Boronic Acid Derivatives

Abstract

The present invention relates to boronic acid derivatives, and provides compounds of formula (I) or pharma-ceutically acceptable salts, solvates, crystalline polymorphs or isomers thereof, pharmaceutical compositions containing these compounds, and the use of such compounds in the treatment of diseases associated with lmp7. [Formula 1] TIFF2024537383000125.tif74115

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to Chinese Patent Application No. 202111200305.3, filed on October 14, 2021, entitled "Boronic Acid Derivatives," Chinese Patent Application No. 202210110439.4, filed on February 7, 2022, entitled "Boronic Acid Derivatives," and Chinese Patent Application No. 202211046052.3, filed on August 30, 2022, entitled "Boronic Acid Derivatives," the disclosures of which are incorporated herein by reference in their entireties. [Technical Field]

[0002] The present application relates to novel boronic acid derivatives represented by formula (I) or pharmaceutically acceptable salts thereof. The present application also provides pharmaceutical compositions containing such compounds and methods for their preparation. The compounds described herein can be used to treat or prevent immunoproteasome-related diseases. [Background technology]

[0003] The ubiquitin-proteasome system (UPS) is present in all eukaryotic cells and is responsible for the degradation of misfolded or redundant proteins within the cell. By regulating protein homeostasis, it regulates almost all important biological processes, including signal transduction, transcriptional regulation, cell differentiation, and apoptosis. The 26S proteasome (called the 26S proteasome because its sedimentation coefficient in density gradient centrifugation is 26S) is structurally divided into two parts: the 19S regulatory particle and the 20S core particle. The 19S regulatory particle recognizes and unfolds ubiquitin-tagged proteins, ultimately sending the unfolded proteins to the 20S core particle for degradation. The 20S proteasome has a barrel-shaped structure composed of four rings. The two outer rings, each of which serves as a binding site for the regulatory particle and also acts as a "gate" to prevent unregulated proteins from entering the core particle. Each ring contains seven α subunits. The two inner rings each contain seven β subunits, including the protease-active subunits β1c, β2c, and β5c, responsible for protein hydrolysis. In hematopoietic cells and cells stimulated with interferon (IFN)-γ or tumor necrosis factor (TNF)-α, these active subunits are replaced by β1i (LMP2, low molecular weight polypeptide 2), β2i (MECL-1, multicatalytic endopeptidase complex-1), and β5i (LMP7), forming the immunoproteasome (Michael Basler et al., EMBO Reports, 2018). LMP7, encoded by the PSMB8 gene, is a small protein of approximately 30 kDa with a total of 276 amino acids. LMP7 is a core catalytic subunit of the immunoproteasome with chymotrypsin activity and plays an important role in the process of protein hydrolysis by the immunoproteasome (A. Arkhjami et al., Immune and non-immune functions of the immunoproteasome, Frontiers in Bioscience, 17(1):1904, 2012).

[0004] The function of the immunoproteasome in immune processes, particularly its antigen presentation function, has been extensively studied. Polypeptides generated by hydrolysis by the catalytic subunit of the immunoproteasome are presented on the cell surface by major histocompatibility complex (MHC)-1, triggering cytotoxic T lymphocyte (CTL) responses. Compared with the proteasome, the immunoproteasome is more efficient at hydrolyzing proteins and presenting antigens, and the generated antigens can trigger stronger CTL responses. Several studies have demonstrated that the immunoproteasome can regulate cytokine production. Selective inhibition of LMP7 with a small molecule inhibitor inhibited both IL-23 in monocytes and TNF-α and IL-6 in T cells, and a similar phenomenon was observed in an animal model of rheumatoid arthritis (T. Muchamuel et al., A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis, Nat Med, 15(7), 781-7, 2009). Several studies have also confirmed the role of the immunoproteasome in T cell differentiation, proliferation, and apoptosis (CM Caudill et al., T cells lacking immunoproteasome subunits MECL-1 and LMP7 hyperproliferate in response to polyclonal mitogens, J. Immunol, 176(7), 4075-82, 2006). In addition to its immune function, the immunoproteasome also plays a role in maintaining protein homeostasis in the cytokine-induced oxidative stress response. In the oxidative stress response, free radicals are released, causing the accumulation of damaged proteins, which ultimately leads to cell death if the oxidative stress response exceeds the normal removal capacity of the proteasome. The immunoproteasome can efficiently resolve protein accumulation and maintain cellular homeostasis.In LMP7 / β5i- and LMP2 / β1i-deficient mice, accumulation of oxidized and polyubiquitinated proteins was observed in the liver and brain (U. Seifert et al., Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress, Cell, 142(4), 613-24, 2010).

[0005] The immunoproteasome is involved in various diseases. Studies have shown that immunoproteasomes are highly expressed in leukemia, and selective inhibition of β1i and LMP7 effectively inhibits the proliferation of patient-derived cells and tumor models (U. Seifert et al., Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress, Cell, 142(4), 613-24, 2010). A study of 668 breast cancer patients found that LMP7 was highly expressed in tumors in 40% of patients (M. Lee et al., Expression of Immunoproteasome Subunit LMP7 in Breast Cancer and Its Association with Immune-Related Markers, Cancer Research and Treatment, 51(1), 2018). The immunoproteasome promotes the development and progression of colorectal cancer, and LMP7 inhibitors can effectively inhibit colorectal cancer formation in mouse models (J. Koerner et al., "Inhibition and deficiency of the immunoproteasome subunit LMP7 suppress the development and progression of colorectal carcinoma in mice," Oncotarget, 8(31):50873-50888, 2017). Recent evidence supports the involvement of the immunoproteasome in autoimmune diseases, making it a promising therapeutic target for such diseases. The immunoproteasome is highly expressed in autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease (T. Egerer et al., "Tissue-specific up-regulation of the proteasome subunit β5i (LMP7) in Sjogren's syndrome," Arthritis Rheum, 54(5), 1501-8, 2006).In two mouse models of arthritis, an LMP7-selective inhibitor reduced the degree of inflammatory infiltration and cytokine levels, alleviating arthritis symptoms (J. Koerner et al., “Inhibition and deficiency of the immunoproteasome subunit LMP7 suppress the development and progression of colorectal carcinoma in mice,” Oncotarget, 8(31):50873-50888, 2017). The immunoproteasome is involved in neurodegenerative diseases, and studies have reported that it is highly expressed in the brains of patients with Alzheimer's disease (M. Diaz-Hernandez et al., “Neuronal Induction of the Immunoproteasome in Huntington's Disease,” Journal of Neuroscience, 23(37):11653-11661, 2003).

[0006] Targeting LMP7, a catalytic subunit of the immunoproteasome, to treat various diseases is an innovative field with ample room for development. Compared to broad-spectrum proteasome inhibitors, selective LMP7 inhibitors have an absolute advantage in terms of safety. Patents such as WO2019099582A1 and WO2019038250A1 disclose several LMP7 inhibitors and methods for using them to treat related diseases.

[0007] This application describes boronic acid derivatives that have excellent inhibitory activity against LMP7 and excellent selectivity for other proteasomes. Furthermore, such compounds have excellent oral bioavailability, plasma protein adsorption, pharmacokinetic properties, and in vivo activity, as well as lower toxicity and CYP-inhibition and a broader potential administration period. Summary of the Invention

[0008] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof:

[0009] [ka] During the ceremony, R a , R b are each independently selected from H and a C alkyl group, or R a and R b may be connected to form a 3-10 membered heterocycle, the heterocycle may be optionally substituted by (C=O), halogen or a C1-6 alkyl group, the alkyl group may be optionally substituted by -COOH, the heterocycle may be optionally fused with a benzene ring or a 5-6 membered heteroaromatic ring, the benzene ring or the 5-6 membered heteroaromatic ring may be optionally substituted by halogen or a C1-6 alkyl group, R 2 , R 20 are each independently selected from H and a C alkyl group; L is -CR 4 R 5 - and R 4 , R 5 are each independently selected from H, a C alkyl group, and a 3-8 membered cycloalkyl group; R 1 is selected from -OH, a C1-6 alkyl group, -O-C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocycloalkyl group, a 6-10-membered aryl group, and a 5-12-membered heteroaryl group, wherein the alkyl group, cycloalkyl group, and heterocycloalkyl group may optionally be oxo-substituted, and the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group may optionally be substituted with halogen, -CN, -OH, -NH2, NO2, -(CH2)0-6-R 7 , -(CH2)0~6-CF3, -OR 6 , -NR 10 R6 , C1-6 alkyl group, -(CH2)0-3-(CO)-R 6 , -(CH2)0~3-(CO)-NH-R 6 , -(CH2)0~3-NH-(CO)-R 6 ,

[0010] [ka] , or

[0011] [ka] or R 1 and R 20 are connected to form a 3- to 12-membered heterocycle, and the heterocycle may optionally be selected from the group consisting of (=O), halogen, -CN, -OH, -NH2, NO2, -(CH2)0-6-R 7 , -(CH2)0~6-CF3, -OR 6 , -NR 10 R 6 , C1-6 alkyl group, -(CH2)0-3-(CO)-R 6 , -(CH2)0~3-(CO)-NH-R 6 , -(CH2)0~3-NH-(CO)-R 6 ,

[0012] [ka] , or

[0013] [ka] may be replaced by R 3is selected from C1-6 alkyl groups, 6- to 10-membered aryl groups, and 5- to 12-membered heteroaryl groups, and the aryl and heteroaryl groups are optionally selected from halogen, -CN, -OH, -NH2, NO2, -(CH2)0-6-R 7 , -(CH2)0~6-CF3, -OR 6 , -NR 10 R 6 , C1-6 alkyl group, -(CH2)0-3-(CO)-R 6 , -(CH2)0~3-(CO)-NH-R 6 , or -(CH2)0~3-NH-(CO)-R 6 may be replaced by R 6 are each independently selected from a C1-6 alkyl group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a 6- to 10-membered aryl group, and a 5- to 12-membered heteroaryl group, and the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are optionally substituted by halogen, —CN, a C1-6 alkyl group, —O—C1-6 alkyl group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 12-membered heteroaryl group; R 10 are each independently selected from H and a C alkyl group; R 7 are each independently selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a 6- to 10-membered aryl group, and a 5- to 12-membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are optionally substituted by halogen, —CN, —OH, —NH2, NO2, —O—C1-6 alkyl group, —N(C1-6 alkyl)(C1-6 alkyl) group, or C1-6 alkyl group; R 8a , R 8b are each independently selected from a C1-6 alkyl group, a 3-8 membered cycloalkyl group, a 3-8 membered heterocycloalkyl group, a 6-10 membered aryl group, and a 5-12 membered heteroaryl group; or R8a and R 8b may be connected to form a 3- to 8-membered heterocycle, R 9 is selected from H, a C1-6 alkyl group, a 3-8 membered cycloalkyl group, a 3-8 membered heterocycloalkyl group, a 6-10 membered aryl group, and a 5-12 membered heteroaryl group; m is 0, 1, 2 or 3; n is 0 or 1.

[0014] In some embodiments, R a , R b are each independently selected from H and a C alkyl group, or R a and R b may be connected to form a 3- to 10-membered heterocycle, R 1 is selected from a C1-6 alkyl group, an —O—C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocycloalkyl group, a 6- to 10-membered aryl group, and a 5- to 12-membered heteroaryl group, wherein the alkyl group, the cycloalkyl group, and the heterocycloalkyl group may optionally be oxo-substituted, and the cycloalkyl group, the heterocycloalkyl group, the aryl group, and the heteroaryl group may optionally be substituted with halogen, —CN, —OH, —NH2, NO2, —(CH2)0-6-R 7 , -(CH2)0~6-CF3, -OR 6 , -NR 10 R 6 , C1-6 alkyl group, -(CH2)0-3-(CO)-R 6 , -(CH2)0~3-(CO)-NH-R 6 , -(CH2)0~3-NH-(CO)-R 6 ,

[0015] [ka] , or

[0016] [ka] or R 1 and R 20 are connected to form a 3- to 12-membered heterocycle, and the heterocycle may optionally be selected from the group consisting of (=O), halogen, -CN, -OH, -NH2, NO2, -(CH2)0-6-R 7 , -(CH2)0~6-CF3, -OR 6 , -NR 10 R 6 , C1-6 alkyl group, -(CH2)0-3-(CO)-R 6 , -(CH2)0~3-(CO)-NH-R 6 , -(CH2)0~3-NH-(CO)-R 6 ,

[0017] [ka] , or

[0018] [ka] may be replaced by R 6 , R 7 , R 8a , R 8b , R 9 and R 10 is as defined above.

[0019] In some embodiments, R a and R b is H.

[0020] In some embodiments, R 2 is H.

[0021] In some embodiments, R 20 is H.

[0022] In some embodiments, R 4 , R5 are each independently selected from H and a C1-6 alkyl group.

[0023] In some embodiments, R 4 , R 5 are each independently selected from C1-6 alkyl groups.

[0024] In some embodiments, R 4 and R 5 is H.

