Boric acid derivatives

Abstract

The present invention relates to boric acid derivatives; the present invention provides compounds of formula (I) or pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof, pharmaceutical compositions comprising these compounds, and the use of such compounds in the treatment of diseases related to lmp7.

Description

[0001] Cross-reference to Related Applications

[0002] This application claims the priority of a Chinese patent application filed on January 19, 2020, with the application number 202010058216.9, the content of which is incorporated herein by reference in its entirety. Technical Field

[0003] This patent relates to a novel class of boronic acid derivatives of formula (I) or pharmaceutically acceptable salts thereof. The present invention also provides pharmaceutical compositions containing such compounds and methods for their preparation. The compounds described in this patent can be used for the treatment or prevention of diseases related to immunoproteasome. Background Art

[0004] The ubiquitin-proteasome system (UPS) exists in all eukaryotic cells and is responsible for the degradation of misfolded or redundant proteins within the cell. By regulating protein level homeostasis, it controls almost all important life activities, such as signal transduction, transcriptional regulation, cell differentiation, and apoptosis. The 26S proteasome (so named because its sedimentation coefficient in density gradient centrifugation is 26S) can be structurally divided into two parts: the 19S regulatory particle and the 20S core particle. The 19S regulatory particle is responsible for recognizing ubiquitin-tagged proteins, unfolding them, and finally transporting 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 containing seven α subunits, serve as the binding site for the regulatory particle on the one hand and act as a "gate" on the other hand to prevent unregulated entry of proteins into the interior of the core particle. The two inner rings, each containing seven β subunits, contain protease active subunits β1c, β2c, and β5c for proteolytic reactions. In hematopoietic cells and cells stimulated by 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-like-1), and β5i (LMP7) to form the immunoproteasome [Michael Basler et al., EMBO reports, 2018]. LMP7 is encoded by the PSMB8 gene, consisting of 276 amino acids, and is a small molecule protein of approximately 30 kDa. LMP7 is the core catalytic subunit of the immunoproteasome, has chymotrypsin-like 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].

[0005] The functions of the immunoproteasome in the immune process have been well studied, especially its antigen presentation function. The catalytic subunits of the immunoproteasome hydrolyze to produce polypeptides, which are presented on the cell surface by major histocompatibility complex (MHC)-1, triggering cytotoxic T lymphocyte responses (CTLs). Compared with the proteasome, the immunoproteasome can hydrolyze proteins and present antigens more efficiently, and the antigens produced can elicit stronger CTLs. Some studies have demonstrated that the immunoproteasome can regulate cytokine production. Selectively inhibiting LMP7 with a small molecule inhibitor suppresses IL-23 in monocytes and TNF-α and IL-6 in T cells. A similar phenomenon was also 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]. In addition, the functions of the immunoproteasome in T cell differentiation, proliferation, and apoptosis have also been verified in some studies [C.M. Caudill et al., T cells lacking immunoproteasome subunit MECL-1 and LMP7 hyperproliferate in response to polyclonal mitogens, J. Immunol, 176(7), 4075-82, 2006]. Besides immune functions, the immunoproteasome plays a role in maintaining protein homeostasis in cytokine-induced oxidative stress responses. Oxidative stress responses release free radicals, leading to the accumulation of a large number of damaged proteins, exceeding the clearance capacity of the general proteasome and ultimately resulting in cell death. The immunoproteasome can efficiently remove protein accumulation and maintain intracellular homeostasis. In LMP7 / β5i- and LMP2 / β1i-deficient mice, the accumulation of oxidized and polyubiquitinated proteins in the liver and brain was observed [U. Seifert et al., Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress, Cell, 142(4), 613-24, 2010].

[0006] The immunoproteasome is associated with a variety of diseases. Research has shown that the immunoproteasome is highly expressed in blood cancers, and the selective inhibition of β1i and LMP7 can effectively inhibit the growth 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 the tumors of 40% of the 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 occurrence and development of colorectal cancer, and inhibitors of LMP7 can effectively inhibit the formation of colorectal cancer 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]. Recently, new evidence has emerged demonstrating the association of the immunoproteasome with autoimmune diseases, making it a promising target for the treatment of 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 murine models of arthritis, selective inhibitors of LMP7 reduce the degree of inflammatory infiltration and cytokine levels, alleviating the symptoms of arthritis [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]. Articles have reported that the immunoproteasome is associated with neurodegenerative diseases, and the immunoproteasome is highly expressed in the brains of Alzheimer's disease patients [M. Díaz Hernández et al., Neuronal Induction of the Immunoproteasome in Huntington's Disease, Journal of Neuroscience, 23(37):11653 - 11661, 2003].

[0007] Targeting the catalytic subunit LMP7 of the immunoproteasome for the treatment of various diseases is an innovative field with broad development space. Compared with broad - spectrum proteasome inhibitors, LMP7 selective inhibitors have an absolute advantage in terms of safety. Patents such as WO2019099582A1 and WO2019038250A1 have disclosed some LMP7 inhibitors and methods for using them to treat related diseases.

