 88%, 2 steps) was obtained according to the preparation method of Example 65-(1). MS (m / z): 373[M+H]

[0575] (2) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-((S)-2-methyl-1-(5,6,7,8-tetrahydronaphthalene-1-carboxamido)propyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.15 g, 73%, two steps) was obtained by the production method of Example 1-(2) and (3) using ethyl 3-((S)-2-methyl-1-(5,6,7,8-tetrahydronaphthalene-1-carboxamido)propyl)-4,5-dihydroisoxazole-5-carboxylate (0.13 g, 0.35 mmol) obtained in (1) above. MS (m / z): 592[M+H]

[0576] (3) Preparation of ((1R)-3-methyl-1-(3-((S)-2-methyl-1-(5,6,7,8-tetrahydronaphthalene-1-carboxamido)propyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.071 g, 61%) was obtained by the production method of Example 1-(4) using 3-((S)-1-(isoquinoline-1-carboxamido)-2-methylpropyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.15 g, 0.25 mmol) obtained in (2) above, according to the method of Example 1-(4). MS (m / z): 458[M+H], 440[M-OH]

[0577] Example 67: Preparation of ((1R)-1-(3-((S)-1-(isoquinoline-1-carboxamido)-2-methylpropyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0578] (1) Preparation of ethyl 3-((S)-1-(isoquinoline-1-carboxamido)-2-methylpropyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using ethyl 3-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-4,5-dihydroisoxazole-5-carboxylate (0.13 g, 0.40 mmol) obtained in Preparation Example 3 and isoquinoline-1-carboxylic acid (0.076 g, 0.44 mmol), the title compound (0.12 g, 82%, two steps) was obtained according to the preparation method of Example 65-(1). MS (m / z): 370[M+H]

[0579] (2) Preparation of 3-((S)-1-(isoquinoline-1-carboxamido)-2-methylpropyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.13 g, 68%, two steps) was obtained by the production method of Example 1-(2) and (3) using ethyl 3-((S)-1-(isoquinoline-1-carboxamido)-2-methylpropyl)-4,5-dihydroisoxazole-5-carboxylate (0.12 g, 0.32 mmol) obtained in (1) above. MS (m / z): 589[M+H]

[0580] (3) Preparation of ((1R)-1-(3-((S)-1-(isoquinoline-1-carboxamido)-2-methylpropyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.070 g, 70%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-((S)-2-methyl-1-(5,6,7,8-tetrahydronaphthalene-1-carboxamido)propyl)-4,5-dihydroisoxazole-5-carboxamide (0.13 g, 0.22 mmol) obtained in (2) above. MS (m / z): 455[M+H], 437[M-OH]

[0581] Example 68: Preparation of ((1R)-1-(3-((2,5-dichlorobenzamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0582] (1) Preparation of ethyl 3-[[(2,5-dichlorobenzoyl)amino]methyl]-4,5-dihydroisoxazole-5-carboxylate [ka] Using ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.1 g, 0.48 mmol) obtained in Example 59-(1) and 2,5-dichlorobenzoic acid (0.1 g, 0.53 mmol), the title compound (0.1 g, 60%) was obtained by the preparation method of Example 59-(2). MS (m / z): 345[M+H]

[0583] (2) Preparation of 3-((2,5-dichlorobenzamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.09 g, 55%, 2 steps) was obtained by the production method of Example 1-(2) and (3) using ethyl 3-[[(2,5-dichlorobenzoyl)amino]methyl]-4,5-dihydroisoxazole-5-carboxylate (0.1 g, 0.29 mmol) obtained in (1) above. MS (m / z): 564[M+H]

[0584] (3) Preparation of ((1R)-1-(3-((2,5-dichlorobenzamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.048 g, 70%) was obtained by the production method of Example 1-(4) using 3-((2,5-dichlorobenzamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.09 g, 0.16 mmol) obtained in (2) above, according to the method of Example 1-(4). 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) MS (m / z): 430[M+H], 412[M-OH]

[0585] Example 69: Preparation of [(1R)-3-methyl-1-[[3-[(naphthalene-2-carbonylamino)methyl]-4,5-dihydro-1,2-oxazole-5-carbonyl]amino]butyl]boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0586] (1) Preparation of ethyl 3-((2-naphthamido)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.12 g, 57%) was obtained by the preparation method of Example 59-(2) using ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.13 g, 0.62 mmol) obtained in Example 59-(1) and 2-naphthoic acid (0.18 g, 0.93 mmol). MS (m / z): 327[M+H]

[0587] (2) Preparation of 3-((2-naphthamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] Using ethyl 3-((2-naphthamido)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.12 g, 0.36 mmol) obtained in (1) above, the title compound (0.074 g, 38%, two steps) was obtained according to the production methods of Example 1-(2) and (3). MS (m / z): 546[M+H]