[0025] In some embodiments, R 3 is selected from 5-12 membered heteroaryl groups, and the heteroaryl groups are optionally substituted by halogen, -CN, -OH, -NH2, NO2, -(CH2)0-6-CF3, -O-C1-6 alkyl group, -NHC1-6 alkyl group, C1-6 alkyl group, 3-8 membered cycloalkyl group, 3-8 membered heterocycloalkyl group, 6-10 membered aryl group, 5-12 membered heteroaryl group, -(CH2)0-3-(CO)-C1-6 alkyl group, -(CH2)0-3-(CO)-NH-C1-6 alkyl group, or -(CH2)0-3-NH-(CO)-C1-6 alkyl group. Preferably, the heteroaryl group is optionally substituted with halogen, —CN, —OH, —NH2, —CF3, —O—C1-6 alkyl group, —NHC1-6 alkyl group, C1-6 alkyl group, 3- to 8-membered cycloalkyl group, 3- to 8-membered heterocycloalkyl group, 6- to 10-membered aryl group, or 5- to 12-membered heteroaryl group, and more preferably, the heteroaryl group is optionally substituted with halogen, —CN, —OH, —NH2, —CF3, —O—C1-6 alkyl group, —NHC1-6 alkyl group, or C1-6 alkyl group. In some embodiments, R 3 teeth,

[0026] [ka] and

[0027] [ka] is optionally substituted by a halogen, —CN, —OH, —NH2, NO2, —(CH2)0-6-CF3, —O—C1-6 alkyl group, —NHC1-6 alkyl group, C1-6 alkyl group, 3- to 8-membered cycloalkyl group, 3- to 8-membered heterocycloalkyl group, 6- to 10-membered aryl group, 5- to 12-membered heteroaryl group, —(CH2)0-3-(CO)—C1-6 alkyl group, —(CH2)0-3-(CO)—NH—C1-6 alkyl group, or —(CH2)0-3-NH-(CO)—C1-6 alkyl group, and preferably

[0028] [ka] is optionally substituted by a halogen, —CN, —OH, —NH2, —CF3, —O—C1-6 alkyl group, —NHC1-6 alkyl group, C1-6 alkyl group, 3-8 membered cycloalkyl group, 3-8 membered heterocycloalkyl group, 6-10 membered aryl group, or 5-12 membered heteroaryl group, and more preferably

[0029] [ka] may be optionally substituted by halogen, -CN, -OH, -NH2, -CF3, -O-C1-6 alkyl group, -NHC1-6 alkyl group, or C1-6 alkyl group. In some embodiments, R 1is selected from a C1-6 alkyl group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocycloalkyl group, a 6- to 10-membered aryl group, and a 5- to 12-membered heteroaryl group, and is preferably selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a 6- to 10-membered aryl group, and a 5- to 12-membered heteroaryl group, and the alkyl group, cycloalkyl group, and heterocycloalkyl group may optionally be oxo-substituted, and the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group may optionally be substituted with halogen, —CN, —OH, —NH2, NO2, —(CH2)0-6-R 7 , -(CH2)0~6-CF3, -OR 6 , -NR 10 R 6 , C1-6 alkyl group, -(CH2)0-3-(CO)-R 6 , -(CH2)0~3-(CO)-NH-R 6 , -(CH2)0~3-NH-(CO)-R 6 ,

[0030] [ka] , or

[0031] [ka] or R 1 and R 20 are connected to form a 3- to 12-membered heterocycle, and the heterocycle may optionally be selected from the group consisting of (=O), halogen, -CN, -OH, -NH2, NO2, -(CH2)0-6-R 7 , -(CH2)0~6-CF3, -OR 6 , -NR 10 R 6 , C1-6 alkyl group, -(CH2)0-3-(CO)-R 6 , -(CH2)0~3-(CO)-NH-R 6 , -(CH2)0~3-NH-(CO)-R6 ,

[0032] [ka] , or

[0033] [ka] may be replaced by R 6 are each independently selected from a C1-6 alkyl group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a 6- to 10-membered aryl group, and a 5- to 12-membered heteroaryl group, preferably selected from a C1-6 alkyl group and a 3- to 8-membered cycloalkyl group, more preferably selected from a C1-6 alkyl group; R 10 are each independently selected from H and a C1-6 alkyl group, preferably H; R 7 are each independently selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a 6- to 10-membered aryl group, and a 5- to 12-membered heteroaryl group, preferably selected from a 3- to 8-membered cycloalkyl group and a 3- to 8-membered heterocycloalkyl group, and the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are optionally substituted by halogen, —CN, —OH, —NH2, NO2, —O—C1-6 alkyl group, —N(C1-6 alkyl)(C1-6 alkyl) group, or C1-6 alkyl group; R 8a , R 8b are each independently selected from a C1-6 alkyl group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a 6- to 10-membered aryl group, and a 5- to 12-membered heteroaryl group, preferably selected from a C1-6 alkyl group and a 3- to 8-membered cycloalkyl group, more preferably selected from a C1-6 alkyl group; or R 8a and R 8bmay be connected to form a 3- to 8-membered heterocycle, R 9 is selected from H, a C1-6 alkyl group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a 6- to 10-membered aryl group, and a 5- to 12-membered heteroaryl group, preferably selected from H, a C1-6 alkyl group, and a 3- to 8-membered cycloalkyl group, more preferably selected from H and a C1-6 alkyl group.

[0034] In some embodiments, m is 0 or 1, preferably 0.

[0035] In some embodiments, n is 1.

[0036] In some embodiments, the present invention provides the following compound or a pharmaceutically acceptable salt, solvate, crystalline polymorph, or isomer thereof:

[0037] [ka] [ka]

[0038] The compounds of the present invention, or their prodrugs, esters, ethers, solvates, polymorphs, isomers, or pharmaceutically acceptable salts of any of the above, or mixtures of two or more of the above in any ratio, can be used to treat diseases associated with lmp7. In some embodiments, the disease associated with lmp7 activity is a malignant hematological disease, a solid tumor, or an immune dysregulation disorder, preferably multiple myeloma, acute myeloid leukemia, myeloid leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, plasma cell neoplasm, follicular lymphoma, immunocytoma, breast cancer, ovarian cancer, colorectal cancer, ovarian cancer, esophageal cancer, lung cancer, head and neck cancer, pancreatic cancer, kidney cancer, These include gastric cancer, thyroid cancer, prostate cancer, bladder cancer, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, scleroderma, adhesive spondylitis, atherosclerosis, Behçet's disease, Crohn's disease, inflammatory bowel disease, ulcerative colitis, autoimmune hepatitis, Sjögren's syndrome, lupus nephritis, asthma, amyotrophic lateral sclerosis (ALS), psoriasis, immunoglobulin A nephropathy, Henoch-Scholein purpura, and Alzheimer's disease (AD).

[0039] In another aspect, the present invention also relates to a pharmaceutical composition comprising a compound of the present invention, or a prodrug, ester, ether, solvate, crystalline polymorph, isomer, or a pharmaceutically acceptable salt of any of the above, or a mixture of two or more of the above in any ratio, optionally containing a pharmaceutically acceptable carrier.

[0040] In another aspect, the present invention provides a method for treating a disease associated with lmp7 activity, the method comprising administering to a subject an effective amount of a compound of the present invention, or a prodrug, ester, ether, solvate, polymorph, isomer, or pharmaceutically acceptable salt of any of the foregoing, or a mixture of two or more of the foregoing in any ratio, or a composition as described above. In some embodiments, the disease associated with lmp7 activity is multiple myeloma, acute myeloid leukemia, myeloid leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, plasma cell neoplasm, follicular lymphoma, immunocytoma, breast cancer, ovarian cancer, colorectal cancer, ovarian cancer, esophageal cancer, lung cancer, head and neck cancer, pancreatic cancer, kidney cancer, gastric cancer, thyroid cancer, or prostate cancer. , bladder cancer, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, scleroderma, adhesive spondylitis, atherosclerosis, Behçet's disease, Crohn's disease, inflammatory bowel disease, ulcerative colitis, autoimmune hepatitis, Sjögren's syndrome, lupus nephritis, asthma, amyotrophic lateral sclerosis (ALS), psoriasis, immunoglobulin A nephropathy, Henoch-Scholein purpura, and Alzheimer's disease (AD).

[0041] In some embodiments of the present invention, the subject according to the present invention is a mammal, including a human.

[0042] In another aspect, the present invention provides the use of a compound of the present invention, or a prodrug, ester, ether, solvate, polymorph, isomer, or pharmaceutically acceptable salt of any of the foregoing, or a mixture of two or more of the foregoing in any ratio, in the manufacture of a medicament for treating a disease associated with lmp7 activity. In some embodiments, the disease associated with lmp7 activity is multiple myeloma, acute myeloid leukemia, myeloid leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, plasma cell neoplasm, follicular lymphoma, immunocytoma, breast cancer, ovarian cancer, colorectal cancer, ovarian cancer, esophageal cancer, lung cancer, head and neck cancer, pancreatic cancer, kidney cancer, stomach cancer, thyroid cancer, or prostate cancer. , bladder cancer, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, scleroderma, adhesive spondylitis, atherosclerosis, Behçet's disease, Crohn's disease, inflammatory bowel disease, ulcerative colitis, autoimmune hepatitis, Sjögren's syndrome, lupus nephritis, asthma, amyotrophic lateral sclerosis (ALS), psoriasis, immunoglobulin A nephropathy, Henoch-Scholein purpura, and Alzheimer's disease (AD). [Brief explanation of the drawings]

[0043] [Figure 1] FIG. 1 shows the tumor growth curve and the weight curve of cancer-bearing mice in in vivo test I. [Figure 2] FIG. 2 shows the tumor growth curve and the weight curve of cancer-bearing mice in in vivo test II.

[0044] The following detailed description of the invention sets forth illustrative embodiments utilizing the principles of the present invention. A better understanding of the features and advantages of the present invention may be obtained by reference to the following disclosure.

[0045] The scope of protection for each aspect of the present invention is determined by the claims, and all methods and structures according to the claims and their equivalents are encompassed within the scope of the claims.

[0046] Unless otherwise defined, scientific and technical terms used herein have the ordinary meanings understood by those skilled in the art to which the claimed subject matter belongs. Unless otherwise stated, all patents, patent applications, and publications referenced herein are incorporated herein by reference in their entirety.

[0047] It should be noted that the above general description and the following detailed description are both exemplary and intended to be interpreted as not limiting the subject matter of the present invention. Unless otherwise specified, the use of the singular includes the plural. Unless otherwise specified, the terms "or" and "or" mean "and / or." Furthermore, the terms "include," "includes," "contains," and the like are not intended to be limiting.

[0048] "Some chemical terms" The terms "optional," "optionally," or "optionally" refer to the subsequently described event or circumstance, which may or may not occur, and include cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, an "optionally substituted alkyl group" refers to an "unsubstituted alkyl group" or a "substituted alkyl group." An optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or any level between monosubstituted and fully substituted (e.g., -CH2CHF2, -CF2CH3, -CFHCHF2, etc.). As will be understood by those skilled in the art, any group containing one or more substituents is not permitted to introduce substitutions or forms of substitution that are spatially incompatible and / or synthetically impossible.

[0049] Unless otherwise specified, conventional methods within the skill of the art are used, such as mass spectrometry, nuclear magnetic resonance, high-performance liquid chromatography, infrared or ultraviolet-visible spectroscopy, and pharmacological methods. Unless otherwise specifically defined, the terms, testing steps, and techniques related to analytical chemistry, synthetic organic chemistry, and medicinal chemistry used herein are known in the art. Standard techniques can be used for chemical synthesis, chemical analysis, drug production, formulation and delivery, and patient treatment. For example, reactions or purification may be performed using kit instructions provided by manufacturers, or by methods well known in the art or as described herein. Generally, the techniques or methods described above can be carried out according to conventional methods well known in the art, based on the various general and specific literature descriptions referenced or cited herein. As used herein, target groups and their substituents may be selected by those of skill in the art to provide stable structural moieties and compounds.

[0050] When a substituent is written in a conventional chemical formula written from the left, the substituent includes the chemically equivalent substituent written from the right. For example, -CH2O- and -OCH2- are equivalent.

[0051] As used herein, the terms "group" and "chemical group" refer to a specific portion or functional group of a molecule. A chemical group is generally recognized as a chemical entity incorporated into or added to a molecule.

[0052] For some chemical groups named herein, the abbreviation may indicate the total number of carbon atoms. For example, a C1-C6 alkyl group is defined as an alkyl group having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated in the abbreviation does not include the carbon atoms of possible substituents.

[0053] The terms "halogen," "halo," or "halide" refer to bromine, chlorine, fluorine, or iodine.

[0054] As used herein, the terms "aromatic," "aromatic ring," "aromatic," and "aromatic ring" refer to a planar ring segment, consisting of one or more rings, having a delocalized, conjugated electron system containing 4n+2 electrons, where n is an integer. Aromatic rings may be formed by 5, 6, 7, 8, 9, or more atoms. Aromatic compounds may be optionally substituted and may be monocyclic or polycyclic, consisting of fused rings. The term "aromatic compound" includes all carbon rings (e.g., benzene rings) and rings containing one or more heteroatoms (e.g., pyridine).

[0055] The terms "heteroatom" or "hetero," as used herein alone or as part of another moiety, refer to atoms other than carbon and hydrogen. Heteroatoms are independently selected from, but are not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. In some embodiments of two or more heteroatoms, the two or more heteroatoms can be the same as each other, or some or all of the two or more heteroatoms can be different from each other.

[0056] The term "bridged ring", as used herein, alone or in combination, refers to a cyclic structure in which two rings in a compound share two carbon atoms that are not directly connected.

[0057] The term "fused" or "fused ring", as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.

[0058] The term "spiro" or "spiro ring", as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

[0059] The term "alkyl group," as used herein alone or as part of another moiety (e.g., a monoalkylamino group), refers to an optionally substituted straight-chain or optionally substituted branched-chain monovalent saturated hydrocarbon group having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms, connected to the rest of the molecule by a single bond, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, and the like.

[0060] The term "cycloalkyl group," as used herein alone or as part of another moiety, refers to a stable, monovalent, non-aromatic, monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms, including fused, spiro, or bridged ring systems, containing 3 to 15 ring carbon atoms, preferably 3 to 10 ring carbon atoms, and more preferably 3 to 8 ring carbon atoms, which may be saturated or unsaturated, and which is connected to the rest of the molecule by a single bond. Non-limiting examples of "cycloalkyl groups" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0061] As used herein, the terms "heterocyclyl group," "heterocycloalkyl group," and "heterocycle," used alone or as part of a moiety, refer to a stable, 3- to 18-membered, monovalent, non-aromatic ring containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, or may include a fused, spirocyclic, or bridged ring system. The heterocyclyl group may optionally oxidize nitrogen, carbon, or sulfur, and optionally quaternize nitrogen atoms. The heterocyclyl group may be partially saturated or fully saturated. A heterocyclyl group may be connected to the rest of the molecule by a single bond through a carbon atom or heteroatom in the ring. A heterocyclyl group containing fused rings may contain one or more aromatic or heteroaromatic rings, as long as the atom connected to the rest of the molecule is not an aromatic ring. In the present application, the heterocyclyl group is preferably a stable 4- to 11-membered monovalent non-aromatic monocyclic or bicyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably a stable 4- to 8-membered monovalent non-aromatic monocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuryl, dihydroindolyl, dioxolane, 1,1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizidinyl, quinuclidinyl, tetrahydrofuryl, tetrahydropyranyl, and the like.

[0062] The term "aryl group" refers to an all-carbon monocyclic or fused ring system having a completely conjugated π-electron system and having 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, and most preferably 6 carbon atoms. Aryl groups can be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, sulfonyl, sulfinyl, phosphoryl, and heteroalicyclic groups. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl groups.

[0063] The term "heteroaryl group" refers to a monocyclic or fused ring system having 5 to 12 ring atoms, including 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, of which 1, 2, 3, or 4 are selected from N, O, and S, and the remaining ring atoms are C, and which has a fully conjugated π-electron system. Heteroaryl groups can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl, and heteroalicyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, and triazinyl groups.

[0064] The term "crystalline polymorphism" or "polymorphism" as used herein refers to the fact that the compounds of the present invention have various crystal lattice configurations. Some compounds of the present invention may have one or more crystalline forms, and all polymorphs or mixtures thereof are included in the present invention.

[0065] Intermediate compounds of the compounds of the present invention and polymorphs thereof are also included within the scope of the present invention.

[0066] Unless otherwise specified, the compounds of the present invention contain olefinic double bonds, including both E and Z isomers.

[0067] The compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently have an R or S configuration. As will be apparent to those skilled in the art, some compounds of the present invention may have cis-trans isomerism. The compounds of the present invention include their geometric isomers or stereoisomers alone or in mixtures thereof, including, for example, racemic mixtures. These isomers may be separated from their mixtures by carrying out or modifying known methods, for example, using chromatographic and recrystallization techniques, or they may be prepared from appropriate isomers of their intermediates.

[0068] As used herein, the term "pharmaceutically acceptable salts" includes both acid and base addition salts.