[0008] This patent describes a class of boric acid derivatives that have good inhibitory activity against LMP7 and good selectivity for other proteasomes. Moreover, such compounds have excellent oral bioavailability, plasma protein binding, pharmacokinetic characteristics, CYP - inhibition, and stability. Summary of the Invention

[0010] In one aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof,

[0011]

[0012] wherein,

[0013] R a and R b each independently selected from H and C 1-6 alkyl, or R a and R b may be joined together to form a 3 - to 10 - membered heterocycle;

[0014] X is a bond, -O-, or -NR 4 -;

[0015] Y is a bond or -(CR 4 R 5 ) m -;

[0016] R 4 and R 5 are each independently selected from H, C 1-6 alkyl, and C 3-8 cycloalkyl;

[0017] m is 1, 2, or 3;

[0018] R 2 is selected from H and C 1-6 alkyl;

[0019] R 3 is selected from C 6-10 aryl and C 5-10 heteroaryl, and the aryl and heteroaryl may optionally be substituted by halogen, -OH, -NH 2 , -O-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -CN, NO 2 , C 1-6 alkyl, C 3-8 cycloalkyl, or C 3-8 heterocycloalkyl;

[0020] R 1 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, and C 5-10 heteroaryl, and the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each substituted by one of and may optionally be substituted by halogen, -OH, -NH 2 , -(CH 2 ) 1-3 -C 3-8 cycloalkyl, -(CH 2 ) 0-6 -CF 3 , -O-C 1-6 alkyl, -NR 9 R 8 , -CN, NO 2 , C 1-6 alkyl, -(CH 2 ) 0-3 -(CO)-R8 ,-(CH 2 ) 0-3 -(CO)-NH-R 8 ,-(CH 2 ) 0-3 -NH-(CO)-R 8 , or R 10 is substituted;

[0021] R 6a and R 6b are each independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, and C 5-10 heteroaryl, and the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be optionally substituted by halogen, C 1-6 alkyl, C 3-8 cycloalkyl, -OH, -NH 2 , -O-C 1-6 alkyl, -NR 9 R 8 , -NO 2 , or -CN, or

[0022] R 6a and R 6b may be linked together to form a 3- to 8-membered heterocycle;

[0023] R 7 is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, and C 5-10 heteroaryl, and the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be optionally substituted by halogen, C 1-6 alkyl, C 3-8 cycloalkyl, -OH, -NH 2 , -O-C 1-6 alkyl, -NR 9 R 8 , -NO 2 , or -CN;

[0024] R 8 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, and C 5-10 heteroaryl, and the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be optionally substituted by halogen, C 1-6 alkyl, -O-C1-6 alkyl, C 6-10 aryl, or C 5-10 heteroaryl substituted;

[0025] R 9 selected from H and C 1-6 alkyl;

[0026] R 10 selected from C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may optionally be substituted by halogen, -OH, -NH 2 , -O-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -CN, NO 2 , or C 1-6 alkyl substituted;

[0027] In some embodiments, R a and R b are H;

[0028] In some embodiments, X is a bond, -O-, or -NR 4 -, R 4 is H;

[0029] In some embodiments, Y is a bond or -(CR 4 R 5 ) m -, R 4 and R 5 are each independently selected from H and C 1-6 alkyl, and m is 1, 2, or 3;

[0030] In some embodiments, Y is a bond or -(CR 4 R 5 ) m -, R 4 and R 5 are H, and m is 1, 2, or 3;

[0031] In some embodiments, Y is a bond or -(CR 4 R 5 ) m -, R 4 and R 5 are each independently selected from H and C 1-6 alkyl, and m is 1 or 2;

[0032] In some embodiments, Y is a bond or -(CR4 R 5 ) m -, R 4 and R 5 is H, and m is 1 or 2;

[0033] In some embodiments, Y is a bond or -(CR 4 R 5 ) m -, R 4 and R 5 each independently selected from H and C 1-6 alkyl, and m is 1;

[0034] In some embodiments, Y is a bond or -(CR 4 R 5 ) m -, R 4 and R 5 are H, and m is 1;

[0035] In some embodiments, R 2 is H;

[0036] In some embodiments, R 3 is selected from C 5-10 heteroaryl, and the heteroaryl may optionally be substituted by halogen, NO 2 , C 1-6 alkyl, C 3-8 cycloalkyl, or C 3-8 heterocycloalkyl;

[0037] In some embodiments, R 3 is the which may optionally be substituted by halogen, NO 2 , C 1-6 alkyl, C 3-8 cycloalkyl, or C 3-8 heterocycloalkyl;