[0588] (3) Preparation of ((1R)-1-(3-((2-naphthamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.027 g, 49%) was obtained by the production method of Example 1-(4) using 3-((2-naphthamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.074 g, 0.14 mmol) obtained in (2) above, according to the method of Example 1-(4). MS (m / z): 412[M+H], 394[M-OH]

[0589] Example 70: Preparation of ((1R)-1-(3-((4-(tert-butyl)benzamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0590] (1) Preparation of ethyl 3-((4-(tert-butyl)benzamido)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.23 g, 50%, 2 steps) was obtained by the preparation method of Example 59-(2) using ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.28 g, 1.4 mmol) obtained in Example 59-(1) and 4-(tert-butyl)benzoic acid (0.27 g, 1.5 mmol). MS (m / z): 333[M+H]

[0591] (2) Preparation of 3-((4-(tert-butyl)benzamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.030 g, 17%, two steps) was obtained by the preparation methods of Example 1-(2) and (3) using ethyl 3-((4-(tert-butyl)benzamido)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.11 g, 0.32 mmol) obtained in (1) above. MS (m / z): 552[M+H]

[0592] (3) Preparation of ((1R)-1-(3-((4-(tert-butyl)benzamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.007 g, 31%) was obtained by the production method of Example 1-(4) using 3-((4-(tert-butyl)benzamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.030 g, 0.05 mmol) obtained in (2) above, according to the method of Example 1-(4). MS (m / z): 418[M+H], 400[M+H]

[0593] Example 71: Preparation of ((1R)-3-methyl-1-(3-((3-phenoxybenzamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0594] (1) Preparation of ethyl 3-[[(3-phenoxybenzoyl)amino]methyl]-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.05 g, 28%) was obtained by the preparation method of Example 59-(2) using ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.1 g, 0.48 mmol) obtained in Example 59-(1) and 3-phenoxybenzoic acid (0.114 g, 0.53 mmol). 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) MS (m / z): 369[M+H]

[0595] (2) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-((3-phenoxybenzamido)methyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.05 g, 69%, two steps) was obtained using ethyl 3-[[(3-phenoxybenzoyl)amino]methyl]-4,5-dihydroisoxazole-5-carboxylate (0.05 g, 0.14 mmol) obtained in Example 71-(1) and the preparation methods of Example 1-(2) and Example 1-(3). MS (m / z): 588[M+H]

[0596] (3) Preparation of ((1R)-3-methyl-1-(3-((3-phenoxybenzamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.025 g, 54%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-((3-phenoxybenzamido)methyl)-4,5-dihydroisoxazole-5-carboxamide (0.06 g, 0.10 mmol) obtained in Example 71-(2). 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) MS (m / z): 454[M+H], 436[M-OH]

[0597] Example 72: Preparation of ((1R)-1-(3-((S)-1-(2,5-dichlorobenzamido)-2-methylpropyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0598] (1) Preparation of ethyl 3-((S)-1-(2,5-dichlorobenzamido)-2-methylpropyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using ethyl 3-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-4,5-dihydroisoxazole-5-carboxylate (0.18 g, 0.57 mmol) obtained in Preparation Example 3 and 2,5-dichlorobenzoic acid (0.14 g, 0.74 mmol), the title compound (0.087 g, 39%) was obtained according to the preparation method of Example 65-(1). MS (m / z): 387[M+H]

[0599] (2) Preparation of 3-((S)-1-(2,5-dichlorobenzamido)-2-methylpropyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.040 g, 29%, two steps) was obtained by the preparation methods of Example 1-(2) and (3) using ethyl 3-((S)-1-(2,5-dichlorobenzamido)-2-methylpropyl)-4,5-dihydroisoxazole-5-carboxylate (0.087 g, 0.22 mmol) obtained in (1) above. MS (m / z): 606[M+H]

[0600] (3) Preparation of ((1R)-1-(3-((S)-1-(2,5-dichlorobenzamido)-2-methylpropyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.004 g, 13%) was obtained by the production method of Example 1-(4) using 3-((S)-1-(2,5-dichlorobenzamido)-2-methylpropyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.040 g, 0.07 mmol) obtained in (2) above, according to the method of Example 1-(4). MS (m / z): 472[M+H], 454[M-OH]

[0601] Example 73: Preparation of ((1R)-1-(3-((S)-1-(isoquinoline-1-carboxamido)-3-methylbutyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), and (4).

[0602] (1) Preparation of ethyl 3-((S)-1-amino-3-methylbutyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride [ka] The title compound (0.41 g, quant.) was obtained by the production method of Example 59-(1) using ethyl 3-((S)-1-((tert-butoxycarbonyl)amino)-3-methylbutyl)-4,5-dihydroisoxazole-5-carboxylate (0.51 g, 1.6 mmol) obtained in Production Example 4.