[0069] A "pharmaceutically acceptable acid addition salt" refers to a biologically acceptable salt that retains the biological effectiveness and properties of the free base of a compound and is formed with inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids, including, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, capric acid, caproic acid, carbonic acid, cinnamic acid, citric acid, etc. A "pharmaceutically acceptable base addition salt" refers to a biologically acceptable salt that retains the biological effectiveness and properties of the free acid of a compound. These salts are prepared by reacting the free acid with an inorganic or organic base. Salts formed by reaction with inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts and manganese salts.

[0070] The organic base for forming the salt includes, but is not limited to, a primary amine, a secondary amine, a tertiary amine, a cyclic amine, etc., such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, caffeine, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0071] Crystals always yield solvates of the compounds of the invention. As used herein, the term "solvate" refers to a complex formed by combining one or more molecules of a compound of the invention with one or more solvent molecules.

[0072] The solvent may be water. In this case, the solvate is a hydrate. It may also be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, etc., but there are other solvate forms as well. The compounds of the present invention may be true solvates, or may be mixtures in which water or water and some other solvents remain in the compounds of the present invention. The compounds of the present invention may react in certain solvents, but may also precipitate or crystallize in certain solvents. Solvates of the compounds of the present invention are also included within the scope of the present invention.

[0073] As used herein, the term "pharmaceutical composition" refers to a formulation comprising a compound of the present invention in admixture with a vehicle generally accepted in the art for use in delivering biologically active compounds to mammals (e.g., humans). Such vehicles include all pharmaceutically acceptable carriers.

[0074] The term "acceptable" as used herein with respect to a formulation, composition, or ingredient refers to having no lasting adverse effects on the health of the treated subject as a whole.

[0075] As used herein, the term "pharmaceutically acceptable" refers to a substance (e.g., a carrier or diluent) that does not affect the physiological activity or properties of the compounds of the present invention, and that is relatively non-toxic, i.e., that does not elicit an adverse physiological response when administered to an individual or interact with any of the components contained in the composition in an undesirable manner.

[0076] "Pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, builders, deodorizers, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, emulsifiers approved for human or veterinary use by the relevant branch of government.

[0077] As used herein, the terms "subject," "patient," "subject," or "individual" refer to an individual suffering from a disease, disorder, condition, or the like, and include mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia, such as humans and non-human primates (e.g., chimpanzees, other apes, and monkeys); livestock, such as cows, horses, sheep, goats, and pigs; companion animals, such as rabbits, dogs, and cats; and laboratory animals, such as rodents, including rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In certain embodiments of the methods and compositions herein, the mammal is a human.

[0078] The term "treatment" as used herein refers to the treatment of mammals, particularly humans, for the relevant disease or condition and includes the following: (i) To prevent a particular disease or condition from occurring in a mammal, particularly a mammal that has previously been exposed to the disease or condition but has not yet been diagnosed with the disease or condition. (ii) inhibiting the disease or condition, i.e., arresting its progression; (iii) alleviating a disease or condition, i.e., reducing or eliminating a disease or condition; (iv) Relieving symptoms caused by a disease or medical condition

[0079] As used herein, the terms "disease" and "condition" may be used interchangeably or may have different meanings, as some specific diseases or conditions have no known etiological agent (i.e., the cause of their occurrence is unknown) and are therefore considered only to be adverse conditions or syndromes rather than diseases, although some symptoms of the syndrome have already been identified by clinical researchers.

[0080] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one drug or compound sufficient, upon administration, to alleviate to some extent one or more symptoms of the disease or condition being treated. This may result in a reduction and / or elimination of signs, symptoms, or causative factors, or some other desired change in the body. For example, a therapeutically "effective amount" is the amount of a composition comprising a compound disclosed herein that is required to produce a clinically significant pathological effect. Techniques such as dose escalation studies can be used to determine the appropriate effective amount for any individual case.

[0081] As used herein, the terms "dosing," "administration," and the like refer to methods by which a compound or composition can be delivered to a predetermined site where a physiological effect occurs. Such methods include, but are not limited to, oral, intraduodenal, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, and intraarterial injection and infusion), topical, and rectal administration. In a preferred embodiment, the compounds and compositions featured herein are administered orally. DETAILED DESCRIPTION OF THE INVENTION

[0082] Synthesis method: The compounds of the present application can be prepared according to the routes described in Scheme 1, Scheme 2, Scheme 3 or Scheme 4.

[0083] [ka]

[0084] [ka]

[0085] In Scheme 1 and Scheme 2, the R1, R2, R3, R4, R5, and R6 substituents include, but are not limited to, hydrogen atoms, aliphatic, and aromatic substituents, and X includes, but is not limited to, fluorine, chlorine, bromine, iodine, triflate groups, and the like. Each product obtained from the reaction in Scheme 1 and Scheme 2 can be obtained by conventional separation techniques, including, but not limited to, filtration, distillation, crystallization, and chromatographic separation. Starting materials can be synthesized or purchased from manufacturers (e.g., including, but not limited to, Aldrich or Sigma). These materials can be characterized using conventional means, such as physical constants and spectroscopic data. The compounds described herein can be obtained as single isomers or mixtures of isomers using synthetic methods.

[0086] In Scheme 1, starting material 1 undergoes Suzuki coupling with bis(pinacolato)diboron in the presence of a copper catalyst, a ligand, and a suitable base to produce intermediate 2. Intermediate 2 then undergoes transesterification with pinanediol to produce optically active intermediate 3. Intermediate 3 then undergoes Matteson homologation with pre-prepared LiCHCl2 reagent in the presence of a zinc reagent catalyst to produce intermediate 4. Intermediate 4 then undergoes substitution reaction with a salt containing hexamethyldisilazane to produce intermediate 5. Intermediate 5 undergoes elimination of the TMS group in the presence of acid to produce intermediate 6. Intermediate 6 then undergoes condensation with oxalyl chloride in the presence of a base to produce oxalylamine intermediate 7. Intermediate 7 then produces a substituted amine compound and oxalyldiamine intermediate 8. Intermediate 8 then undergoes transesterification with an excess of a substituted boronic acid to produce target compound 9.

[0087] In Scheme 2, starting material 1 undergoes Suzuki coupling with bis(pinacolato)diboron in the presence of a copper catalyst, a ligand, and a suitable base to produce intermediate 2. Intermediate 2 then undergoes transesterification with pinanediol to produce optically active intermediate 3. Intermediate 3 then undergoes Matteson homologation with pre-prepared LiCHCl2 reagent in the presence of a zinc reagent catalyst to produce intermediate 4. Intermediate 4 then undergoes substitution reaction with a salt containing hexamethyldisilazane to produce intermediate 5. Intermediate 5 undergoes removal of the TMS group in the presence of acid to produce intermediate 6. Intermediate 6 and a substituted 2-oxoacyl chloride are then reacted with a base to produce 2-oxoamide intermediate 10. Intermediate 10 then undergoes transesterification with an excess of a substituted boronic acid to produce the target compound 11.

[0088] [ka]

[0089] [ka]

[0090] In Scheme 3 and Scheme 4, R 1 , R 2 , R 3 , R 4 , R a and R b Substituents include, but are not limited to, hydrogen atoms, aliphatic and aromatic substituents, and X includes, but is not limited to, fluorine, chlorine, bromine, iodine, triflate groups, and the like. R a and R bmay be linked to form a ring, a bridged ring, a fused ring, or an aromatic fused ring. Each product from the reaction in Scheme 1 and Scheme 2 can be obtained by conventional separation techniques, including, but not limited to, filtration, distillation, crystallization, chromatographic separation, and the like. Starting materials may be synthesized or purchased from manufacturers (e.g., including, but not limited to, Aldrich or Sigma). These materials may be characterized using conventional means, such as physical constants and spectroscopic data. The compounds described herein can be obtained as single isomers or mixtures of isomers using synthetic methods.

[0091] In Scheme 3, starting material 1 can be condensed with oxalyl chloride in the presence of a base to produce oxalylamine intermediate 2, which can be combined with a substituted amine compound to produce oxalyldiamine intermediate 3, which can be transesterified with an excess of a substituted boronic acid to produce compound 4, which can be combined with a carboxylic acid or alcohol to produce prodrug compound 5.

[0092] In Scheme 4, starting material 1 can be reacted with oxalyl chloride monomethyl ester under alkaline conditions to produce compound 6, which can be hydrolyzed under alkaline conditions to produce intermediate 7, which can then be converted to a substituted amine and compound 4, which can then be transesterified with an excess of a substituted boronic acid to produce the desired compound 5.

[0093] Example 1 ((R)-1-(2-(((1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl)amino)-2-oxoacetylamino)-2-(benzofuran-3-yl)ethyl)boronic acid

[0094] [ka]

[0095] Step A: (1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-amine

[0096] [ka]

[0097] (1S,2R,4R)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (obtained with reference to the method of Patent WO2019 / 038250A1) (1.0 g) and triethylamine (0.75 g) were mixed with toluene (10 mL) and stirred at 25°C for 30 minutes. Diphenylphosphoryl azide (2.05 g) was added and the mixture was stirred at room temperature for 2 hours. Water (0.3 g) was added, and the mixture was heated to 70°C and stirred overnight. The mixture was cooled to room temperature, water (10 mL) was added, the organic phase was separated, 4 mol / L hydrochloric acid solution (15 mL) was added and stirred thoroughly, the aqueous phase was separated, washed with ethyl acetate (15 mL × 2), adjusted to pH 10 with 4 mol / L aqueous sodium hydroxide solution, and then extracted with dichloromethane (15 mL × 3), the extracts were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (0.23 g). 1 H NMR (400 MHz, CDCl3) δ 4.71 (d, J = 8.4 Hz, 1H), 4.32 (d, J = 5.2 Hz, 1H), 2.05-2.35 (brs, 2H), 1.96 (dd, J = 13.2 Hz, 8.0 Hz, 1H), 1.57-1.70 (m, 3H), 1.31-1.45 (m, 3H).

[0098] Step B: ((R)-1-(2-(((1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl)amino)-2-oxoacetylamino)-2-(benzofuran-3-yl)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0099] [ka]

[0100] At 0°C, a dichloromethane (5 mL) solution of 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (obtained in accordance with the method of Patent WO2019 / 038250A1) (75 mg) and diisopropylethylamine (80 mg) were added dropwise in this order to a dichloromethane (5 mL) solution containing oxalyl chloride (250 mg). The mixture was then warmed to room temperature and stirred for 2 hours. The mixture was then concentrated under reduced pressure, and the residue was converted to dichloromethane. The residue was dissolved in methane (10 mL), and a solution of (1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-amine (23 mg) in dichloromethane (5 mL) was added dropwise to the solution, followed by stirring at room temperature for 4 hours. 1 mol / L hydrochloric acid (5 mL) was added to quench the reaction, and the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a preparative silica gel plate (ethyl acetate:petroleum ether = 1:1) to obtain the product (53 mg). 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 6.4 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.18-7.28 (m, 2H), 4.62 (t, J = 9.2 Hz, 1H), 4.36 (d, J = 5.2 Hz, 1H), 4.27 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 4.01 (td, J = 8.4 Hz, 2.8 Hz, 1H), 3.67-3.72 (m, 1H), 3.11 (dd, J = 14.8 Hz, 5.6 Hz, 1H), 3.00 (dd, J = 15.2 Hz, 7.2 Hz, 1H), 2.19-2.33 (m, 2H), 2.06-2.12 (m, 1H), 1.95-2.02 (m, 1H), 1.80-1.91 (m, 2H), 1.60-1.74 (m, 3H), 1.42-1.55 (m, 2H), 1.38 (s, 3H), 1.22-1.24 (m, 3H), 0.99 (t, J = 4.0 Hz, 1H), 0.78 (s, 3H).

[0101] Step C: ((R)-1-(2-(((1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl)amino)-2-oxoacetylamino)-2-(benzofuran-3-yl)ethyl)boronic acid

[0102] [ka]

[0103] ((R)-1-(2-(((1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl)amino)-2-oxoacetylamino)-2-(benzofuran-3-yl)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (53 mg) was dissolved in methanol (10 mL). To the solution were added isobutylboronic acid (52 mg), 1 mol / L hydrochloric acid (0.1 mL), and n-hexane (10 mL), and the mixture was stirred at room temperature overnight. The methanol phase was separated, washed with n-hexane, and concentrated under reduced pressure. The residue was recrystallized from a dichloromethane / diethyl ether system to obtain the product (23 mg). 1 H NMR (400 MHz, CD3OD) δ 7.57 (d, J = 7.2 Hz, 1H), 7.52 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.17-7.27 (m, 2H), 4.60 (t, J = 4.8 Hz, 1H), 4.34 (d, J = 5.2 Hz, 1H), 3.91 (dd, J = 8.0 Hz, 3.2 Hz, 1H), 3.53 (t, J = 7.2 Hz, 1H), 3.03 (dd, J = 14.8 Hz, 6.8 Hz, 1H), 2.93 (dd, J = 14.8 Hz, 7.2 Hz, 1H), 1.98 (dd, J = 12.8 Hz, 8.4 Hz, 1H), 1.58-1.66 (m, 3H), 1.42-1.53 ​​(m, 2H), 1.34-1.37 (m, 1H).

[0104] Example 2 (R)-(2-(benzofuran-3-yl)-1-(2-(methylamino)-2-oxoacetylamino)ethyl)boronic acid

[0105] [ka]

[0106] Referring to the methods of Steps B and C of Example 1, the product (15 mg) was obtained using 30% methylamine methanol solution, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as the main raw materials. 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.6 Hz, 1H), 7.55 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.17-7.27 (m, 2H), 3.51 (t, J = 7.2 Hz, 1H), 3.12 (dd, J = 14.4 Hz, 7.2 Hz, 1H), 2.92 (dd, J = 14.48 Hz, 6.4 Hz, 1H), 2.90 (s, 3H).

[0107] Example 3 (R)-(2-(benzofuran-3-yl)-1-(2-(methoxy(methyl)amino)-2-oxoacetylamino)ethyl)boronic acid

[0108] [ka]

[0109] Referring to the methods of Step B and Step C of Example 1, the product (21 mg) was obtained using N,O-dimethylhydroxyamine hydrochloride, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as the main raw materials. 1H NMR (400 MHz, CDCl3) δ 7.58-7.62 (m, 1H), 7.53 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.18-7.27 (m, 2H), 3.90 (s, 3H), 3.49-3.54(m, 1H), 3.33 (s, 3H), 3.03 (dd, J = 14.8 Hz, 6.8 Hz, 1H), 2.93 (dd, J = 14.8 Hz, 7.2 Hz, 1H).

[0110] Example 4 (R)-(2-(benzofuran-3-yl)-1-(2-(diethylamino)-2-oxoacetylamino)ethyl)boronic acid

[0111] [ka]

[0112] Referring to the methods of Step B and Step C of Example 1, the product (18 mg) was obtained using diethylamine hydrochloride, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as the main raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.62 (d, J = 7.2 Hz, 1H), 7.58 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.20-7.28 (m, 2H), 3.33-3.39 (m, 1H), 3.25-3.30 (m, 4H), 2.89-3.04 (m, 2H), 1.11-1.14 (m, 6H).