[0038] In some embodiments, R 1 is selected from C 3-8 cycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, and the cycloalkyl, aryl and heteroaryl are each substituted by one of and may optionally be substituted by halogen, -CF 3 , -O-C 1-6 alkyl, NO 2 , C 1-6 alkyl, -(CO)-R 8 , -(CO)-NH-R 8 , or R 10 ;

[0039] R 6a and R 6b each independently selected from C 1-6 alkyl and C 3-8 cycloalkyl, or R 6a and R 6b may be joined together to form a 3- to 8-membered heterocycle;

[0040] R 7 is selected from H, C 1-6 alkyl and C 3-8 cycloalkyl;

[0041] R 8 is selected from C 1-6 alkyl and C 3-8 cycloalkyl, the cycloalkyl being optionally substituted by C 1-6 alkyl;

[0042] R 10 is selected from C 3-8 cycloalkyl and C 3-8 heterocycloalkyl, the cycloalkyl and heterocycloalkyl being optionally substituted by C 1-6 alkyl;

[0043] In some embodiments, the present invention provides the following compounds or pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof:

[0044]

[0045] In some embodiments, the present invention provides the following compounds or pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof:

[0046]

[0047] The compound of formula (I) of the present invention can be used for treating diseases related to lmp7; in some embodiments, the diseases related to lmp7 activity are malignant hematological diseases, solid tumors or immunomodulatory abnormalities, more preferably multiple myeloma, acute myeloid leukemia, myelocytic leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, plasmacytoma, follicular lymphoma, immunocytoma, breast cancer, liver cancer, colorectal cancer, ovarian cancer, esophageal cancer, lung cancer, head and neck cancer, pancreatic cancer, kidney cancer, gastric cancer, thyroid cancer, prostate cancer, bladder cancer, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, scleroderma, ankylosing 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-Schönlein purpura, Alzheimer's disease (AD);

[0048] On the other hand, the present invention also relates to a pharmaceutical composition, which comprises a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier;

[0049] In another aspect, the present invention provides a method for treating a disease related to lmp7 activity, the method comprising administering to a subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or the above composition; in some embodiments, the diseases related to lmp7 activity are multiple myeloma, acute myeloid leukemia, myelocytic leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, plasmacytoma, follicular lymphoma, immunocytoma, breast cancer, liver cancer, colorectal cancer, ovarian cancer, esophageal cancer, lung cancer, head and neck cancer, pancreatic cancer, kidney cancer, gastric cancer, thyroid cancer, prostate cancer, bladder cancer, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, scleroderma, ankylosing 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-Schönlein purpura, Alzheimer's disease (AD);

[0050] In some embodiments of the present invention, the subject involved in the present invention is a mammal including humans;

[0051] In another aspect, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof in the preparation 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, myelocytic leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, plasmacytoma, follicular lymphoma, immunocytoma, breast cancer, liver cancer, colorectal cancer, ovarian cancer, esophageal cancer, lung cancer, head and neck cancer, pancreatic cancer, kidney cancer, gastric cancer, thyroid cancer, prostate cancer, bladder cancer, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, scleroderma, ankylosing 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-Schönlein purpura, Alzheimer's disease (AD). DETAILED DESCRIPTION OF THE INVENTION

[0053] Exemplary embodiments using the principles of the present invention are set forth in the detailed description of the invention below. The features and advantages of the present invention may be better understood by reference to the following description of the invention.

[0054] It should be understood that the scope of protection of various aspects of the present invention is determined by the claims, and the methods and structures within the scope of these claims and their equivalent methods and structures are all within the scope covered by the present claims.

[0055] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of the claims pertains. All patents, patent applications, and published materials cited herein in their entirety are incorporated herein by reference unless otherwise indicated.

[0056] It should be understood that the above summary and the following detailed description are exemplary and explanatory and not restrictive of any subject matter of the present invention. Unless otherwise specifically stated, the singular form also includes the plural. Unless otherwise indicated, the terms "or" or "either...or" mean "and / or". In addition, the term "comprising" and other forms such as "comprises", "containing", and "includes" are not restrictive.

[0057] Certain chemical terms

[0058] The terms "optional", "optionally", or "optionally" mean that the subsequent described event or circumstance may or may not occur, and the description includes the occurrence and non-occurrence of the described event or circumstance. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl". Also, an optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), monosubstituted (e.g., -CH 2 CH 2 F), or any level between monosubstituted and fully substituted (e.g., -CH 2 CHF 2 , -CF 2 CH 3 , -CFHCHF 2 , etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized will be introduced.

[0059] Unless otherwise specified, conventional methods within the scope of those skilled in the art are employed, such as mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet / visible spectroscopy, and pharmacological methods. Unless specifically defined, the relevant terms, experimental procedures, and techniques in analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and the treatment of patients. For example, the instructions provided by the manufacturer for the use of the kit can be utilized, or the reactions and purification can be carried out in a manner known in the art or as described in the present invention. Generally, the above-mentioned techniques and methods can be implemented according to the descriptions in a number of general and more specific documents cited and discussed in this specification, in accordance with the conventional methods well-known in the art. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0060] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.