[0603] (2) Preparation of ethyl 3-((S)-1-(isoquinoline-1-carboxamido)-3-methylbutyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using ethyl 3-((S)-1-amino-3-methylbutyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.14 g, 0.53 mmol) obtained in (1) above and isoquinoline-1-carboxylic acid (0.092 g, 0.53 mmol), the title compound (0.10 g, 49%) was obtained according to the production method of Example 59-(2). MS (m / z): 384[M+H]

[0604] (3) Preparation of 3-((S)-1-(isoquinoline-1-carboxamido)-3-methylbutyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.11 g, 63%, two steps) was obtained by the production method of Example 1-(2) and (3) using ethyl 3-((S)-1-(isoquinoline-1-carboxamido)-3-methylbutyl)-4,5-dihydroisoxazole-5-carboxylate (0.10 g, 0.26 mmol) obtained in (2) above. MS (m / z): 603[M+H]

[0605] (4) Preparation of ((1R)-1-(3-((S)-1-(isoquinoline-1-carboxamido)-3-methylbutyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.065 g, 76%) was obtained by the production method of Example 1-(4) using 3-((S)-1-(isoquinoline-1-carboxamido)-3-methylbutyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.11 g, 0.18 mmol) obtained in (3) above, according to the method of Example 1-(4). MS (m / z): 469[M+H], 451[M-OH]

[0606] Example 74: Preparation of ((1R)-1-(3-((S)-1-(2,5-dichlorobenzamido)-3-methylbutyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0607] (1) Preparation of ethyl 3-((S)-1-(2,5-dichlorobenzamido)-3-methylbutyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using ethyl 3-((S)-1-amino-3-methylbutyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.12 g, 0.45 mmol) obtained in Example 73-(1) and 2,5-dichlorobenzoic acid (0.096 g, 0.50 mmol), the title compound (0.098 g, 54%) was obtained by the preparation method of Example 59-(2). MS (m / z): 401[M+H]

[0608] (2) Preparation of 3-((S)-1-(2,5-dichlorobenzamido)-3-methylbutyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.047 g, 31%, two steps) was obtained by the preparation methods of Example 1-(2) and (3) using ethyl 3-((S)-1-(2,5-dichlorobenzamido)-3-methylbutyl)-4,5-dihydroisoxazole-5-carboxylate (0.098 g, 0.24 mmol) obtained in (1) above. MS (m / z): 620[M+H]

[0609] (3) Preparation of ((1R)-1-(3-((S)-1-(2,5-dichlorobenzamido)-3-methylbutyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.006 g, 17%) was obtained by the production method of Example 1-(4) using 3-((S)-1-(2,5-dichlorobenzamido)-3-methylbutyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.047 g, 0.08 mmol) obtained in (2) above, according to the method of Example 1-(4). MS (m / z): 486[M+H], 488[M+H], 468[M-OH], 470[M-OH]

[0610] Example 75: Preparation of ((1R)-1-(3-((2,5-dichlorobenzyl)carbamoyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), and (4).

[0611] (1) Preparation of ethyl 3-{[(2,5-dichlorophenyl)methyl]carbamoyl}-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] 5-(Ethoxycarbonyl)-4,5-dihydro-1,2-oxazole-3-carboxylic acid (0.15 g, 0.82 mmol) obtained in Preparation 5 was dissolved in dimethylformamide (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.4 g, 4.06 mmol), 2,5-dichlorobenzylamine (0.16 g, 0.90 mmol), and diisopropylethylamine (0.43 mL) were added sequentially and stirred at room temperature for 16 hours. The solvent was distilled under reduced pressure, and aqueous sodium bicarbonate solution was added. The mixture was extracted twice with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to obtain the title compound (0.16 g, 57%). 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) MS (m / z): 345[M+H]

[0612] (2) Preparation of 3-{[(2,5-dichlorophenyl)methyl]carbamoyl}-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.15 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 3-{[(2,5-dichlorophenyl)methyl]carbamoyl}-4,5-dihydro-1,2-oxazole-5-carboxylate (0.16 g, 0.46 mmol) obtained in (1) above, according to the method of Example 1-(2). MS (m / z): 317[M+H]

[0613] (3) Preparation of N3-(2,5-dichlorobenzyl)-N5-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-3,5-dicarboxamide [ka] The title compound (0.18 g, 69%) was obtained by the production method of Example 1-(3) using 3-{[(2,5-dichlorophenyl)methyl]carbamoyl}-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.15 g, 0.47 mmol) obtained in (2) above. MS (m / z): 564[M+H]

[0614] (4) Preparation of ((1R)-1-(3-((2,5-dichlorobenzyl)carbamoyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.092 g, 65%) was obtained by the production method of Example 1-(4) using N3-(2,5-dichlorobenzyl)-N5-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-3,5-dicarboxamide (0.18 g, 0.33 mmol) obtained in (3) above, according to the method of Example 1-(4). 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) MS (m / z): 430[M+H], 412[M-OH]