[0113] Example 5 (R)-(2-(benzofuran-3-yl)-1-(2-morpholinyl-2-oxoacetylamino)ethyl)boronic acid

[0114] [ka]

[0115] Referring to the methods of Step B and Step C of Example 1, the product (25 mg) was obtained using morpholine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as the main raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.62 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.20-7.28 (m, 2H), 3.61-3.63 (m, 2H), 3.49-3.53 (m, 4H), 3.28-3.35 (m, 3H), 3.02 (dd, J = 14.8 Hz, 6.4 Hz, 1H), 2.92 (dd, J = 14.8 Hz, 8.8 Hz, 1H).

[0116] Example 6 (R)-(2-(benzofuran-3-yl)-1-(2-(dimethylamino)-2-oxoacetylamino)ethyl)boronic acid

[0117] [ka]

[0118] Referring to the methods of Step B and Step C of Example 1, the product (33 mg) was obtained using diethylamine hydrochloride, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as the main raw materials. 1H NMR (400 MHz, CD3OD) δ 7.62 (d, J = 7.2 Hz, 1H), 7.57 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.19-7.28 (m, 2H), 3.29-3.30 (m, 1H), 2.98-3.10 (m, 2H), 2.92 (s, 3H), 2.91 (s, 3H).

[0119] Example 7 ((R)-2-(benzofuran-3-yl)-1-(2-oxo-2(((S)-tetrahydrofuran-3-yl)amino)acetylamino)ethyl)boronic acid

[0120] [ka]

[0121] Referring to the methods of Step B and Step C of Example 1, the product (8 mg) was obtained using (S)-3-aminotetrahydrofuran tosylate, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as main raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.58 (d, J = 7.2 Hz, 1H), 7.53 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.18-7.27 (m, 2H), 4.35-4.41 (m, 1H), 3.73-3.95 (m, 3H), 3.51-3.65 (m, 2H), 3.00-3.09 (m, 1H), 2.94 (dd, J = 14.4 Hz, 7.6 Hz, 1H), 2.18-2.27 (m, 1H), 1.88-1.95 (m, 1H).

[0122] Example 8 ((R)-2-(benzofuran-3-yl)-1-(2-oxo-2-(((R)-1-(pyridin-2-yl)ethyl)amino)acetylamino)ethyl)boronic acid

[0123] [ka]

[0124] Referring to the methods of Step B and Step C of Example 1, the product (10 mg) was obtained using (R)-1-(pyridin-2-yl)ethylamine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as the main raw materials. 1 H NMR (400 MHz, CD3OD) δ 8.76 (d, J = 3.6 Hz, 1H), 8.62 (t, J =7.6 Hz, 1H), 7.99-8.12 (m, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.13-7.26 (m, 2H), 5.22-5.28 (m, 1H), 3.54-3.59 (m, 1H), 3.05 (dd, J = 14.8 Hz, 6.4 Hz, 1H), 2.94 (dd, J = 14.4 Hz, 8.0 Hz, 1H), 1.68 (d, J = 6.8 Hz, 3H).

[0125] Example 9 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrazin-2-ylamino)acetylamino)ethyl)boronic acid

[0126] [ka]

[0127] Referring to the methods of Step B and Step C of Example 1, the product (13 mg) was obtained using aminopyrazine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as the main raw materials. 1 H NMR (400 MHz, CD3OD) δ 9.43 (s, 1H), 8.69 (s, 1H), 8.48 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.54 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.15-7.24 (m, 2H), 3.64-3.67 (m, 1H), 3.08 (dd, J = 14.4 Hz, 6.4 Hz, 1H), 2.99 (dd, J = 14.4 Hz, 8.0 Hz, 1H).

[0128] Example 10 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyridazin-3-ylamino)acetylamino)ethyl)boronic acid

[0129] [ka]

[0130] Referring to the methods of Step B and Step C of Example 1, the product (15 mg) was obtained using 3-aminopyridazine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as the main raw materials. 1H NMR (400 MHz, CD3OD) δ 8.38-8.39 (m, 1H), 7.75-7.78 (m, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.51 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.31-7.34 (m, 1H), 7.17-7.27 (m, 2H), 3.49-3.53 (m, 1H), 3.02 (dd, J = 14.4 Hz, 6.4 Hz, 1H), 2.94 (dd, J = 14.8 Hz, 7.2 Hz, 1H).

[0131] Example 11 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((tetrahydro-2H-pyran-4-yl)amino)acetylamino)ethyl)boronic acid

[0132] [ka]

[0133] Referring to the methods of Step B and Step C of Example 1, the product (7 mg) was obtained using 4-aminotetrahydropyran, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as the main raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.58 (d, J = 7.2 Hz, 1H), 7.52 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.17-7.27 (m, 2H), 3.82-3.99 (m, 3H), 3.42-3.59 (m, 3H), 3.03 (dd, J = 14.4 Hz, 6.4 Hz, 1H), 2.93 (dd, J = 14.8 Hz, 7.2 Hz, 1H), 1.72-1.78 (m, 2H), 1.58-1.67 (m, 2H).

[0134] Example 12 (R)-(2-((benzofuran-3-yl)-1-(2-oxo-2-(pyridin-2-ylamino)acetylamino)ethyl)boronic acid

[0135] [ka]

[0136] Referring to the methods of Step B and Step C of Example 1, the product (18 mg) was obtained using 2-aminopyridine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as the main raw materials. 1 H NMR (400 MHz, CD3OD) δ 8.32 (d, J = 4.8 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.83 (td, J = 8.4 Hz, 1.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.16-7.26 (m, 3H), 3.64 (t, J = 7.2 Hz, 1H), 3.09 (dd, J = 14.4 Hz, 6.8 Hz, 1H), 3.00 (dd, J = 14.4 Hz, 7.6Hz, 1H).

[0137] Example 13 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(thiazol-2-ylamino)acetylamino)ethyl)boronic acid

[0138] [ka]

[0139] Referring to the methods of Step B and Step C of Example 1, the product (10 mg) was obtained using 2-aminothiazole, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as the main raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.68-7.75 (m, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.55 (s, 1H), 7.51 (d, J = 3.2 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.16-7.25 (m, 2H), 3.67-3.70 (m, 1H), 3.08 (dd, J = 14.4 Hz, 6.4 Hz, 1H), 3.01 (dd, J = 14.8 Hz, 8.0 Hz, 1H).

[0140] Example 14 (R)-(2-(benzofuran-3-yl)-1-(2-oxopropionamido)ethyl)boronic acid

[0141] [ka]

[0142] Step A: (R)-(2-(benzofuran-3-yl)-1-(2-oxopropionamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0143] [ka]

[0144] Sulfinyl chloride (288 mg) was added to a solution of pyruvic acid (100 mg) in tetrahydrofuran (10 mL) and heated to reflux for 2 hours. After cooling to room temperature and concentration under reduced pressure, the residue was dissolved in dichloromethane (10 mL) and cooled to 0°C. A solution of 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (450 mg) in dichloromethane (10 mL) and diisopropylethylamine (620 mg) were added dropwise to the solution and stirred at room temperature for 4 hours. The reaction was quenched by the addition of 1 mol / L hydrochloric acid (5 mL). The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a preparative silica gel plate (ethyl acetate:petroleum ether = 1:1) to obtain the product (110 mg). 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.6 Hz, 1H), 7.43-7.46 (m, 2H), 7.19-7.28 (m, 2H), 4.28-4.32 (m, 1H), 4.36 (d, J = 5.2 Hz, 1H), 3.67-3.72 (m, 1H), 3.12 (dd, J = 14.8 Hz, 5.6 Hz, 1H), 3.00 (dd, J = 14.8 Hz, 7.2 Hz, 1H), 2.45 (s, 3H), 2.28-2.35 (m, 2H), 2.09-2.15 (m, 1H), 1.97-2.04 (m, 2H), 1.54-1.66 (m, 2H), 1.25-1.34 (m, 5H), 0.81 (s, 3H).

[0145] Step B: (R)-(2-(benzofuran-3-yl)-1-(2-oxopropionamido)ethyl)boronic acid

[0146] [ka]

[0147] Referring to the method of Step C of Example 1, the product (26 mg) was obtained using (R)-(2-(benzofuran-3-yl)-1-(2-oxopropionamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester and isobutylboronic acid as main raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.57 (d, J = 7.6 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.17-7.27 (m, 2H), 3.33-3.36 (m, 1H), 3.01 (dd, J = 14.4 Hz, 7.6 Hz, 1H), 2.92 (dd, J = 14.4 Hz, 7.6 Hz, 1H), 1.89 (s, 3H).

[0148] Example 15 (R)-(2-(benzofuran-3-yl)-1-(2-cyclopropyl-2-oxoacetamido)ethyl)boronic acid

[0149] [ka]

[0150] Referring to the method of Example 14, 2-cyclopropyl-2oxoacetic acid, sulfinyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride were reacted as the main raw materials to obtain the product (22 mg). 1H NMR (400 MHz, CD3OD) δ 7.58 (d, J = 7.6 Hz, 1H), 7.52 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.18-7.27 (m, 2H), 3.44-3.48 (m, 1H), 3.01 (dd, J = 14.4 Hz, 7.6 Hz, 1H), 2.93 (dd, J = 14.8 Hz, 7.6 Hz, 1H), 2.81-2.84 (m, 1H), 1.07-1.17 (m, 4H).

[0151] Example 16 ((R)-2-(benzofuran-3-yl)-1-(2-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoacetylamino)ethyl)boronic acid

[0152] [ka]

[0153] Referring to the methods of Step B and Step C of Example 1, (S)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione (synthesized by referring to the method of Patent WO2018140809A1), diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride were used as main raw materials to obtain the product (19 mg). 1H NMR (400 MHz, CD3OD) δ 7.74 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.46 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.20-7.28 (m, 2H), 5.05-5.10 (m, 1H), 4.39-4.43 (m, 1H), 4.13-4.16 (m, 2H), 3.67-3.76 (m, 3H), 3.44-3.48 (m, 4H), 3.09-3.18 (m, 2H), 2.90-3.05 (m, 2H), 2.85-2.93 (m, 1H), 2.63-2.83 (m, 4H), 2.39 (t, J = 8.0 Hz, 2H), 2.17-2.37 (m, 1H), 1.92-2.13 (m, 3H), 1.77-1.85 (m, 1H).

[0154] Example 17 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrazin-2-ylamino)acetylamino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0155] [ka]

[0156] At 0°C, a dichloromethane (50 mL) solution of 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (obtained in accordance with the method of Patent WO2019 / 038250A1) (1.5 g) in dichloromethane (50 mL) and diisopropylethylamine (1.55 g) were added dropwise in this order to a dichloromethane (50 mL) solution containing oxalyl chloride (2.5 g). The mixture was then heated to room temperature and stirred for 2 hours. The reaction mixture was then decompressed under reduced pressure. After concentration under reduced pressure, the residue was dissolved in dichloromethane (10 mL), and a solution of aminopyrazine (0.38 g) in dichloromethane (25 mL) was added dropwise to the solution and stirred at room temperature for 4 hours. 1 mol / L hydrochloric acid (25 mL) was added to quench the reaction, and the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a preparative silica gel plate (ethyl acetate:petroleum ether = 1:1) to give the product (1.22 g). 1 H NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 9.51 (s, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 7.67 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.48 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.21-7.30 (m, 2H), 4.31 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 3.84 (dd, J = 13.2 Hz, 7.2 Hz, 1H), 3.18 (dd, J = 14.8Hz, 5.6Hz, 1H), 3.06 (dd, J = 14.8 Hz, 7.2 Hz, 1H), 2.30-2.36 (m, 1H), 2.10-2.15 (m, 1H), 1.98-2.01 (m, 1H), 1.82-1.91 (m, 2H), 1.26 (s, 3H), 1.24 (s, 3H), 1.04 (d, J = 10.8 Hz, 1H), 0.81 (s, 3H).

[0157] Example 18 (R)-2,2'-(2-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrazin-2-ylamino)acetylamino)ethyl)-5-oxo-1,3,2-dioxaborolane-4,4-diyl)diacetic acid

[0158] [ka]

[0159] Step A: (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrazin-2-ylamino)acetylamino)ethyl)boronic acid [ka]

[0160] (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrazin-2-ylamino)acetylamino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (1.20 g) obtained in Example 1 was dissolved in methanol (50 mL), and isobutylboronic acid (1.23 g), 1 mol / L hydrochloric acid (0.5 mL), and n-hexane (50 mL) were added to the solution, followed by stirring at room temperature overnight. The methanol phase was separated, washed with n-hexane, and concentrated under reduced pressure. The residue was recrystallized from a dichloromethane / diethyl ether system to obtain the product (835 mg). 1 H NMR (400 MHz, CD3OD) δ 9.43 (s, 1H), 8.69 (s, 1H), 8.48 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.54 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.15-7.24 (m, 2H), 3.64-3.67 (m, 1H), 3.08 (dd, J = 14.4 Hz, 6.4 Hz, 1H), 2.99 (dd, J = 14.4 Hz, 8.0 Hz, 1H).

[0161] Step B: (R)-2,2'-(2-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrazin-2-ylamino)acetylamino)ethyl)-5-oxo-1,3,2-dioxaborolane-4,4-diyl)diacetic acid

[0162] [ka]

[0163] Anhydrous citric acid (0.076 g) was added to anhydrous acetonitrile (6 mL) at 80° C., and after 10 minutes, (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrazin-2-ylamino)acetylamino)ethyl)boronic acid (0.14 g) was added, followed by stirring for 6 hours. After cooling to room temperature, the solid was collected by filtration to give the product (0.16 g). 1 H NMR (400 MHz, DMSO -d6 ) δ 10.58-10.74 (brs, 1H), 9.17 (s, 1H), 8.44-8.47 (m, 2H), 7.63-7.67 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.17-7.25 (m, 2H), 3.34-3.43 (m, 1H), 2.91 (dd, J = 15.2 Hz, 4.4 Hz, 1H), 2.62-2.74 (m, 3H), 2.51-2.59 (m, 2H).

[0164] Example 19 N-((1R)-2-(1-benzofuran-3-yl)-1-(tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)-N'-(pyrazin-2-yl)oxamide

[0165] [ka]

[0166] At 80°C, pinacol (9 mg) was added to anhydrous acetonitrile (2 mL), and after 10 minutes, (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrazin-2-ylamino)acetylamino)ethyl)boronic acid (26 mg) was added, followed by stirring for 16 hours. After cooling to room temperature and concentration under reduced pressure, the product (30 mg) was obtained. 1 H NMR (400 MHz, DMSO -d6 ) δ 10.52 (s, 1H), 9.22 (d, J = 6.8 Hz, 1H), 9.17 (s, 1H), 8.44-8.47 (m, 2H), 7.74 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 3.35-3.41 (m, 1H), 2.99 (dd, J = 15.2 Hz, 9.2 Hz, 1H), 2.92 (dd, J = 15.2 Hz, 6.0 Hz, 1H), 1.17 (s, 6H), 1.16 (s, 6H).