[0061] As used herein, the terms "group", "chemical group" refer to a specific part or functional group of a molecule. Chemical groups are often recognized as chemical entities embedded in or attached to a molecule.

[0062] Some of the chemical groups named herein can be represented by abbreviated notations indicating the total number of carbon atoms. For example, C1 -C 6 "Alkyl" describes an alkyl group as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated by the shorthand notation does not include the carbon atoms on any possible substituents.

[0063] The terms "halogen", "halo" or "halide" refer to bromine, chlorine, fluorine or iodine.

[0064] As used herein, the terms "aromatic", "aromatic ring", "aromatic", "aromaticity", "aromatic ring moiety" refer to a planar ring or ring moieties of one or more rings having a delocalized electron conjugation system containing 4n + 2 electrons, where n is an integer. The aromatic ring can be formed by 5, 6, 7, 8, 9 or more than 9 atoms. Aromatic compounds can be optionally substituted and can be monocyclic or polycyclic with fused rings. The term aromatic compounds includes all carbocyclic rings (such as benzene rings) and rings containing one or more heteroatoms (such as pyridine).

[0065] As used herein, the term "heteroatom" or "hetero" when used alone or as part of other components refers to atoms other than carbon and hydrogen. Heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms occur, 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.

[0066] As used herein, the term "fused" or "fused ring" when used alone or in combination refers to a cyclic structure in which two or more rings share one or more bonds.

[0067] As used herein, the term "spiro" or "spiro ring" when used alone or in combination refers to a cyclic structure in which two or more rings share one or more atoms.

[0068] As used herein, the term "alkyl" when used alone or as part of other components (such as: monoalkylamino) refers to an optionally substituted straight-chain or optionally substituted branched-chain monovalent saturated hydrocarbon having 1 - 12 carbon atoms, preferably 1 - 8 carbon atoms, more preferably 1 - 6 carbon atoms, and is connected to the rest of the molecule by a single bond, such as 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, etc.

[0069] As used herein, the term "alkenyl" when used alone or in combination refers to an optionally substituted straight-chain or optionally substituted branched-chain monovalent hydrocarbon group having one or more C═C double bonds and having 2 - about 10 carbon atoms, more preferably 2 - about 6 carbon atoms. The double bonds in these groups can be in the cis or trans conformation and should be understood to include both isomers. Examples include but are not limited to vinyl (CH═CH 2)、1-propenyl (CH 2 CH=CH 2 )、isopropenyl (C(CH3)=CH 2 ), butenyl, 1,3 - butadienyl, etc.

[0070] As used herein, the term "cycloalkyl", alone or as part of other components, refers to a stable monovalent non - aromatic monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms, which may include fused - ring, spiro - ring or bridged - ring systems, containing 3 - 15 ring - forming carbon atoms, preferably 3 - 10 ring - forming carbon atoms, more preferably 3 - 8 ring - forming carbon atoms, which may be saturated or unsaturated and is linked to the rest of the molecule by a single bond. Non - limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0071] As used herein, the terms "heterocyclic group", "heterocycloalkyl", "heterocycle" refer to a stable 3 - to 18 - membered monovalent non - aromatic ring, including 2 - 12 carbon atoms and 1 - 6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specified, the heterocyclic group may be a monocyclic, bicyclic, tricyclic or tetracyclic system, which may include fused - ring, spiro - ring or bridged - ring systems. The nitrogen, carbon or sulfur on the heterocyclic group may be optionally oxidized, the nitrogen atom may be optionally quaternized, and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be linked to the rest of the molecule by a single bond through a carbon atom or a heteroatom on the ring. A heterocyclic group containing a fused - ring may contain one or more aromatic rings or heteroaromatic rings, provided that the atom connecting to the rest of the molecule is on a non - aromatic ring. For the purposes of this application, the heterocyclic group is preferably a stable 4 - to 11 - membered monovalent non - aromatic monocyclic or bicyclic ring containing 1 - 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4 - to 8 - membered monovalent non - aromatic monocyclic ring containing 1 - 3 heteroatoms selected from nitrogen, oxygen and sulfur. Non - limiting examples of heterocyclic groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, dihydroindolyl, dioxolanyl, 1,1 - dioxo - thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4 - piperidinone, pyranyl, pyrazolidinyl, pyrrolidinyl, quinuclidinyl, quinuclidine, tetrahydrofuranyl, tetrahydropyranyl, etc.

[0072] The term "aryl" refers to a fully conjugated π-electron system of all-carbon monocyclic or fused rings having 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, and most preferably 6 carbon atoms. The aryl can be unsubstituted or substituted by one or more substituents, examples of which include but are not limited to alkyl, alkoxy, aryl, aralkyl, amino, halogen, hydroxy, sulfonyl, sulfinyl, phosphoryl, and heterocycloalkyl. Non-limiting examples of unsubstituted aryl include but are not limited to phenyl, naphthyl, and anthracenyl.