[0615] Example 76: Preparation of ((1R)-3-methyl-1-(3-(naphthalen-1-ylcarbamoyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0616] (1) Preparation of ethyl 3-[(naphthalen-1-yl)carbamoyl]-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] Using 5-(ethoxycarbonyl)-4,5-dihydro-1,2-oxazole-3-carboxylic acid (0.16 g, 0.85 mmol) obtained in Preparation Example 5 and the preparation method of Example 75-(1), the title compound (0.15 g, 56%) was obtained. NMR: 1H-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) MS (m / z): 313[M+H]

[0617] (2) Preparation of 3-[(naphthalen-1-yl)carbamoyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.14 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 3-[(naphthalen-1-yl)carbamoyl]-4,5-dihydro-1,2-oxazole-5-carboxylate (0.15 g, 0.49 mmol) obtained in (1) above and the production method of Example 1-(2). MS (m / z): 285[M+H]

[0618] (3) Preparation of ((1R)-3-methyl-1-(3-(naphthalen-1-ylcarbamoyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.076 g, 38%, 2 steps) was obtained by the preparation method of Example 75-(3) and (4) using 3-[(naphthalen-1-yl)carbamoyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.14 g, 0.50 mmol) obtained in (2) above. NMR: 1H-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) MS (m / z): 398[M+H], 380[M-OH / ]

[0619] Example 77: Preparation of ((1R)-1-(3-((3-chlorophenyl)carbamoyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0620] (1) Preparation of ethyl 3-[(3-chlorophenyl)carbamoyl]-4,5-dihydro-1,2-oxazole-5-carboxylate [ka] Using 5-(ethoxycarbonyl)-4,5-dihydro-1,2-oxazole-3-carboxylic acid (0.17 g, 0.91 mmol) obtained in Preparation Example 5 and the preparation method of Example 75-(1), the title compound (0.16 g, 56%) was obtained. NMR: 1 H-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) MS (m / z): 297[M+H]

[0621] (2) Preparation of 3-[(3-chlorophenyl)carbamoyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid [ka] The title compound (0.14 g, 99%) was obtained by the production method of Example 1-(2) using ethyl 3-[(3-chlorophenyl)carbamoyl]-4,5-dihydro-1,2-oxazole-5-carboxylate (0.16 g, 0.52 mmol) obtained in (1) above and the production method of Example 1-(2). MS (m / z): 269[M+H]

[0622] (3) Preparation of ((1R)-1-(3-((3-chlorophenyl)carbamoyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.081 g, 42%, 2 steps) was obtained by the preparation method of Example 75-(3) and (4) using 3-[(3-chlorophenyl)carbamoyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.14 g, 0.51 mmol) obtained in (2) above. NMR: 1 H-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) MS (m / z): 382[M+H], 364[M-OH]

[0623] Example 78: Preparation of ((1R)-1-(3-((2,3-dihydro-1H-indene-2-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0624] (1) Preparation of ethyl 3-((2,3-dihydro-1H-indene-2-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.15 g, 36%) was obtained by the preparation method of Example 59-(2) using ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.28 g, 1.4 mmol) obtained in Example 59-(1) and 2-indancarboxylic acid (0.24 g, 1.5 mmol). MS (m / z): 317[M+H]

[0625] (2) Preparation of 3-((2,3-dihydro-1H-indene-2-carboxamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.10 g, 37%, two steps) was obtained using the preparation method of Example 1-(2) and (3) using ethyl 3-((2,3-dihydro-1H-indene-2-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.15 g, 0.48 mmol) obtained in (1) above. MS (m / z): 536[M+H]

[0626] (3) Preparation of ((1R)-3-methyl-1-(3-((2-phenylacetamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.024 g, 32%) was obtained by the production method of Example 1-(4) using 3-((2,3-dihydro-1H-indene-2-carboxamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.10 g, 0.19 mmol) obtained in (2) above, according to the method of Example 1-(4). MS (m / z): 402[M+H], 384[M-OH]

[0627] Example 79: Preparation of ((1R)-3-methyl-1-(3-((2-phenylacetamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0628] (1) Preparation of ethyl 3-((2-phenylacetamido)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] The title compound (0.19 g, 50%) was obtained by the preparation method of Example 59-(2) using ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.28 g, 1.3 mmol) obtained in Example 59-(1) and phenylacetic acid (0.2 g, 1.5 mmol). MS (m / z): 333[M+H]

[0629] (2) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-((2-phenylacetamido)methyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.042 g, 12%, two steps) was obtained by the preparation methods of Example 1-(2) and (3) using ethyl 3-((2-phenylacetamido)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.19 g, 0.67 mmol) obtained in (1) above. MS (m / z): 552[M+H]

[0630] (3) Preparation of ((1R)-3-methyl-1-(3-((2-phenylacetamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.011 g, 36%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-((2-phenylacetamido)methyl)-4,5-dihydroisoxazole-5-carboxamide (0.042 g, 0.08 mmol) obtained in (2) above, according to the method of Example 1-(4). MS (m / z): 376[M+H], 358[M-OH]