[0167] Example 20 N'-((1R)-2-(1-benzofuran-3-yl)-1-(4-oxo-2,4-dihydro-1,3,2-benzodioxaborinan-2-yl)ethyl)-N-(pyrazin-2-yl)oxamide

[0168] [ka]

[0169] At 85°C, salicylic acid (17 mg) was added to anhydrous acetonitrile (3 mL), and after 10 minutes, (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrazin-2-ylamino)acetylamino)ethyl)boronic acid (44 mg) was added, followed by stirring for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to give the product (50 mg). 1H NMR (400 MHz, DMSO -d6 ) δ 10.88 (s, 1H), 9.28-9.47 (brs, 1H), 9.17 (s, 1H), 8.44-8.46 (m, 2H), 7.75 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.62-7.65 (m, 2H), 7.45-7.50 (m, 2H), 7.18-7.26 (m, 2H), 6.91-6.96 (m, 2H), 3.51 (q, J = 7.6 Hz, 1H), 2.90 (d, J = 7.6 Hz, 2H).

[0170] Example 21 (R)-(2-(benzofuran-3-yl)-1-(2-(pyridin-3-yl)amino-2-oxoacetylamino)ethyl)boronic acid

[0171] [ka]

[0172] Referring to the methods of Example 1 and Step A of Example 2, the product (55 mg) was obtained using 3-aminopyridine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 9.42 (s, 1H), 8.77-8.80 (m, 1H), 8.61 (d, J = 6.0 Hz, 1H), 8.05 (dd, J = 8.8 Hz, 6.0 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.57 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.18-7.28 (m, 2H), 3.68 (t, J = 7.2 Hz, 1H), 2.98-3.12 (m, 2H).

[0173] Example 22 (R)-(2-(benzofuran-3-yl)-1-(2-(((tetrahydrofuran-2-yl)methyl)amino)-2-oxoacetylamino)ethyl)boronic acid

[0174] [ka]

[0175] Referring to the methods of Example 1 and Step A of Example 2, the product (23 mg) was obtained using 3-aminopyridine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.59 (d, J = 7.6 Hz, 1H), 7.54 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.26 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 3.97-4.03 (m, 1H), 3.82-3.87 (m, 1H), 3.70-3.75 (m, 1H), 3.53 (t, J = 7.2 Hz, 1H), 3.26-3.38 (m, 2H), 2.92-3.04 (m, 2H), 1.84-2.02 (m, 3H), 1.52-1.62 (m, 1H).

[0176] Example 23 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyridin-2-ylamino)acetylamino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0177] [ka]

[0178] Referring to the method of Example 1, 2-aminopyridine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride were used as raw materials to obtain the product (12 mg).

[0179] 1 H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 8.35 (dd, J = 5.2 Hz, 1.2 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.67 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.20-7.30 (m, 2H), 7.08-7.11 (m, 1H), 4.31 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 3.79 (dd, J = 13.2 Hz, 5.6 Hz, 1H), 3.18 (dd, J = 14.8 Hz, 7.6 Hz, 1H), 3.06 (dd, J = 14.8 Hz, 7.2 Hz, 1H), 2.29-2.36 (m, 1H), 2.09-2.16 (m, 1H), 1.98-2.00 (m, 1H), 1.85-1.89 (m, 2H), 1.26 (s, 3H), 1.24 (s, 3H), 1.06 (d, J = 10.8 Hz, 1H), 0.81 (s, 3H).

[0180] Example 24 ((R)-2-(benzofuran-3-yl)-1-(2-oxo-2-((2,5-dichlorophenyl)amino)acetylamino)ethyl)boronic acid

[0181] [ka]

[0182] Referring to the methods of Example 1 and Step A of Example 2, the product (8 mg) was obtained using 2,5-dichloroaniline, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 8.35 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.18-7.28 (m, 3H), 3.65 (t, J = 7.2 Hz, 1H), 2.98-3.10 (m, 2H).

[0183] Example 25 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(thiazol-2-ylamino)acetylamino)ethyl)boronic acid

[0184] [ka]

[0185] Referring to the methods of Example 1 and Step A of Example 2, the product (10 mg) was obtained using 2-aminothiazole, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as main raw materials. 1H NMR (400 MHz, CD3OD) δ 7.68-7.75 (m, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.55 (s, 1H), 7.51 (d, J = 3.2 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.16-7.25 (m, 2H), 3.67-3.70 (m, 1H), 3.08 (dd, J = 14.4 Hz, 6.4 Hz, 1H), 3.01 (dd, J = 14.8 Hz, 8.0 Hz, 1H).

[0186] Example 26 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((6-methoxybenzo[d]thiazol-2-yl)amino)acetylamino)ethyl)boronic acid

[0187] [ka]

[0188] Referring to the methods of Example 1 and Step A of Example 2, the product (11 mg) was obtained using 6-methoxybenzo[d]thiazol-2-amine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.67 (d, J = 9.2 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.57 (s, 1H), 7.37-7.46 (m, 2H), 7.18-7.27 (m, 2H), 7.05 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 3.84 (s, 3H), 3.65 (t, J = 7.2 Hz, 1H), 2.98-3.10 (m, 2H).

[0189] Example 27 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((benzo[d]thiazol-2-yl)amino)acetylamino)ethyl)boronic acid

[0190] [ka]

[0191] Referring to the methods of Example 1 and Step A of Example 2, the product (16 mg) was obtained using benzo[d]thiazol-2-amine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.89 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.41-7.47 (m, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.18-7.27 (m, 2H), 3.66 (t, J = 7.6 Hz, 1H), 2.98-3.10 (m, 2H).

[0192] Example 28 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((2,3-dihydrobenzofuran-7-yl)amino)acetylamino)ethyl)boronic acid

[0193] [ka]

[0194] Referring to the methods of Example 1 and Step A of Example 2, the product (15 mg) was obtained using 2,3-dihydrobenzofuran-7-amine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.79 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.19-7.27 (m, 2H), 7.03 (d, J = 7.2 Hz, 1H), 6.81 (t, J = 8.0 Hz, 1H), 4.63 (t, J = 8.8 Hz, 2H), 3.60 (t, J = 7.2 Hz, 1H), 3.25 (t, J = 8.8 Hz, 2H), 2.96-3.08 (m, 2H).

[0195] Example 29 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)acetylamino)ethyl)boronic acid

[0196] [ka]

[0197] Referring to the methods of Example 1 and Step A of Example 2, the product (8 mg) was obtained using hexahydro-1H-furo[3,4-c]pyrrole, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1H NMR (400 MHz, CD3OD) δ 7.61 (d, J = 7.2 Hz, 1H), 7.57 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.26 (td, J = 7.6 Hz, 1.6 Hz, 1H), 7.21 (td, J = 7.6 Hz, 1.2 Hz, 1H), 3.70-3.86 (m, 3H), 3.68 (dd, J = 12.8 Hz, 7.6 Hz, 1H), 3.61 (dd, J = 9.2 Hz, 3.2 Hz, 1H), 3.43-3.57 (m, 4H), 2.88-3.02 (m, 4H).

[0198] Example 30 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)acetylamino)ethyl)boronic acid

[0199] [ka]

[0200] Referring to the methods of Example 1 and Step A of Example 2, the product (6 mg) was obtained using 2,3-dihydrobenzo[b][1,4]dioxin-5-amine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1H NMR (400 MHz, CD3OD) δ 7.75 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.62 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.56 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.19-7.28 (m, 2H), 6.80 (t, J = 7.6 Hz, 1H), 6.66 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 4.35-4.37 (m, 2H), 4.26-4.28 (m, 2H), 3.61 (t, J = 7.6 Hz, 1H), 2.97-3.09 (m, 2H).

[0201] Example 31 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((4-methylthiazol-2-yl)amino)acetylamino)ethyl)boronic acid

[0202] [ka]

[0203] Referring to the methods of Example 1 and Step A of Example 2, the product (9 mg) was obtained using 4-methylthiazol-2-amine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.61 (d, J = 6.8 Hz, 1H), 7.55 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.17-7.27 (m, 2H), 6.76 (s, 1H), 3.61-3.65 (m, 1H), 2.91-3.12 (m, 2H), 2.32 (s, 3H).

[0204] Example 32 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((5-methylthiazol-2-yl)amino)acetylamino)ethyl)boronic acid

[0205] [ka]

[0206] Referring to the methods of Example 1 and Step A of Example 2, the product (10 mg) was obtained using 5-methylthiazol-2-amine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.61 (d, J = 7.2 Hz, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 3.70 (t, J = 7.2 Hz, 1H), 2.98-3.10 (m, 2H), 2.48 (s, 3H).

[0207] Example 33 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((5-fluorothiazol-2-yl)amino)acetylamino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0208] [ka]

[0209] Referring to the method of Example 1, 5-fluorothiazol-2-amine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride were used as raw materials to obtain the product (30 mg). 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.2 Hz, 1H), 7.44-7.47 (m, 2H), 7.28 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 4.30 (d, J = 8.4 Hz, 1H), 3.83-3.87 (m, 1H), 3.18 (dd, J = 15.2 Hz, 6.0 Hz, 1H), 3.05 (dd, J = 15.2 Hz, 6.8 Hz, 1H), 2.29-2.35 (m, 1H), 2.10-2.16 (m, 1H), 1.99 (t, J = 5.6 Hz, 1H), 1.80-1.90 (m, 2H), 1.25 (s, 3H), 1.22 (s, 3H), 1.03 (d, J = 11.2 Hz, 1H), 0.80 (s, 3H).

[0210] Example 34 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((5-fluorothiazol-2-yl)amino)acetylamino)ethyl)boronic acid

[0211] [ka]

[0212] Referring to the method of Step A of Example 2, the product (6 mg) was obtained using (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((5-fluorothiazol-2-yl)amino)acetylamino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester and isobutylboronic acid as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.61 (d, J = 7.6 Hz, 1H), 7.55 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.16-7.27 (m, 3H), 3.63 (t, J = 7.2 Hz, 1H), 2.96-3.08 (m, 2H).

[0213] Example 35 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((5-chlorothiazol-2-yl)amino)acetylamino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0214] [ka]

[0215] Referring to the method of Example 1, 5-chlorothiazol-2-amine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride were used as raw materials to obtain the product (25 mg). 1H NMR (400 MHz, CDCl3) δ 10.66-11.40 (m, 1H), 7.55-7.60 (m, 2H), 7.43-7.48 (m, 3H), 7.28 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.22 (td, J = 7.6 Hz, 1.2 Hz, 1H), 4.31 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 3.83-3.88 (m, 1H), 3.18 (dd, J = 14.8 Hz, 6.0 Hz, 1H), 3.06 (dd, J = 14.8 Hz, 7.2 Hz, 1H), 2.28-2.36 (m, 1H), 2.10-2.16 (m, 1H), 1.99 (t, J = 5.6 Hz, 1H), 1.81-1.91 (m, 2H), 1.25 (s, 3H), 1.23 (s, 3H), 1.03 (d, J = 11.2 Hz, 1H), 0.80 (s, 1H).

[0216] Example 36 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((5-chlorothiazol-2-yl)amino)acetylamino)ethyl)boronic acid

[0217] [ka]

[0218] Referring to the method of Step A of Example 2, the product (9 mg) was obtained using (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((5-chlorothiazol-2-yl)amino)acetylamino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester and isobutylboronic acid as raw materials. 1H NMR (400 MHz, CD3OD) δ 7.56 (d, J = 6.8 Hz, 1H), 7.50 (s, 1H), 7.32-7.39 (m, 2H), 7.11-7.23 (m, 2H), 3.55-3.63 (m, 1H), 2.90-3.05 (m, 2H).

[0219] Example 37 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((1-methyl-1H-imidazol-2-yl)amino)acetylamino)ethyl)boronic acid

[0220] [ka]

[0221] Referring to the methods of Example 1 and Step A of Example 2, the product (16 mg) was obtained using 1-methyl-1H-imidazol-2-amine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.60 (d, J = 7.2 Hz, 1H), 7.55 (s, 1H), 7.36-7.45 (m, 3H), 7.16-7.26 (m, 2H), 3.76 (s, 3H), 3.69 (t, J = 6.8 Hz, 1H), 2.96-3.09 (m, 2H).

[0222] Example 38 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)acetylamino)ethyl)boronic acid

[0223] [ka]

[0224] Referring to the methods of Example 1 and Step A of Example 2, the product (8 mg) was obtained using 2-oxa-6-azaspiro[3.3]heptane, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.59 (d, J = 7.2 Hz, 1H), 7.54 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.19-7.28 (m, 2H), 4.23-4.33 (m, 2H), 3.82-3.88 (m, 4H), 3.72-3.73 (m, 2H), 3.42-3.44 (m, 1H), 3.00 (dd, J = 14.4 Hz, 7.2 Hz, 1H), 3.06 (dd, J = 14.4 Hz, 7.6 Hz, 1H).

[0225] Example 39 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)acetylamino)ethyl)boronic acid

[0226] [ka]

[0227] Referring to the methods of Example 1 and Step A of Example 2, the product (13 mg) was obtained using 3-oxa-8-azabicyclo[3.2.1]octane, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1H NMR (400 MHz, CD3OD) δ 7.60 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.19-7.27 (m, 2H), 4.44-4.54 (m, 2H), 3.49-3.61 (m, 5H), 2.93-2.98 (m, 2H), 1.85-1.98 (m, 4H).

[0228] Example 40 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)acetylamino)ethyl)boronic acid

[0229] [ka]

[0230] Referring to the methods of Example 1 and Step A of Example 2, the product (10 mg) was obtained using 8-oxa-3-azabicyclo[3.2.1]octane, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.62 (d, J = 7.2 Hz, 1H), 7.58 (d, J = 4.4 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.20-7.29 (m, 2H), 4.43 (d, J = 6.0 Hz, 1H), 3.97 (d, J = 12.8 Hz, 1H), 3.51-3.60 (m, 2H), 3.18-3.29 (m, 2H), 2.88-3.01 (m, 3H), 1.65-1.86 (m, 4H).

[0231] Example 41 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(2-oxa-6-azaspiro[3.4]octan-6-yl)acetylamino)ethyl)boronic acid

[0232] [ka]

[0233] Referring to the methods of Example 1 and Step A of Example 2, the product (8 mg) was obtained using 2-oxa-6-azaspiro[3.4]octane, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.59 (d, J = 7.2 Hz, 1H), 7.55 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.18-7.27 (m, 2H), 3.29-3.83 (m, 9H), 2.88-3.00 (m, 2H), 1.26-1.36 (m, 2H).

[0234] Example 42 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(8-oxa-2-azaspiro[4.5]decan-2-yl)acetylamino)ethyl)boronic acid

[0235] [ka]

[0236] Referring to the methods of Example 1 and Step A of Example 2, the product (5 mg) was obtained using 8-oxa-2-azaspiro[4.5]decane, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.61 (d, J = 7.2 Hz, 1H), 7.56 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.18-7.28 (m, 2H), 3.43-3.73 (m, 9H), 2.88-2.98 (m, 2H), 1.60-1.86 (m, 2H), 1.55-1.57 (m, 2H), 1.35-1.38 (m, 2H).