[0073] The term "heteroaryl" refers to a monocyclic or fused ring having 5 to 12 ring atoms, having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, containing 1, 2, 3, or 4 ring atoms selected from N, O, S, with the remaining ring atoms being C, and having a fully conjugated π-electron system. The heteroaryl can be unsubstituted or substituted, and the substituents include but are not limited to alkyl, alkoxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl, and heterocycloalkyl. Non-limiting examples of unsubstituted heteroaryl include but are not limited to pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, and triazinyl.

[0074] The term "polymorph" or "polymorphism" as used in the present invention means that the compounds of the present invention have multiple lattice forms. Some compounds of the present invention may have more than one crystal form, and the present invention encompasses all polymorphic forms or mixtures thereof.

[0075] The intermediate compounds of the compounds of the present invention and their polymorphs are also within the scope of the present invention.

[0076] Unless otherwise specified, the olefinic double bonds contained in the compounds of the present invention include E and Z isomers.

[0077] It should be understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers can independently be in the R or S configuration. Some compounds of the present invention may also exhibit cis-trans isomerism, which is obvious to those skilled in the art. It should be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers, as well as mixtures thereof, including racemic mixtures. These isomers can be separated from their mixtures by implementing or modifying known methods, such as chromatography techniques and recrystallization techniques, or they can be prepared separately from appropriate isomers of their intermediates.

[0078] The term "pharmaceutically acceptable salt" as used herein includes both acid addition salts and base addition salts.

[0079] "Pharmaceutically acceptable addition salts" refer to salts that retain the biological potency and properties of the free base of the compound, are not biologically or otherwise undesirable, and are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as, 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. "Pharmaceutically acceptable addition base salts" refer to salts that retain the biological potency and properties of the free acid of the compound and are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic or organic base. Salts formed by reacting 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.

[0080] Organic bases that form salts include, but are not limited to, primary amines, secondary amines, tertiary amines, cyclic amines, etc., such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, and caffeine, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0081] Crystallization often produces solvates of the compounds of the present invention. As used herein, the term "solvate" refers to an entity formed by the combination of one or more molecules of a compound of the present invention and one or more solvent molecules.

[0082] The solvent can be water, in which case the solvate is a hydrate. It can also be an organic solvent. Thus, the compounds of the present invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, etc., as well as the corresponding solvated forms. The compounds of the present invention can be true solvates, but in some other cases, the compounds of the present invention may only accidentally retain water or a mixture of water and some other solvent. The compounds of the present invention can react in a solvent or precipitate or crystallize in a solvent. The solvates of the compounds of the present invention are also included within the scope of the present invention.

[0083] As used herein, the term "pharmaceutical composition" refers to a preparation in which a compound of the present invention is mixed with a medium that is commonly accepted in the art for delivering a biologically active compound to a mammal (such as a human). Such a medium contains all pharmaceutically acceptable carriers.

[0084] As used herein, the term "acceptable" in relation to a formulation, composition, or ingredient means that it has no continuing harmful effect on the overall health of the treated subject.

[0085] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing adverse biological reactions or interacting in an adverse manner with any of the components contained in the composition.

[0086] "Pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, auxiliaries, deodorants, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administrative departments for use in humans and domesticated animals.

[0087] As used herein, the terms "subject", "patient", "subject", or "individual" refer to an individual suffering from a disease, disorder, or condition, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (such as chimpanzees and other apes and monkeys); domestic animals, such as cattle, horses, sheep, goats, pigs; domesticated animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, etc. Examples of non-human mammals include, but are not limited to, birds and fish, etc. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0088] As used herein, the term "treatment" refers to the treatment of a relevant disease or disorder in mammals, particularly humans, including

[0089] (i) preventing a mammal, particularly a mammal that has been previously exposed to a disease or disorder but has not been diagnosed with the disease or disorder, from developing the corresponding disease or disorder;

[0090] (ii) inhibiting a disease or disorder, i.e., controlling its development;

[0091] (iii) alleviating a disease or disorder, i.e., causing the disease or disorder to subside;

[0092] (iv) relieving the symptoms caused by a disease or disorder.

[0093] As used herein, the terms "disease" and "disorder" may be used interchangeably or may have different meanings, because for some specific diseases or disorders, there are no known causative agents (so the cause of the disease is not yet clear), so they cannot be recognized as diseases but can only be regarded as unwanted conditions or syndromes, and more or less specific symptoms of the syndromes have been confirmed by clinical researchers.

[0094] As used herein, the terms "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refer to the amount of at least one agent or compound that, upon administration, is sufficient to alleviate, to some extent, one or more symptoms of the disease or disorder being treated. The result can be the reduction and / or alleviation of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide a significant alleviation of the disorder clinically. Techniques such as dose escalation trials can be used to determine the effective amount suitable for any individual case.