[0631] Example 80: Preparation of ((1R)-3-methyl-1-(3-((1,2,3,4-tetrahydronaphthalene-1-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0632] (1) Preparation of ethyl 3-[(1,2,3,4,4a,8a-hexahydronaphthalene-1-carbonylamino)methyl]-4,5-dihydroisoxazole-5-carboxylate [ka] Using ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.17 g, 0.82 mmol) obtained in Example 59-(1) and 1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (0.14 g, 0.90 mmol), the title compound (0.11 g, 41%) was obtained by the preparation method of Example 59-(2). 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) MS (m / z): 333[M+H]

[0633] (2) Preparation of 3-((1,2,3,4,4a,8a-hexahydronaphthalene-1-carboxamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.073 g, 40%, two steps) was obtained by the production method of Example 1-(2) and (3) using ethyl 3-[(1,2,3,4,4a,8a-hexahydronaphthalene-1-carbonylamino)methyl]-4,5-dihydroisoxazole-5-carboxylate (0.11 g, 0.33 mmol) obtained in (1) above. MS (m / z): 550[M+H]

[0634] (3) Preparation of ((1R)-3-methyl-1-(3-((1,2,3,4-tetrahydronaphthalene-1-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.025 g, 45%) was obtained by the production method of Example 1-(4) using 3-((1,2,3,4,4a,8a-hexahydronaphthalene-1-carboxamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.073 g, 0.13 mmol) obtained in (2) above, according to the method of Example 1-(4). 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) MS (m / z): 416[M+H], 398[M-OH]

[0635] Example 81: Preparation of ((1R)-3-methyl-1-(3-((5-methylisoxazole-3-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0636] (1) Preparation of ethyl 3-[[(5-methylisoxazole-3-carbonyl)amino]methyl]-4,5-dihydroisoxazole-5-carboxylate [ka] Using ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.18 g, 0.87 mmol) obtained in Example 59-(1) and 5-methyl-isoxazole-3-carboxylic acid (0.11 g, 0.87 mmol), the title compound (0.07 g, 29%) was obtained according to the preparation method of Example 59-(2). 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) MS (m / z): 282[M+H]

[0637] (2) Preparation of 5-methyl-N-((5-(((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)carbamoyl)-4,5-dihydroisoxazol-3-yl)methyl)isoxazole-3-carboxamide [ka] The title compound (0.04 g, 34%, two steps) was obtained by the preparation methods of Example 1-(2) and (3) using ethyl 3-[[(5-methylisoxazole-3-carbonyl)amino]methyl]-4,5-dihydroisoxazole-5-carboxylate (0.07 g, 0.25 mmol) obtained in (1) above. MS (m / z): 501[M+H]

[0638] (3) Preparation of ((1R)-3-methyl-1-(3-((5-methylisoxazole-3-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.017 g, 59%) was obtained by the production method of Example 1-(4) using 5-methyl-N-((5-(((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)carbamoyl)-4,5-dihydroisoxazol-3-yl)methyl)isoxazole-3-carboxamide (0.04 g, 0.08 mmol) obtained in Example 81-(2). 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) MS (m / z): 367[M+H], 349[M-OH]

[0639] Example 82: Preparation of ((1R)-1-(3-((5-fluoro-2-methylbenzamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0640] (1) Preparation of ethyl 3-[[(5-fluoro-2-methyl-benzoyl)amino]methyl]-4,5-dihydroisoxazole-5-carboxylate [ka] Using ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.14 g, 0.67 mmol) obtained in Example 59-(1) and 5-fluoro-2-methyl-benzoic acid (0.1 g, 0.67 mmol), the title compound (0.12 g, 58%) was obtained by the preparation method of Example 59-(2). NMR: 1 H-NMR(400MHz, CDCl3); δ 7.20-7.01 (m, 3H) 6.62 (m, 1H), 5.06-5.02 (dd, 1H), 4.41-4.37 (d, 2H), 4.29-4.21 (q, 2H), 3.38-3.12 (m, 2H), 2.38 (s, 3H), 1.32-1.29 (t, 3H) MS (m / z): 309[M+H]

[0641] (2) Preparation of 3-((5-fluoro-2-methylbenzamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.05 g, 27%, 2 steps) was obtained by the production method of Example 1-(2) and (3) using ethyl 3-[[(5-fluoro-2-methyl-benzoyl)amino]methyl]-4,5-dihydroisoxazole-5-carboxylate (0.12 g, 0.39 mmol) obtained in (1) above. MS (m / z): 528[M+H]