[0237] Example 43 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(2-oxa-8-azaspiro[4.5]decan-8-yl)acetylamino)ethyl)boronic acid

[0238] [ka]

[0239] Referring to the methods of Example 1 and Step A of Example 2, the product (6 mg) was obtained using 2-oxa-8-azaspiro[4.5]decane, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.61 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.18-7.28 (m, 2H), 3.83-3.86 (m, 2H), 3.39-3.65 (m, 5H), 2.88-3.01 (m, 2H), 1.74-1.86 (m, 2H), 1.41-1.65 (m, 3H), 1.22-1.38 (m, 3H).

[0240] Example 44 ((R)-2-(benzofuran-3-yl)-1-(2-oxo-2(((R)-tetrahydrofuran-3-yl)amino)acetylamino)ethyl)boronic acid

[0241] [ka]

[0242] Referring to the methods of Example 1 and Step A of Example 2, the product (12 mg) was obtained using (R)-3-aminotetrahydrofuran tosylate, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.58 (d, J = 7.2 Hz, 1H), 7.53 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 4.35-4.41 (m, 1H), 3.88-3.94 (m, 1H), 3.85 (dd, J = 8.8 Hz, 6.0 Hz, 1H), 3.74-3.80 (m, 1H), 3.62 (dd, J = 8.8 Hz, 3.6 Hz, 1H), 3.52 (t, J = 7.2 Hz, 1H), 3.01 (dd, J = 14.8 Hz, 7.2 Hz, 1H), 2.93 (dd, J = 14.8 Hz, 4.2 Hz, 1H), 2.17-2.26 (m, 1H), 1.87-1.94 (m, 1H).

[0243] Example 45 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((2-methoxypyridin-3-yl)amino)acetylamino)ethyl)boronic acid

[0244] [ka]

[0245] Referring to the methods of Example 1 and Step A of Example 2, the product (21 mg) was obtained using 2-methoxypyridin-3-amine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 8.53 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 6.8 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.19-7.28 (m, 2H), 6.98 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 4.03 (s, 3H), 3.78-3.81 (m, 1H), 2.94-3.01 (m, 2H).

[0246] Example 46 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((5-methylpyrazin-2-yl)amino)acetylamino)ethyl)boronic acid

[0247] [ka]

[0248] Referring to the methods of Example 1 and Step A of Example 2, the product (15 mg) was obtained using 5-methylpyrazin-2-amine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1H NMR (400 MHz, CD3OD) δ 9.32 (s, 1H), 8.82 (s, 0.6H), 8.78 (s, 0.4H), 7.61 (d, J = 7.6 Hz, 1H), 7.55 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.17-7.26 (m, 2H), 3.64-3.68 (m, 1H), 3.08 (dd, J = 14.8 Hz, 6.8 Hz, 1H), 3.00 (dd, J = 14.4 Hz, 8.0 Hz, 1H), 2.70 (s, 1.8H), 2.69 (s, 1.2H).

[0249] Example 47 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(quinoxalin-2-ylamino)acetylamino)ethyl)boronic acid

[0250] [ka]

[0251] Referring to the methods of Example 1 and Step A of Example 2, the product (31 mg) was obtained using 2-aminoquinoxaline, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 9.66 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.18-7.27 (m, 2H), 3.68 (t, J = 7.6 Hz, 1H), 2.99-3.11 (m, 2H).

[0252] Example 48 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrimidin-5-ylamino)acetylamino)ethyl)boronic acid

[0253] [ka]

[0254] Referring to the methods of Example 1 and Step A of Example 2, the product (7 mg) was obtained using 5-aminopyrimidine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 9.29 (s, 2H), 9.02 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 3.65 (t, J = 7.6 Hz, 1H), 2.97-3.09 (m, 2H).

[0255] Example 49 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((4-chloropyridin-2-yl)amino)acetylamino)ethyl)boronic acid

[0256] [ka]

[0257] Referring to the methods of Example 1 and Step A of Example 2, the product (14 mg) was obtained using 2-amino-4-chloropyridine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 8.09 (s, 1H), 7.60-7.63 (m, 2H), 7.55 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 3.69 (t, J = 7.2 Hz, 1H), 2.98-3.10 (m, 2H).

[0258] Example 50 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((4-dimethylaminopyridin-2-yl)amino)acetylamino)ethyl)boronic acid

[0259] [ka]

[0260] Referring to the methods of Example 1 and Step A of Example 2, the product (11 mg) was obtained using 2-amino-4-dimethylaminopyridine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1H NMR (400 MHz, CD3OD) δ 7.87 (d, J = 5.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.18-7.28 (m, 3H), 6.62 (d, J = 5.6 Hz, 1H), 3.66 (t, J = 7.2 Hz, 1H), 2.96-3.16 (m, 8H).

[0261] Example 51 ((R)-1-(2-(((1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl)amino)-2-oxoacetylamino)-2-(benzofuran-3-yl)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0262] [ka]

[0263] Referring to the method of Example 1, the product (53 mg) was obtained using (1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-amine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 6.4 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.18-7.28 (m, 2H), 4.62 (t, J = 9.2 Hz, 1H), 4.36 (d, J = 5.2 Hz, 1H), 4.27 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 4.01 (td, J = 8.4 Hz, 2.8 Hz, 1H), 3.67-3.72 (m, 1H), 3.11 (dd, J = 14.8 Hz, 5.6 Hz, 1H), 3.00 (dd, J = 15.2 Hz, 7.2 Hz, 1H), 2.19-2.33 (m, 2H), 2.06-2.12 (m, 1H), 1.95-2.02 (m, 1H), 1.80-1.91 (m, 2H), 1.60-1.74 (m, 3H), 1.42-1.55 (m, 2H), 1.38 (s, 3H), 1.22-1.24 (m, 3H), 0.99 (t, J = 4.0 Hz, 1H), 0.78 (s, 3H).

[0264] Example 52 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(2-fluorophenylamino)acetylamino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0265] [ka]

[0266] Referring to the method of Example 1, 2-fluoroaniline, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride were used as raw materials to obtain the product (38 mg). 1 H NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 8.28-8.32 (m, 1H), 7.70 (d, J = 6.4 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.09-7.17 (m, 3H), 4.31 (d, J = 8.0 Hz, 1H), 3.82 (q, J = 6.8 Hz, 1H), 3.17 (dd, J = 14.8 Hz, 6.0 Hz, 1H), 3.06 (dd, J = 14.8 Hz, 7.2 Hz, 1H), 2.28-2.36 (m, 1H), 2.09-2.16 (m, 1H), 1.99 (t, J = 5.6 Hz, 1H), 1.81-1.91 (m, 2H), 1.25 (s, 3H), 1.24 (s, 3H), 1.03 (d, J = 11.2 Hz, 1H), 0.81 (s, 3H).

[0267] Example 53 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((5-fluorothiazol-2-yl)amino)acetylamino)ethyl)boronic acid

[0268] [ka]

[0269] Referring to the method of Step A of Example 2, the product (11 mg) was obtained using (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(2-fluorophenylamino)acetylamino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester and isobutylboronic acid as raw materials. 1H NMR (400 MHz, CD3OD) δ 8.02-8.06 (m, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.16-7.28 (m, 5H), 3.63 (t, J = 7.2 Hz, 1H), 2.97-3.09 (m, 2H).

[0270] Example 54 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(2,4-difluorophenylamino)acetylamino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0271] [ka]

[0272] Referring to the method of Example 1, 2,4-difluoroaniline, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride were used as raw materials to obtain the product (40 mg). 1H NMR (400 MHz, CDCl3) δ 9.37 (s, 1H), 8.23-8.29 (m, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.28 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.22 (t, J = 7.2 Hz, 1H), 6.88-6.97 (m, 2H), 4.31 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 3.82 (q, J = 6.8 Hz, 1H), 3.17 (dd, J = 14.8 Hz, 5.6 Hz, 1H), 3.06 (dd, J = 14.8 Hz, 7.2 Hz, 1H), 2.28-2.36 (m, 1H), 2.09-2.16 (m, 1H), 1.99 (t, J = 5.6 Hz, 1H), 1.81-1.90 (m, 2H), 1.25 (s, 3H), 1.24 (s, 3H), 1.02 (d, J = 11.2 Hz, 1H), 0.81 (s, 3H).

[0273] Example 55 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(2,4-difluorophenylamino)acetylamino)ethyl)boronic acid

[0274] [ka]

[0275] Referring to the method of Step A of Example 2, the product (12 mg) was obtained using (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(2,4-diphenylamino)acetylamino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester and isobutylboronic acid as raw materials. 1H NMR (400 MHz, CD3OD) δ 7.91-7.96 (m, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.56 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.2 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.06-7.11 (m, 1H), 6.95-7.01 (m, 1H), 3.62 (t, J = 7.2 Hz, 1H), 2.96-3.08 (m, 2H).

[0276] Example 56 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(3,3-difluoropiperidin-1-yl)acetylamino)ethyl)boronic acid

[0277] [ka]

[0278] Referring to the methods of Example 1 and Step A of Example 2, the product (18 mg) was obtained using 3,3-difluoropiperidine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.60-7.63 (m, 1H), 7.56-7.57 (m, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.19-7.29 (m, 2H), 3.75-3.88 (m, 2H), 3.44-3.62 (m, 2H), 3.32-3.38 (m, 1H), 2.88-3.02 (m, 2H), 1.99-2.12 (m, 2H), 1.64-1.78 (m, 2H).

[0279] Example 57 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)acetylamino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0280] [ka]

[0281] Referring to the method of Example 1, 3-amino-1-methyl-pyridin-2(1H)-one, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride were used as raw materials to obtain the product (40 mg). 1 H NMR (400 MHz, CDCl3) δ 10.70-10.85 (brs, 1H), 10.14 (s, 1H), 8.33 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.60 (d, J = 6.4 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.47 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.19-7.29 (m, 2H), 7.05 (dd, J = 6.8 Hz, 1.6 Hz, 1H), 4.30 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 3.76 (q, J = 6.8 Hz, 1H), 3.64-3.79 (m, 1H), 3.61 (s, 3H), 3.16 (dd, J = 14.8 Hz, 5.6 Hz, 1H), 3.04 (dd, J = 14.8 Hz, 7.2 Hz, 1H), 2.27-2.33 (m, 1H), 2.08-2.14 (m, 1H), 1.98 (t, J = 5.6 Hz, 1H), 1.80-1.89 (m, 1H), 1.25 (s, 3H), 1.23 (s, 3H), 1.05 (d, J = 10.8 Hz, 1H), 0.80 (s, 3H).

[0282] Example 58 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)acetylamino)ethyl)boronic acid

[0283] [ka]

[0284] Referring to the method of Step A of Example 2, the product (12 mg) was obtained using (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)acetylamino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester and isobutylboronic acid as raw materials. 1 H NMR (400 MHz, CD3OD) δ 8.38 (d, J = 7.2 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.55 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 6.8 Hz, 1H), 7.18-7.27 (m, 2H), 6.36 (t, J = 6.8 Hz, 1H), 3.67-3.74 (m, 1H), 3.61 (s, 3H), 3.05 (dd, J = 14.0 Hz, 7.6 Hz, 1H), 2.99 (dd, J = 14.8 Hz, 7.6 Hz, 1H).

[0285] Example 59 (R)-(3-methyl-1-(2-oxo-2-(thiazol-2-ylamino)acetylamino)butyl)boronic acid

[0286] [ka]

[0287] Referring to the methods of Example 1 and Step A of Example 2, the product (5 mg) was obtained using 2-aminothiazole, diisopropylethylamine, oxalyl chloride, and (R)-1-amino-3-methylbutylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester trifluoroacetate as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.80 (d, J = 3.2 Hz, 1H), 7.62 (d, J = 3.2 Hz, 1H), 3.48 (dd, J = 9.2 Hz, 5.2 Hz, 1H), 1.58-1.63 (m, 2H), 1.44-1.48 (m, 1H), 0.91-0.93 (m, 6H).

[0288] Example 60 (R)-(3-methyl-1-(2-oxo-2-(pyridin-2-ylamino)acetylamino)butyl)boronic acid

[0289] [ka]

[0290] Referring to the methods of Example 1 and Step A of Example 2, the product (6 mg) was obtained using 2-aminopyridine, diisopropylethylamine, oxalyl chloride, and (R)-1-amino-3-methylbutylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester trifluoroacetate as raw materials. 1 H NMR (400 MHz, CD3OD) δ 8.46-8.51 (m, 2H), 8.02 (d, J = 8.8 Hz, 1H), 7.68 (t, J = 6.8 Hz, 1H), 3.50 (dd, J = 8.8 Hz, 6.0 Hz, 1H), 1.53-1.67 (m, 2H), 1.42-1.49 (m, 1H), 0.92-0.95 (m, 6H).

[0291] Example 61 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-methoxyamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0292] [ka]

[0293] 2-(Benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (120 mg) was dissolved in dichloromethane (20 mL), cooled to 0 °C, and diisopropylethylamine (82 mg) was added, followed by oxalyl chloride monomethyl ester (40 mg). The mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with water, extracted with dichloromethane, and the organic phase was washed with 1 mol / L hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a preparative silica gel plate (ethyl acetate / petroleum ether = 30%) to give the product (50 mg). 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 6.8 Hz, 1H), 7.44-7.46 (m, 2H), 7.20-7.30 (m, 3H), 4.31 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 3.86 (s, 3H), 3.71-3.76 (m, 1H), 3.15 (dd, J = 15.2 Hz, 6.0 Hz, 1H), 3.04 (dd, J = 15.2 Hz, 7.6 Hz, 1H), 2.28-2.35 (m, 1H), 2.09-2.16 (m, 1H), 1.99 (t, J = 5.6 Hz, 1H), 1.81-1.90 (m, 2H), 1.25 (s, 3H), 1.24 (s, 3H), 1.07 (d, J = 11.6 Hz, 1H), 0.80 (s, 3H).

[0294] Example 62 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-methoxyamido)ethyl)boronic acid

[0295] [ka]

[0296] Following the method of Step A of Example 2, the product (18 mg) was obtained using (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-methoxyamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester as the starting material. 1 H NMR (400 MHz, CD3OD) δ 7.60 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 3.84 (s, 3H), 3.52 (t, J = 7.6 Hz, 1H), 2.93-3.05 (m, 2H).

[0297] Example 63 (R)-2-((2-(benzofuran-3-yl)-1-ethylboronic acid)amino)-2-oxoacetic acid

[0298] [ka]

[0299] (R)-2-(benzofuran-3-yl)-1-(2-methoxy-2-oxoacetylamino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (20 mg) was dissolved in methanol (2 mL) and water (2 mL), and lithium hydroxide monohydrate (8 mg) was added and stirred at room temperature for 2 hours. Subsequently, 1 mol / L hydrochloric acid (1 mL), isobutylboronic acid (40 mg), and n-hexane (5 mL) were added and stirred at room temperature overnight. The methanol phase was separated, washed with n-hexane, and then added with dichloromethane (10 mL), washed with water, and then concentrated under reduced pressure to obtain the product (3 mg). 1 H NMR (400 MHz, CD3OD) δ 7.60 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 3.44-3.50 (m, 1H), 2.91-3.05 (m, 2H).