[0095] As used herein, the terms "administering", "administered", "administration" and the like refer to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral route, duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0096] Preparation of the compounds of the present invention

[0097] The following non-limiting examples are illustrative only and do not limit this application in any way.

[0098] Unless otherwise specified, the temperature is in degrees Celsius. Reagents are purchased from commercial suppliers such as Sinopharm Chemical Reagent Co., Ltd. Beijing, Alfa Aesar, or Beijing J&K Scientific Ltd., and these reagents can be used directly without further purification, unless otherwise specified.

[0099] Unless otherwise specified, the following reactions are carried out at room temperature, in an anhydrous solvent, under a positive pressure of nitrogen or argon or using a drying tube; the reaction flask is equipped with a rubber septum for adding substrates and reagents by syringe; the glassware is dried by baking and / or heating.

[0100] Unless otherwise specified, column chromatography purification uses silica gel with 200 - 300 mesh from Qingdao Marine Chemical Factory; preparative thin-layer chromatography uses pre-coated thin-layer chromatography silica gel plates (HSGF254) produced by Yantai Chemical Industry Research Institute; the determination of MS is carried out using a Thermo LCQ Fleet type (ESI) liquid chromatography - mass spectrometry instrument; the determination of optical rotation uses an SGW-3 automatic polarimeter, Shanghai Shenguang Instrument & Meter Co., Ltd.

[0101] Nuclear magnetic resonance data ( 1 H NMR) is run at 400 MHz using a Varian instrument. The solvents used for nuclear magnetic resonance data are CDCl 3 、CD 3 OD、D 2 O、DMSO-d6 etc., using tetramethylsilane (0.00 ppm) as a reference or using the residual solvent as a reference (CDCl 3 : 7.26 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d 6 -DMSO: 2.50 ppm). When indicating the peak shape diversity, the following abbreviations represent different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (doublet of doublets), dt (doublet of triplets). If the coupling constant is given, it is in Hertz (Hz).

[0102] Example 1

[0103] ((1R)-2-(Benzofuran-3-yl)-1-(((((2R)-1-(N-(tert-butyl)phenylsulfonylimino)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid

[0104]

[0105] Step A: Benzofuran-3-ylmethanol

[0106]

[0107] N 2 Under N protection, a methanol (200 mL) solution containing benzofuran-3-ylaldehyde (15.0 g) was cooled to 0 °C, and sodium borohydride (5.9 g) was added portionwise to the system. After naturally returning to room temperature, it was stirred for 2 hours. After monitoring the reaction to completion, the solvent was removed by rotary evaporation. The residue was separated in ethyl acetate and 1 mol / L hydrochloric acid aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to obtain the product (14.8 g).

[0108] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.64 - 7.66 (m, 2H), 7.58 (s, 1H), 7.46 - 7.48 (m, 1H), 7.23 - 7.32 (m, 2H), 4.81 (s, 2H).

[0109] Step B: 3-(Chloromethyl)benzofuran

[0110]

[0111] Cool the dichloromethane (100 mL) solution containing benzofuran-3-ylmethanol (10.0 g) to 0 °C, and add phosphorus pentachloride (18.2 g) to the system in portions. After addition, allow the system to return to room temperature naturally. Stir for 1 hour and then quench the reaction with water. The organic phase is washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated to obtain the product (12.1 g).

[0112] 1 H NMR(400MHz,CDCl 3 )δ7.65-7.70(m,2H),7.49(d,J=8.4Hz,1H),7.30-7.35(m,2H),4.75(s,2H).

[0113] Step C: Benzofuran-3-ylmethylboronic acid pinacol ester

[0114]

[0115] Cool the suspension of 3-(chloromethyl)benzofuran (12.0 g), copper(I) iodide (1.3 g), bis(pinacolato)diboron (18.9), and triphenylphosphine (1.78 g) in N,N-dimethylformamide (80 mL) to 0 °C, and add lithium tert-butoxide (8.68 g) to the system in portions. After addition, allow the reaction mixture to return to room temperature naturally and stir for 2 hours; quench the reaction with water, extract the reaction mixture with dichloromethane, wash with saturated brine, dry the organic phase over anhydrous sodium sulfate, filter, evaporate the solvent, and purify the residue by silica gel column chromatography (eluting with a 10 - 20% ethyl acetate mixed solution) to obtain the product (14.1 g).

[0116] 1 H NMR(400MHz,CDCl 3 )δ7.50-7.55(m,2H),7.43(d,J=8.4Hz,1H),7.20-7.25(m,2H),2.21(s,2H),1.26(s,12H).