[0642] (3) Preparation of ((1R)-1-(3-((5-fluoro-2-methylbenzamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid [ka] The title compound (0.019 g, 50%) was obtained by the production method of Example 1-(4) using 3-((5-fluoro-2-methylbenzamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide (0.05 g, 0.095 mmol) obtained in (2) above, according to the production method of Example 1-(4). NMR: 1 H-NMR(500MHz, CD3OD); δ 7.27-7.24 (dd, 1H), 7.14-7.05 (m, 2H), 5.28-5.23 (m, 1H), 4.28 (s, 2H), 3.52-3.46 (m, 1H), 3.33-3.29 (m, 1H), 2.83-2.80 (m, 1H), 2.34 (s, 3H), 1.66-1.62 (m, 1H), 1.37-1.33 (m, 2H), 0.90-0.88 (dd, 6H) MS (m / z): 394[M+H], 376[M-OH]

[0643] Example 83: Preparation of ((1R)-3-methyl-1-(3-((pyrazine-2-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid The title compound was obtained through the following steps (1), (2), and (3).

[0644] (1) Preparation of ethyl 3-((pyrazine-2-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Using ethyl 3-(aminomethyl)-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.14 g, 0.67 mmol) obtained in Example 59-(1) and pyrazine-2-carboxylic acid (0.084 g, 0.67 mmol), the title compound (0.07 g, 37%) was obtained according to the preparation method of Example 59-(2). NMR: 1 H-NMR(400MHz, CDCl3); δ 9.43 (s, 1H), 8.79-8.77 (d, 1H), 8.57-8.56 (d, 1H), 8.25 (m, 1H), 5.11-5.04 (dd, 1H), 4.51-4.56 (dd, 2H), 4.29-4.22 (q, 2H), 3.36-3.29 (m, 2H), 1.32-1.29 (t, 3H) MS (m / z): 279[M+H]

[0645] (2) Preparation of N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-((pyrazine-2-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The title compound (0.02 g, 16%, 2 steps) was obtained using ethyl 3-((pyrazine-2-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.07 g, 0.25 mmol) obtained in Example 83-(1) and the preparation methods of Example 1-(2) and (3). MS (m / z): 501[M+H], 349[M+H]

[0646] (3) Preparation of ((1R)-3-methyl-1-(3-((pyrazine-2-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)butyl)boronic acid [ka] The title compound (0.005 g, 33%) was obtained by the production method of Example 1-(4) using N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-((pyrazine-2-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamide (0.02 g, 0.04 mmol) obtained in Example 83-(2). NMR: 1 H-NMR(500MHz, CD3OD); δ 9.22 (s, 1H), 8.78-8.67 (m, 2H), 5.24-5.21 (m, 1H), 4.36 (s, 2H), 3.50-3.44 (m, 1H), 3.27-3.24 (m, 1H), 2.81-2.78 (m, 1H), 1.62-1.60 (m, 1H), 1.35-1.31 (m, 2H), 0.89-0.88 (d, 6H) MS (m / z): 364[M+H], 349[M+H]

[0647] Example 84: Preparation of ((1R)-1-(5-benzyl-3-((isoquinoline-1-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxamido)-3-methylbutyl)boronic acid The title compound was obtained through the following steps (1), (2), (3), (4), and (5).

[0648] (1) Preparation of methyl 3-(aminomethyl)-5-benzyl-4,5-dihydroisoxazole-5-carboxylate hydrochloride [ka] Methyl 5-benzyl-3-(((tert-butoxycarbonyl)amino)methyl)-4,5-dihydroisoxazole-5-carboxylate (2.6 g, 7.47 mmol) obtained in Preparation Example 6 was dissolved in dichloromethane (30 ml). 4N hydrochloric acid in 1,4-dioxane (15 ml, 59.74 mmol) was slowly added at 0°C, and the mixture was stirred for 5 hours while warming to room temperature. The solvent was distilled under reduced pressure, and then solidified with dichloromethane and hexane. The remaining solvent was distilled under reduced pressure and dried under reduced pressure to obtain the title compound (2.1 g, 99%). MS (m / z): 249[M+H]

[0649] (2) Preparation of methyl 5-benzyl-3-((isoquinoline-1-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxylate [ka] Methyl 3-(aminomethyl)-5-benzyl-4,5-dihydroisoxazole-5-carboxylate hydrochloride (0.29 g, 1.02 mmol) obtained in (1) above was dissolved in dimethylformamide (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.254 g, 1.32 mmol), hydroxybenzotriazole (0.179 g, 1.32 mmol), and isoquinoline-1-carboxylic acid (0.194 g, 1.12 mmol) were added sequentially. Diisopropylethylamine (0.53 mL, 3.06 mmol) was slowly added, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled under reduced pressure, and aqueous sodium bicarbonate was added. The mixture was extracted twice with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (0.32 g, 78%). NMR: 1H-NMR(400MHz, CDCl3); δ 9.55-9.52 (d, 1H), 8.48-8.47 (t, 1H), 8.39 (m, 1H), 7.88-7.83 (m, 2H), 7.76-7.68 (m, 2H), 7.22-7.14 (m, 5H), 4.35-4.24 (m, 2H), 3.76 (s, 3H), 3.50-3.46 (d, 1H), 3.33-3.29 (d, 1H), 3.14-3.11 (d, 1H), 3.10-3.06 (d, 1H) MS (m / z): 404[M+H]