[0300] Example 64 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-((2-chloropyridin-3-yl)amino)acetylamino)ethyl)boronic acid

[0301] [ka]

[0302] Referring to the methods of Example 1 and Step A of Example 2, the product (21 mg) was obtained using 2-chloropyridin-3-amine, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride as raw materials. 1H NMR (400 MHz, CD3OD) δ 8.62 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 8.17 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.40-7.44 (m, 2H), 7.25 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.20 (td, J = 7.6 Hz, 0.8 Hz, 1H), 3.65 (t, J = 7.6 Hz, 1H), 3.07 (dd, J = 14.4 Hz, 7.2 Hz, 1H), 3.01 (dd, J = 14.4 Hz, 7.2 Hz, 1H).

[0303] Example 65 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)acetylamino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0304] [ka]

[0305] Referring to the method of Example 1, 1,4-dioxa-8-azaspiro[4.5]decane, diisopropylethylamine, oxalyl chloride, and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride were used as raw materials to obtain the product (28 mg). 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.24-7.31 (m, 2H), 7.22 (td, J = 7.2 Hz, 1H), 4.28 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 4.00-4.03 (m, 2H), 3.96 (s, 4H), 3.67-3.70 (m, 2H), 3.58-3.63 (m, 1H), 3.12 (dd, J = 15.2 Hz, 5.2 Hz, 1H), 2.99 (dd, J = 15.2 Hz, 8.0 Hz, 1H), 2.27-2.34 (m, 1H), 2.06-2.13 (m, 1H), 1.97 (t, J = 5.2 Hz, 1H), 1.79-1.88 (m, 2H), 1.70-1.75 (m, 4H), 1.24 (s, 3H), 1.23 (s, 3H), 1.07 (d, J = 11.2 Hz, 1H), 0.80 (s, 3H).

[0306] Example 66 (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)acetylamino)ethyl)boronic acid

[0307] [ka]

[0308] Referring to the method of Step A of Example 2, the product (7 mg) was obtained using (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)acetylamino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester and isobutylboronic acid as raw materials. 1H NMR (400 MHz, CD3OD) δ 7.62 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.20-7.28 (m, 2H), 3.94 (s, 4H), 3.49-3.63 (m, 3H), 3.36-3.39 (m, 2H), 2.89-3.02 (m, 2H), 1.65-1.68 (m, 2H), 1.57-1.60 (m, 2H).

[0309] Example 67 N-((1R)-2-(1-benzofuran-3-yl)-1-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)ethyl)-N'-(pyrazin-2-yl)oxamide

[0310] [ka]

[0311] Referring to the method of Example 19, the product (15 mg) was obtained using (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrazin-2-ylamino)acetylamino)ethyl)boronic acid and 2-methyl-2,4-pentanediol as main raw materials. 1 H NMR (400 MHz, DMSO -d6) δ 10.50 (s, 1H), 9.19 (d, J = 2.8 Hz, 1H), 8.80 (d, J = 6.8 Hz, 0.5H), 8.71 (d, J = 6.8 Hz, 0.5H), 8.45 (dd, J = 6.4 Hz, 1.2 Hz, 2H), 7.71 (s, 0.5H), 7.70 (s, 0.5H), 7.61 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.18-7.27 (m, 2H), 4.10-4.15 (m, 1H), 3.24-3.29 (m, 1H), 2.90-2.94 (m, 2H), 1.78-1.81 (m, 1H), 1.99-2.12 (m, 2H), 1.30-1.37 (m, 1H), 1.11-1.27 (m, 7H).

[0312] Example 68 N-(1R)-2-(1-benzofuran-3-yl)-1-(4-methyl-1,3,2-dioxaborolan-2-yl)ethyl)-N'-(pyrazin-2-yl)oxamide

[0313] [ka]

[0314] Referring to the method of Example 19, the product (53 mg) was obtained using (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrazin-2-ylamino)acetylamino)ethyl)boronic acid and 1,2-propanediol as main raw materials. 1 H NMR (400 MHz, DMSO -d6) δ 10.40 (s, 1H), 9.20 (s, 1H), 8.58 (d, J = 8.4 Hz, 1H),8.46 (d, J = 2.4 Hz, 1H), 8.45 (d, J = 4.0 Hz, 1H), 7.65-7.68 (m, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.18-7.27 (m, 2H), 4.37 (t, J = 5.6 Hz, 1H), 3.52-3.57 (m, 2H), 3.22-3.33 (m, 1H), 3.12-3.16 (m, 1H), 2.97-3.00 (m, 1H), 0.97 (d, J = 6.0 Hz, 3H).

[0315] Example 69 N-(1R)-2-(1-benzofuran-3-yl)-1-((R)-4-methyl-1,3,2-dioxaborolan-2-yl)ethyl)-N'-(pyrazin-2-yl)oxamide

[0316] [ka]

[0317] Referring to the method of Example 19, the product (22 mg) was obtained using (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrazin-2-ylamino)acetylamino)ethyl)boronic acid and (R)-1,2-propanediol as main raw materials. 1 H NMR (400 MHz, DMSO -d6) δ 10.41 (s, 1H), 9.20 (s, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.45 (d, J = 4.0 Hz, 1H), 7.65-7.68 (m, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.18-7.27 (m, 2H), 4.42 (t, J = 5.6 Hz, 1H), 3.52-3.57 (m, 2H), 3.21-3.32 (m, 1H), 3.12-3.16 (m, 1H), 2.97-3.00 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H).

[0318] Example 70 (R)-N-2-(1-benzofuran-3-yl)-1-(1,3,2-dioxaborinan-2-yl)ethyl)-N'-(pyrazin-2-yl)oxamide

[0319] [ka]

[0320] Referring to the method of Example 19, the product (21 mg) was obtained using (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrazin-2-ylamino)acetylamino)ethyl)boronic acid and 1,3-propanediol as main raw materials. 1 H NMR (400 MHz, DMSO -d6 ) δ 10.41 (s, 1H), 9.20 (d, J = 3.2 Hz, 1H), 8.71 (d, J = 6.8 Hz, 1H), 8.45 (dd, J = 6.4 Hz, 1.2 Hz, 2H), 7.69 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.19-7.27 (m, 2H), 4.26-4.29 (m, 1H), 3.52-3.58 (m, 4H), 2.97-3.05 (m, 2H), 1.51-1.57 (m, 2H).

[0321] Example 71 (R)-N-2-(1-benzofuran-3-yl)-1-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)ethyl)-N'-(pyrazin-2-yl)oxamide

[0322] [ka]

[0323] Referring to the method of Example 19, the product (30 mg) was obtained using (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrazin-2-ylamino)acetylamino)ethyl)boronic acid and neopentyl glycol as main raw materials. 1 H NMR (400 MHz, DMSO -d6 ) δ 10.50 (s, 1H), 9.17 (s, 1H), 8.99 (d, J = 7.2 Hz, 1H), 8.45 (d, J = 1.2 Hz, 1H), 8.44 (d, J = 2.8 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.17-7.26 (m, 2H), 3.56 (s, 4H), 3.34-3.39 (m, 1H), 3.30 (m, 2H), 0.87 (s, 6H).

[0324] Example 72 (R)-N-2-(1-benzofuran-3-yl)-1-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)ethyl)-N'-(pyrazin-2-yl)oxamide

[0325] [ka]

[0326] Referring to the method of Example 19, the product (53 mg) was obtained using (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrazin-2-ylamino)acetylamino)ethyl)boronic acid and 2,4-dimethyl-2,4-pentanediol as main raw materials. 1 H NMR (400 MHz, DMSO -d6 ) δ 10.48 (s, 1H), 9.20 (d, J = 1.2 Hz, 1H), 8.77 (d, J = 6.8 Hz, 1H), 8.45-8.47 (m, 2H), 7.72 (s, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.18-7.27 (m, 2H), 3.21-3.26 (m, 1H), 2.92-2.95 (m, 2H), 1.76 (s, 1H), 1.30-1.37 (m, 1H), 1.21 (s, 12H).

[0327] Example 73 (R)-N-2-(benzofuran-3-yl)-1-(4-oxo-1,3,2-dioxaborolan-2-yl)ethyl)-N'-(pyrazin-2-yl)oxamide

[0328] [ka]

[0329] Referring to the method of Example 20, the product (112 mg) was obtained using (R)-(2-(benzofuran-3-yl)-1-(2-oxo-2-(pyrazin-2-ylamino)acetylamino)ethyl)boronic acid and glycolic acid as main raw materials. 1 H NMR (400 MHz, DMSO -d6) δ 10.43 (s, 1H), 9.20 (s, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.42-8.46 (m, 2H), 7.62-7.68 (m, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.18-7.26 (m, 2H), 3.88 (s, 1H), 3.51-3.57 (m, 1H), 2.92-3.03 (m, 1H), 2.81 (d, J = 6.8 Hz, 2H).

[0330] Biological testing: 1. Measurement of enzymatic inhibitory activity of compounds against LMP7: LMP7 is a catalytic subunit of the immunoproteasome. In this study, we established an enzymatic detection platform utilizing its hydrolytic enzyme activity and used it to detect the activity of compounds. Ac-ANW-AMC (Bonston Biochem, Catalog No. S-320) was used as the substrate for LMP7. The amount of the fluorescent group AMC (7-Amino-4-methylcoumarin) released after hydrolysis can reflect enzymatic activity. MOLT-4 cells are human acute lymphoblastic leukemia cells that were identified as cells highly expressing LMP7. We established an enzymatic detection method for compounds against LMP7 using MOLT-4 cell lysate as the enzyme source of LMP7, and measured the inhibitory activity of compounds (half maximal inhibitory concentration, IC ). 50 ) was detected.

[0331] MOLT-4 cells were cultured at 75 cm in RPMI-1640 (Biological Industries) medium containing 10% fetal bovine serum (Biological Industries) and 1% Pen-Strep (Gibco). 2 The cells were cultured in a cell culture flask (Corning) at 37°C, 95% air and 5% CO2, and subcultured 2-3 times a week. 7MOLT-4 cells were harvested, resuspended in 1 mL of PBS (Solarbio), and centrifuged at 3,000 rpm for 5 minutes. The supernatant was aspirated. The cells were resuspended in 500 μL of lysis buffer (20 mM Tris, pH 8.0, 5 mM EDTA, with protease inhibitor (1:1,000) and phosphatase inhibitor (1:100) added immediately before use) and incubated on ice for 30 minutes. The cells were disrupted by sonication (0.5 seconds on, 0.5 seconds off, sonication time: 2.5 seconds). The cells were centrifuged at 12,000 rpm for 10 minutes at 4°C. The supernatant was the cell lysate, and protein was quantified using the BCA method (Thermo, #23225).

[0332] The compounds were diluted 5-fold using 100% DMSO, resulting in a total of nine concentrations. 2 μL of each concentration was added to 48 μL of reaction buffer (20 mM Tris, pH 8.0, 0.5 mM EDTA) and mixed thoroughly to prepare 4× compound (final concentrations: 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, and 0 nM). 4× MOLT-4 cell lysate (final concentration: 20 ng / μL) and 2× Ac-ANW-AMC (final concentration: 100 μM) were prepared using the reaction buffer. 5 μL of the 4× compound was added to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), 5 μL of 4× cell lysis solution was added, the plate was centrifuged, and the reaction was allowed to proceed in an incubator at 23°C for 1 hour. 10 μL of 2× Ac-ANW-AMC was added, the plate was centrifuged, and the reaction was allowed to proceed in the dark at 23°C for 2 hours. After the reaction was completed, the plate was incubated with CLARIO star Plus The signal value was read at an excitation wavelength of 345 nm / emission wavelength of 445 nm in a PBS (purchased from BMG LRBTECH). The enzyme activity of each compound was measured at nine concentrations, and the data was processed using the software GraphPad Prism to calculate the half-maximal inhibitory concentration (IC) of the compound against LMP7. 50 The value was calculated.

[0333] 2. Measurement of the enzymatic inhibitory activity of compounds against β5: β5 is the catalytic subunit of the proteasome. In this study, we established an enzymatic detection platform utilizing its hydrolytic enzyme activity and used it to detect the activity of compounds. Ac-WLA-AMC (Bonston Biochem, Catalog No. S-330) was used as the substrate for β5. The amount of the fluorescent group AMC (7-Amino-4-methylcoumarin) released after hydrolysis can reflect enzymatic activity. HEK-293 cells are human embryonic kidney cells that constitutively express proteasomes but do not express immunoproteasomes. We established an enzymatic detection method for compounds against β5 using HEK-293 cell lysates as the enzyme source for β5, and measured the inhibitory activity of the compounds (half maximal inhibitory concentration, IC ). 50 The enzymatic inhibitory activity of the compounds against β5 was used as a detection index for the selectivity of the compounds.

[0334] HEK-293 cells were cultured at 75 cm in DMEM (Biological Industries) medium containing 10% fetal bovine serum (Biological Industries) and 1% Pen-Strep (Gibco). 2 The cells were cultured in a cell culture flask (Corning) at 37°C, 95% air and 5% CO2, and subcultured 2-3 times a week. 7HEK-293 cells were harvested, resuspended in 1 mL of PBS (Solarbio), and centrifuged at 3,000 rpm for 5 minutes. The supernatant was aspirated. The cells were resuspended in 500 μL of lysis buffer (20 mM Tris, pH 8.0, 5 mM EDTA, with protease inhibitor (1:1,000) and phosphatase inhibitor (1:100) added immediately before use) and incubated on ice for 30 minutes. The cells were disrupted by sonication for 2.5 seconds, with an on / off period of 0.5 seconds. The cells were centrifuged at 12,000 rpm for 10 minutes at 4°C. The supernatant was used as the cell lysate, and protein was quantified using the BCA method (Thermo, #23225).

[0335] The compounds were diluted 5-fold using 100% DMSO, resulting in a total of nine concentrations. 2 μL of each concentration was added to 48 μL of reaction buffer (20 mM Tris, pH 8.0, 0.5 mM EDTA) and mixed thoroughly to prepare 4× compound (final concentrations: 100,000 nM, 20,000 nM, 4,000 nM, 800 nM, 160 nM, 32 nM, 6.4 nM, 1.28 nM, and 0 nM). 4× HEK-293 cell lysate (final concentration: 25 ng / μL) and 2× Ac-WLA-AMC (final concentration: 20 μM) were prepared using the reaction buffer. 5 μL of the 4× compound was added to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), and 5 μL of 4× HEK-293 cell lysate was added. The plate was centrifuged and incubated in an incubator at 23°C for 1 hour. 10 μL of 2× Ac-WLA-AMC was added and centrifuged to initiate the reaction. The reaction was incubated in the dark at 23°C for 2 hours. After the reaction was completed, CLARIO star Plus The signal was read at an excitation wavelength of 345 nm / emission wavelength of 445 nm in a PBS (purchased from BMG LRBTECH). The enzyme activity of each compound was measured at nine concentrations, and the data was processed using the software GraphPad Prism to calculate the half-maximal inhibitory concentration (IC) of the compound against β5. 50 The value was calculated.