[0117] Step D: Benzofuran-3-ylmethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0118]

[0119] Benzofuran-3-ylmethylboronic acid pinacol ester (14.0 g) and (1S,2S,3R,5S)-(+)-pinane-2,3-diol (18.4 g) were added to anhydrous diethyl ether (200 mL). The suspension was stirred overnight at room temperature. After detecting the completion of the reaction, it was washed three times with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (50% dichloromethane / petroleum ether) to obtain the product (10.5 g).

[0120] 1 H NMR (400 MHz, CDCl 3 ) δ 7.44 - 7.56 (m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.20 - 7.26 (m, 2H), 4.31 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 2.30 - 2.36 (m, 1H), 2.26 (s, 2H), 2.17 - 2.21 (m, 1H), 2.06 (t, J = 6.0 Hz, 1H), 1.86 - 1.91 (m, 2H), 1.40 (s, 3H), 1.27 (s, 3H), 1.11 (d, J = 11.2 Hz, 1H), 0.87 (s, 3H).

[0121] Step E: 2-(Benzofuran-3-yl)-1-(S)-chloroethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0122]

[0123] Dry dichloromethane (4.11 g) was dissolved in anhydrous tetrahydrofuran (30 mL). After thoroughly displacing nitrogen, the solution was cooled to -100 °C. A 2.5 mol / L solution of butyllithium in n-hexane (9.6 mL) was slowly added dropwise along the inner wall of the reaction flask over a period of no less than 10 minutes. The resulting milky suspension was stirred at -100 °C for half an hour. A solution of benzofuran-3-ylmethylboronic acid (+)-pinanediol ester (5.0 g) in anhydrous tetrahydrofuran (30 mL) was slowly added along the inner wall of the reaction flask. After 10 minutes, a 1 mol / L solution of zinc chloride in tetrahydrofuran (8.8 mL) was added dropwise to the reaction system, and the temperature was gradually restored to room temperature. The mixture was stirred overnight. The reaction was quenched by adding water. The reaction solution was separated between ethyl acetate (100 mL) and saturated aqueous ammonium chloride solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to obtain the crude product, which was directly used in the next step of the reaction. (6.0 g).

[0124] 1 H NMR (400 MHz, CDCl 3)δ 7.58 - 7.60 (m, 1H), 7.48 - 7.55 (m, 2H), 7.25 - 7.30 (m, 2H), 4.30 - 4.33 (m, 1H), 3.72 - 3.76 (m, 1H), 3.29 (dd, J = 15.2 Hz, 8.0 Hz, 1H), 3.18 (dd, J = 15.2 Hz, 8.0 Hz, 1H), 2.28 - 2.35 (m, 1H), 2.06 - 2.17 (m, 2H), 1.86 - 1.91 (m, 2H), 1.27 (s, 3H), 1.22 (s, 3H), 1.12 - 1.17 (m, 1H), 0.84 (s, 3H).

[0125] Step F: 2 - ((Benzofuran - 3 - yl) - 1 - (R) - aminoethyl)boronic acid - (1S,2S,3R,5S) - (+) - pinane - 2,3 - diol ester hydrochloride

[0126]

[0127] Dissolve 2 - ((S) - 2 - (benzofuran - 3 - yl) - 1 - chloroethyl)boronic acid - (1S,2S,3R,5S) - (+) - pinane - 2,3 - diol ester (6.0 g) in anhydrous n - hexane. After thoroughly displacing nitrogen, cool the above - mentioned solution to - 78 °C, slowly drip 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran solution (16 mL) into the system, slowly warm it back to room temperature, and stir overnight. The resulting suspension is filtered through diatomaceous earth and rinsed with n - hexane. The obtained mother liquor is cooled to 0 °C, and 4 M hydrogen chloride in 1,4 - dioxane solution (16 mL) is slowly dripped into this solution. After dripping, warm it back to room temperature and stir for 2 hours. The reaction solution is concentrated by rotary evaporation to remove the solvent, then n - hexane is added and stirred thoroughly, and then filtered. The obtained solid is rinsed with n - hexane to obtain the product (2.91 g).

[0128] 1 H NMR (400 MHz, CDCl 3 )δ 8.32 (brs, 3H), 7.81 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.22 - 7.28 (m, 2H), 4.27 (d, J = 8.0 Hz, 1H), 3.30 - 3.36 (m, 3H), 2.19 - 2.22 (m, 1H), 2.08 - 2.15 (m, 1H), 1.95 - 2.05 (m, 1H), 1.80 - 1.88 (m, 2H), 1.27 (s, 3H), 1.25 (s, 3H), 1.03 - 1.06 (m, 1H), 0.70 (s, 3H).

[0129] Step G: tert-Butyl (R)-2-(((chlorocarbonyl)oxy)methyl)pyrrolidine-1-carboxylate

[0130]

[0131] Place tert-Butyl (R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (314 mg) in a three-necked flask, add dichloromethane (10 mL) and diisopropylethylamine (402 mg), protect with nitrogen and cool to 0 °C. Dropwise add a dichloromethane solution of bis(trichloromethyl) carbonate (232 mg) to the reaction solution. After completion, stir at 0 °C for 2 hours and use directly for the next step.