[0650] (3) Preparation of 5-benzyl-3-[(isoquinoline-1-carbonylamino)methyl]-4-1,2-oxazole-5-carboxylic acid [ka] Methyl 5-benzyl-3-((isoquinoline-1-carboxamido)methyl)-4,5-dihydroisoxazole-5-carboxylate (0.32 g, 0.80 mmol) obtained in (2) above was dissolved in methanol (10 mL), and 1N aqueous sodium hydroxide solution (4.0 mL, 4.0 mmol) was added. The mixture was stirred at room temperature for 5 hours. The pH was adjusted to 1 with 1N hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain 5-benzyl-3-[(isoquinoline-1-carbonylamino)methyl]-4H-1,2-oxazole-5-carboxylic acid (0.31 g, 99%). MS (m / z): 390[M+H]

[0651] (4) Preparation of 5-benzyl-3-((isoquinoline-1-carboxamido)methyl)-N-((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-4,5-dihydroisoxazole-5-carboxamide [ka] The 5-benzyl-3-[(isoquinoline-1-carbonylamido)methyl]-4H-1,2-oxazole-5-carboxylic acid (0.31 g, 0.80 mmol) obtained in (3) above, (1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0] 2,6 [Decan-4-yl]butan-1-amine hydrochloride (0.24 g, 0.81 mmol) and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.29 g, 0.89 mmol) were dissolved in dimethylformamide (5 mL) at 0°C. While maintaining the temperature at 0°C, diisopropylethylamine (0.42 mL, 2.42 mmol) was slowly added, and the mixture was stirred for 18 hours while warming to room temperature. The solv...

Claims

1. A compound represented by the following chemical formula 1, a pharmaceutically acceptable salt or stereoisomer thereof: 【Chemical 1】 (In the above formula, R １ represents a 5-6 membered heteroaryl or heterocycloalkyl containing 1 or 2 heteroatoms selected from C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, N, O, and S atoms, or a fused bicyclo ring in which a substituted or unsubstituted 4-8 membered aliphatic ring or 5-6 membered aromatic ring having 0-4 heteroatoms selected from the group consisting of O, N, and S is fused to a substituted or unsubstituted 4-8 membered aliphatic ring or 5-6 membered aromatic ring having 0-4 heteroatoms selected from the group consisting of O, N, and S; R １ is a halogen, an amine, nitro, a nitrile, an acetonitrile, an ether, an alkyl halide, a C1-C6 alkyl, a C3-C6 cycloalkyl, a C1-C6 heteroalkyl having one or two heteroatoms selected from N, O, and S atoms, a C1-C6 alkoxy, a phenyl, a phenoxy, a 5- to 6-membered heteroaryl or heterocycloalkyl containing one or two heteroatoms selected from N, O, and S atoms, or a 5- to 6-membered heteroaryloxy or heterocycloalkyloxy containing one or two heteroatoms selected from N, O, and S atoms, and R １２ (C═O)NH, and R １２ is hydrogen or C1-C3 alkyl, and the substituent may be substituted with one or more selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 alkoxy; R ２ represents hydrogen; R ３ represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, or 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S atoms, or R ２ and R ３ may be bonded to each other to form a 3- to 6-membered aliphatic ring, in which case L ２ does not exist, R ３ is optionally substituted with halogen, halogenated methyl, C1-C3 alkyl, phenyl, or C1-C3 alkoxy; R ４ represents C1-C6 alkyl, C3-C6 cycloalkyl, or phenyl; L １ａ is (CH ２ ) ｌ (l is an integer of 0 to 3) or C(CH ２ CH ２ ) represents; L １ｂ is a direct bond or (C=O)NH, NH(C=O), NH, (CH ２ ) ｍ O (m is an integer of 0 to 3), (C=O)N(CH ３ ), or S(O ２ ) represents NH; L １ｃ is (CH ２ ) ｎ (n is an integer of 0 to 3), CHR ５ or CR ６ R ７ where R ５ is a C1-C3 heteroalkyl or a C1-C4 alkyl having 1 or 2 heteroatoms selected from the group consisting of O, N, and S; R ６ and R ７ are each independently C1-C3 alkyl; L ２ is (CH ２ ) ｏ (o is an integer of 0 to 3), (CH ２ ) ｐ O (p is an integer of 1 to 3), CHR ８ , CX １ X ２ , or C(CH ２ CH ２ ), where R ８ is OH, halogen, or C1-C3 alkyl; X １ and X ２ are each independently a halogen; L ３ is (CH ２ ) ｑ (q is an integer of 0 to 3) or CHR ９ where R ９ is C1-C3 alkyl; Z １ and Z ２ are each independently OH, or both are 【Chemistry 2】 Alternatively, a cyclic borate ester of the following structure may be formed: 【Chemistry 3】 (where r is 0 or 1, and R １１ ~R １６ are each independently hydrogen, hydroxy, or substituted or unsubstituted C1-C4 alkyl, wherein the substituent is hydroxy.