[0336] 3. Measurement of the cytological inhibitory activity of compounds against LMP7: MOLT-4 is a human acute lymphoblastic leukemia cell line that has been identified as a cell line that highly expresses LMP7. In this study, compounds were pre-incubated with MOLT-4 cells, and Ac-ANW-AMC (Bonston Biochem, Cat. No. S-320) was used as a substrate for LMP7. A method for detecting compounds against intracellular LMP7 enzyme activity was established, and the inhibitory activity of the compounds (50% maximal inhibitory concentration, IC 50 ) was detected.

[0337] 1.5 x 10 cells per well 5Cells were plated in 24-well plates (Corning) at a concentration of 1000kJ / mL. The following day, compounds were prepared and diluted 5-fold with 100% DMSO starting from 2 mM, for a total of eight concentrations. 2 μL of each compound was added to 1 mL of cell culture medium, followed by 1 mL of RPMI-1640 (FBS final concentration: 5%, V:V) to mix the compounds evenly. After incubation in an incubator for 2 hours, the cells were centrifuged at 2000 rpm for 8 minutes, the supernatant discarded, and washed once with 2 mL of PBS (Solarbio), centrifuged again, and the supernatant discarded. The cells were resuspended in 100 μL of lysis buffer (20 mM Tris, pH 8.0, 5 mM EDTA, with protease inhibitor (1:100) and phosphatase inhibitor (1:100) added immediately before use) and placed in a refrigerator at 4°C for 45 minutes. After centrifugation at 2000 rpm for 2 minutes, the lysate was transferred from the 24-well plate to a 96-well plate and centrifuged at 2000 rpm at 4°C for 15 minutes. The supernatant was used as the lysate. Protein was quantified using the BCA method (Thermo, #23225). A 2x lysate with a final concentration of 20 ng / μL was prepared using reaction buffer (20 mM Tris, pH 8.0, 0.5 mM EDTA). 2x Ac-ANW-AMC with a final concentration of 100 μM was prepared using reaction buffer. 10 μL of the 2× lysis solution was added to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), and 10 μL of 2× Ac-ANW-AMC was added. The plate was centrifuged to initiate the reaction, which was then incubated at 23°C in the dark for 1 hour. Plus The signal value was read at excitation wavelength 345 nm / emission wavelength 445 nm in a 1000-well plate (purchased from BMG LRBTECH). The enzyme activity of each compound was measured at eight concentrations, and the data was processed using the software GraphPad Prism to calculate the half-maximal inhibitory concentration (IC) of the compound against LMP7 hydrolase in MOLT-4 cells. 50 The value was calculated.

[0338] In the above, "x" refers to multiplication and represents a multiple.

[0339] The test results for some of the above compounds are shown in Table 1.

[0340] [Table 1-1]

[0341] [Table 1-2]

[0342] 4. Pharmacokinetic studies of compounds in animals: Three healthy adult male rats provided by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. were used for the animal pharmacokinetic study. The compound was suspended in a 20% sulfobutylether-β-cyclodextrin (W:W:V) solution at a concentration of 1 mg / mL and administered orally at a dose of 5 mL / kg. The compound was administered orally at a single dose of 5 mg / kg. The animals were fasted overnight before the study, with the fasting period lasting from 10 hours before administration until 4 hours after administration. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The animals were anesthetized with isoflurane, and approximately 0.4 mL of whole blood was collected from the orbital venous plexus using a glass blood collection tube and placed in a heparinized anticoagulant blood collection tube. The sample was centrifuged at 4°C at 4200 rpm for 5 minutes. The plasma was transferred to a centrifuge tube and stored at -80°C for analysis. For the analysis of plasma samples, the test compound and internal standard (warfarin or propranolol) were extracted from rat plasma using the acetonitrile protein precipitation method, and the extract was analyzed by LC / MS / MS. The measured plasma concentration-time data of each animal was analyzed using a non-compartmental model in WinNonlin (version 5.2.1, Pharsight) software, and the maximum blood concentration C was calculated as a pharmacokinetic parameter. max , Time to reach maximum blood concentration T max , blood concentration half-life T 1 / 2, the area under the plasma drug concentration-time curve when extrapolated to infinity, AUC0~ inf obtained.

[0343] [Table 2]

[0344] 5. In Vivo Testing In vivo test I: Evaluation of LMP7 inhibitors in a mouse subcutaneous xenograft model of human multiple myeloma MM.1S cells: 1. Test Materials 1.1 Test equipment Digital display caliper (model number: 36-111-23, resolution: 0.01mm, STANLEY), JEB2002 electronic balance (resolution: 0.01g, Shanghai Puchun Weighing Equipment Co., Ltd.), XS105 electronic balance (resolution: 0.01 mg, Mettler-Toledo), AL204 electronic balance (resolution: 0.1 mg, Mettler-Toledo), biological safety cabinet (model number: HR40-IIA2, Qingdao Haier Special Electric Appliance Co., Ltd.).

[0345] 1.2 Test animals Female NOD / SCID mice, 5-6 weeks old, with a qualification certificate number of SCXK(Kyoto)2021-0006, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. 2. Test Method Grouping and dosing of mice: The specific methods were as follows: Mice were housed in an SPF environment, with five mice per cage. The animals had free access to water and food and were allowed to adapt for one week. The laboratory room temperature was 18-24°C, the relative humidity was 40-70%, and the room was ventilated with a ventilation fan and provided with 12 hours of natural light each day. Cages, bedding, drinking water, and food were changed twice a week. After changing the cages and drinking water bottles, they were washed and sterilized by autoclaving. The frame, walls, and floor of the room were cleaned twice a week with 84 disinfectant or benzyldimethyldodecylammonium bromide.

[0346] MM.1S cells (Cell Resources Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences) were cultured in RPMI-1640 medium supplemented with 20% fetal bovine serum and 1% penicillin-streptomycin at 37°C in an atmosphere of 5% CO2 in air. Cells were routinely subcultured twice weekly, and exponentially growing cells were harvested, counted, and homogenized in 30% Matrigel™ (Corning Matrigel™ rich basement membrane) for tumor cell inoculation.

[0347] Mice were pretreated with continuous intraperitoneal injections of cyclophosphamide for 3 days, and then 0.1 mL of MM.1S cell suspension (1.0 × 10 cells) suspended in PBS was added. 7 A mouse subcutaneous tumor model of multiple myeloma cells MM.1S was established by subcutaneous injection of 30% Matrigel into the left and right axillary regions of each mouse. The tumor size was 400-700 mm. 3 Once the tumor mass reached the target size, it was harvested under sterile conditions and frozen for further use. MM.1S tumor masses were resuscitated, harvested under sterile conditions, and passaged for two generations before in vivo efficacy evaluation studies were performed. The average tumor volume was approximately 100-150 mm. 3 At this time, 20 tumor-bearing mice with regular tumor shape and uniform size were selected for the study. They were divided into four groups, each consisting of five mice. Group 1 was the model group and received oral administration of the vehicle once daily; Group 2 received oral administration of Example 9 (2 mg / kg) once daily; Group 3 received oral administration of Example 67 (2 mg / kg) once daily; and Group 4 received oral administration of Example 73 (2 mg / kg) once daily. Administration began on the day of grouping and continued for 14 consecutive days. During the study, tumor diameter and body weight were measured three times a week. At the end of the study, blood was collected from the medial canthus of the eye. The mice were immediately sacrificed after blood collection to obtain tumor tissue.

[0348] The study endpoints were tumor growth inhibition, maximum tumor burden (individual tumor size equal to 10% of body weight), and weight loss of more than 20% of the body weight at the start of treatment. The formula for tumor volume calculation was V = 0.5 × a × b 2 where V is the tumor volume, and a and b are the length and width of the tumor, respectively. The formula for calculating the tumor growth inhibition rate was TGI (%) = (1 - (tumor volume in the treatment group - tumor volume at the time of grouping into the treatment group) / (tumor volume in the control group - tumor volume at the time of grouping into the control group)) × 100%. Complete regression (CR) of the tumor was defined as the tumor growth rate at the palpable limit (mm 3 A partial tumor regression (PR) was defined as a tumor that decreased to half of its initial tumor volume. A minimum duration of CR or PR on three or more consecutive tumor measurements was required for the CR or PR to be considered durable.

[0349] Summary statistics (including mean and standard error of the mean (SEM)) were provided for tumor volume in each group at each time point, and differences in tumor volume were shown in corresponding records. A t-test was used to compare the significance between groups, with p<0.05 considered to indicate statistical significance.

[0350] 3. Test Results The results are shown in Figure 1 (A is the tumor growth curve, and B is the weight curve of the tumor-bearing mice). As can be seen from Figure 1, at the end of the study (day 14), the tumor volume of the mice in the vehicle control group (Vehicle) was 957.04 mm 3The TGI and T / C of Example 9 (2 mg / kg) were 112.28% and 0.88%, respectively, demonstrating significant tumor-inhibitory effects (p<0.01). The TGI and T / C of Example 67 (2 mg / kg) were 112.06% and 1.57%, respectively, demonstrating significant tumor-inhibitory effects (p<0.01). The TGI and T / C of Example 73 (2 mg / kg) were 112.56% and 0.53%, respectively, demonstrating significant tumor-inhibitory effects (p<0.001). Furthermore, no compound-induced animal deaths or weight loss were observed during the study, indicating the compounds' good safety. These results demonstrate that Examples 9, 67, and 73 are promising oral small molecule LMP7 inhibitors for the treatment of multiple myeloma.

[0351] In vivo test II: Evaluation of LMP7 inhibitors in a mouse subcutaneous xenograft model of human multiple myeloma U266B1 cells: 1. Test Materials 1.1 Test equipment Digital display caliper (model number: 36-111-23, resolution: 0.01mm, STANLEY), JEB2002 electronic balance (resolution: 0.01g, Shanghai Puchun Weighing Equipment Co., Ltd.), XS105 electronic balance (resolution: 0.01 mg, Mettler-Toledo), AL204 electronic balance (resolution: 0.1 mg, Mettler-Toledo), biological safety cabinet (model number: HR40-IIA2, Qingdao Haier Special Electric Appliance Co., Ltd.).

[0352] 1.2 Test animals Female NOG mice, 6-8 weeks old, with a qualification certificate number of SCXK(Kyoto)2021-0006, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. 2. Test Method Grouping and dosing of mice: The specific methods were as follows: Mice were housed in an SPF environment, with five mice per cage. The animals had free access to water and food and were allowed to adapt for one week. The laboratory room temperature was 18-24°C, the relative humidity was 40-70%, and the room was ventilated with a ventilation fan and provided with 12 hours of natural light each day. Cages, bedding, drinking water, and food were changed twice a week. After changing the cages and drinking water bottles, they were washed and sterilized by autoclaving. The frame, walls, and floor of the room were cleaned twice a week with 84 disinfectant or benzyldimethyldodecylammonium bromide.

[0353] U266B1 cells (China Center for Typical Culture Cultures, School of Life Sciences, Wuhan University) were cultured in RPMI-1640 medium supplemented with 20% fetal bovine serum and 1% penicillin-streptomycin at 37°C in an atmosphere of 5% CO2 in air. Cells were routinely subcultured twice weekly, and exponentially growing cells were harvested, counted, and homogenized in a 1:1 ratio in Matrigel™ (Corning Matrigel™ standard concentration basement membrane) for tumor cell inoculation.

[0354] 0.1 mL of U266B1 cell suspension (1.0 × 10 cells) suspended in PBS 7 A mouse subcutaneous tumor model of multiple myeloma cells U266B1 was established by subcutaneous injection of 50% Matrigel into the left and right axillary regions of each mouse. The average tumor volume was approximately 100–150 mm. 3 At this time, 10 tumor-bearing mice with tumors of regular shape and uniform size were selected for the study. They were divided into two groups, each with 5 mice. Group 1 was the model group and received oral administration of the vehicle once daily, while Group 2 received oral administration of Example 9 (0.3 mg / kg) once daily. Administration began on the day of grouping and continued for 14 consecutive days. During the study, tumor diameter and body weight were measured three times a week. At the end of the study, blood was collected from the medial canthus of the eye, and the mice were immediately sacrificed to obtain tumor tissue.

[0355] The study endpoints were tumor growth inhibition, maximum tumor burden (individual tumor size equal to 10% of body weight), and weight loss of more than 20% of the body weight at the start of treatment. The formula for tumor volume calculation was V = 0.5 × a × b 2 where V is the tumor volume, and a and b are the length and width of the tumor, respectively. The formula for calculating the tumor growth inhibition rate was TGI (%) = (1 - (tumor volume in the treatment group - tumor volume at the time of grouping into the treatment group) / (tumor volume in the control group - tumor volume at the time of grouping into the control group)) × 100%. Complete regression (CR) of the tumor was defined as the tumor growth inhibition rate at the palpable limit (mm 3 A partial tumor regression (PR) was defined as a tumor that decreased to half of its initial tumor volume. A minimum duration of CR or PR on three or more consecutive tumor measurements was required for the CR or PR to be considered durable.

[0356] Summary statistics (including mean and standard error of the mean (SEM)) were provided for tumor volume in each group at each time point, and differences in tumor volume were shown in corresponding records. A t-test was used to compare the significance between groups, with p<0.05 considered to indicate statistical significance.

[0357] 3. Test Results The results are shown in Figure 2 (A is the tumor growth curve, and B is the weight curve of the tumor-bearing mice). As can be seen from Figure 1, at the end of the study (day 14), the tumor volume of the mice in the vehicle control group (Vehicle) was 1041.51 mm 3 The TGI and T / C of Example 9 (0.3 mg / kg) were 104.45% and 9.76%, respectively, demonstrating a significant tumor-inhibiting effect (p<0.001). Furthermore, no compound-induced animal deaths or weight loss were observed during the study, indicating the compound's good safety. These results demonstrate that Example 9, as an oral small molecule LMP7 inhibitor, has great promise for treating multiple myeloma.

[0358] To summarize the above test results, it was found that the LMP7 inhibitors (Examples 9, 67, and 73) have a good tumor-suppressing effect on multiple myeloma.

Claims

1. The following compounds 【Chemistry 16-1】 【Chemistry 16-2】 or a pharmaceutically acceptable salt or solvate thereof.

2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

3. Use of a compound described in claim 1 or a pharmaceutically acceptable salt or solvate thereof, or a composition described in claim 2, in the manufacture of a drug for treating a disease associated with lmp7 activity.

4. The diseases associated with lmp7 activity include multiple myeloma, acute myeloid leukemia, myeloid leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, plasma cell neoplasms, follicular lymphoma, immunocytoma, breast cancer, ovarian cancer, colorectal cancer, ovarian cancer, esophageal cancer, lung cancer, head and neck cancer, pancreatic cancer, kidney cancer, stomach cancer, thyroid cancer, prostate cancer, bladder cancer, and rheumatoid arthritis.

4. The use according to claim 3, wherein the treatment is selected from the group consisting of inflammatory bowel disease, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, scleroderma, adhesive spondylitis, atherosclerosis, Behcet's disease, Crohn's disease, inflammatory bowel disease, ulcerative colitis, autoimmune hepatitis, Sjogren's syndrome, lupus nephritis, asthma, amyotrophic lateral sclerosis (ALS), psoriasis, immunoglobulin A nephropathy, Henoch-Scholein purpura, and Alzheimer's disease (AD).

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