2. R １ represents a C3-C6 cycloalkyl, a 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from phenyl, N, O, and S atoms, or a fused bicyclo ring in which a substituted or unsubstituted 4-8 membered aliphatic ring or a 5-6 membered aromatic ring having 0-4 heteroatoms selected from the group consisting of O, N, and S is fused to a substituted or unsubstituted 4-8 membered aliphatic ring or a 5-6 membered aromatic ring having 0-4 heteroatoms selected from the group consisting of O, N, and S; R １ is a halogen, an amine, nitro, a nitrile, an acetonitrile, an ether, an alkyl halide, a C1-C6 alkyl, a C3-C6 cycloalkyl, a C1-C6 heteroalkyl having one or two heteroatoms selected from N, O, and S atoms, a C1-C6 alkoxy, a phenyl, a phenoxy, a 5- to 6-membered heteroaryl or heterocycloalkyl containing one or two heteroatoms selected from N, O, and S atoms, or a 5- to 6-membered heteroaryloxy or heterocycloalkyloxy containing one or two heteroatoms selected from N, O, and S atoms, and R １２ (C═O)NH; R １２ is hydrogen or C1-C3 alkyl, and the substituent may be substituted with one or more selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 alkoxy; R ２ represents hydrogen; R ３ represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, or 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S atoms, or R ２ and R ３ may be bonded to each other to form a 3- to 6-membered aliphatic ring, in which case L ２ does not exist, R ３ is optionally substituted with halogen, halogenated methyl, C1-C3 alkyl, or C1-C3 alkoxy; R ４ represents C1-C6 alkyl or phenyl; L １ａ is (CH ２ ) ｌ (l is an integer of 0 to 3) or C(CH ２ CH ２ ) represents; L １ｂ is a direct bond or (C=O)NH, NH, (CH ２ ) ｍ O (m is an integer of 0 to 3), (C=O)N(CH ３ ), or S(O ２ ) represents NH; L １ｃ is (CH ２ ) ｎ (n is an integer of 0 to 3), CHR ５ or CR ６ R ７ where R ５ is a C1-C3 heteroalkyl or a C1-C4 alkyl having one heteroatom that is O, and R ６ and R ７ are each independently C1-C3 alkyl; L ２ is (CH ２ ) ｏ (o is an integer of 0 to 3), (CH ２ ) ｐ O (p is an integer of 1 to 3), CHR ８ , CX １ X ２ , or C(CH ２ CH ２ ), where R ８ is OH, halogen, or C1-C3 alkyl; X １ and X ２ are each independently a halogen; L ３ is (CH ２ ) ｑ (q is an integer of 0 to 3); Z １ and Z ２ are each independently OH, or both are 【Chemistry 4】 Alternatively, the compound of claim 1, its pharmaceutically acceptable salt or stereoisomer may form a cyclic boric acid ester of the following structure: 【Chemistry 5】 (where r is 1 and R １１ ~R １６ are each independently hydrogen, hydroxy, or substituted or unsubstituted C1-C4 alkyl, wherein the substituent is hydroxy.

3. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, for use as an inhibitor of chymotrypsin-like activity in the proteasome.

4. 10. A compound according to claim 1, a pharmaceutically acceptable salt or stereoisomer thereof, for use in the prevention or treatment of a proteasome-mediated disease.

5. A pharmaceutical composition for inhibiting chymotrypsin-like activity in the proteasome, comprising the compound of claim 1 or 2, a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition for preventing or treating a proteasome-mediated disease, comprising the compound of claim 1 or 2, a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition for preventing or treating a proteasome-mediated disease according to claim 6, wherein the proteasome-mediated disease is cancer.

8. The cancers include brain tumors, benign astrocytoma, malignant astrocytoma, pituitary adenoma, brain meningioma, brain lymphoma, oligodendroglioma, craniopharyngioma, ependymoma, brain stem tumor, head and neck tumor, laryngeal cancer, oropharynx cancer, nasal cavity / paranasal sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, neuroblastoma, breast tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, stomach cancer, liver cancer, gallbladder cancer, The pharmaceutical composition for preventing or treating a proteasome-mediated disease described in claim 7, wherein the cancer is selected from the group consisting of biliary tract cancer, pancreatic cancer, small intestine cancer, colon cancer, anal cancer, bladder cancer, kidney cancer, male reproductive organ tumors, penile cancer, urethral cancer, prostate cancer, female reproductive organ tumors, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female external genital organ cancer, female urethral cancer, skin cancer, myeloma, leukemia, lymphoma, and malignant lymphoma.

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