[0132] Step H: ((1R)-2-(Benzofuran-3-yl)-1-(((((2R)-N-Boc-pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinanediol ester

[0133]

[0134] Add 2-(Benzofuran-3-yl)-1-(R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinanediol ester hydrochloride (470 mg) and diisopropylethylamine (273 mg) to dry dichloromethane, protect with nitrogen and cool to 0 °C. Dropwise add a dichloromethane solution of tert-Butyl (R)-2-(((chlorocarbonyl)oxy)methyl)pyrrolidine-1-carboxylate to the reaction solution. After completion, warm to room temperature and stir for 2 hours. Quench the reaction with water and extract with dichloromethane. Wash the organic phase with saturated brine. Dry the organic phase over anhydrous sodium sulfate, filter and evaporate the solvent. The residue obtained is purified by silica gel column chromatography (1:1 ethyl acetate / petroleum ether) to obtain the product (350 mg).

[0135] 1 H NMR(400MHz,CDCl 3)δ 7.56 (d, J = 7.2 Hz, 1H), 7.42 - 7.45 (m, 2H), 7.27 (t, J = 8.0 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 4.93 (s, 1H), 4.28 (d, J = 8.0 Hz, 1H), 3.82 - 4.17 (m, 3H), 3.48 - 3.55 (m, 1H), 3.24 - 3.40 (m, 2H), 3.11 (dd, J = 14.8 Hz, 6.0 Hz, 1H), 2.96 (dd, J = 14.8 Hz, 7.2 Hz, 1H), 2.28 - 2.33 (m, 1H), 2.07 - 2.14 (m, 1H), 1.97 (t, J = 5.6 Hz, 1H), 1.76 - 1.92 (m, 6H), 1.45 (s, 9H), 1.25 (s, 3H), 1.20 (s, 3H), 0.85 (d, J = 6.8 Hz, 1H), 0.80 (s, 3H).

[0136] Step J: ((1R)-2-(Benzofuran-3-yl)-1-(((((2R)-pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester trifluoroacetate

[0137]

[0138] ((1R)-2-(Benzofuran-3-yl)-1-(((((2R)-N-Boc-pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (191 mg) was added to dichloromethane (5 mL), and then trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 3 hours, and the solvent was evaporated under reduced pressure to obtain the product (190 mg).

[0139] This intermediate was confirmed by mass spectrometry, [M + H + = 467.

[0140] Step K: N-(tert-Butyl)benzenesulfinamide

[0141]

[0142] tert-Butylamine (414 mg) was added to dry dichloromethane under nitrogen protection and cooled to 0 °C. Triethylamine (1.14 g) was added to the reaction solution, and then phenylsulfonyl chloride (63 mg) was added dropwise. After completion, a dichloromethane solution of triphenylphosphine (1.48 g) was added dropwise slowly to the above reaction solution at 0 °C, and the addition was completed in 1 hour. The mixture was warmed to room temperature and stirred overnight. The solvent was evaporated, and the residue obtained was purified by silica gel column chromatography (1:4 ethyl acetate / petroleum ether) to obtain the product (280 mg).

[0143] 1 H NMR (400 MHz, CDCl 3 ), 7.66 - 7.69 (m, 2H), 7.43 - 7.48 (m, 3H), 3.86 (s, 1H), 1.39 (s, 9H).

[0144] Step L: N-(tert-Butyl)phenylsulfinyl chloride

[0145]

[0146] N-(tert-Butyl)benzenesulfinamide (280 mg) was added to dry dichloromethane under nitrogen protection and cooled to 0 °C. tert-Butyl hypochlorite (185 mg) was added dropwise to the reaction solution. After completion, the mixture was warmed to room temperature and stirred for 1 hour. The reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain the product (140 mg).

[0147] Step M: ((1R)-2-(Benzofuran-3-yl)-1-(((((2R)-1-(N-(tert-butyl)phenylsulfinyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0148]

[0149] ((1R)-2-(Benzofuran-3-yl)-1-(((((2R)-pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester trifluoroacetate (190 mg) and diisopropylethylamine (132 mg) were added to dry dichloromethane under nitrogen protection and cooled to 0 °C. A dichloromethane solution of N-(tert-butyl)phenylsulfinyl chloride (106 mg) was added dropwise to the reaction solution. After completion, the mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue obtained was purified by silica gel preparative plate (1:4 ethyl acetate / petroleum ether) to obtain the product (90 mg).

[0150] 1 H NMR(400MHz,CDCl 3 )δ7.87 - 7.97(m,2H),7.41 - 7.58(m,6H),7.26(t,J = 7.6Hz,1H),7.20(t,J = 8.0Hz,1H),4.86 - 4.96(m,1H),3.78 - 4.29(m,4H),2.92 - 3.70(m,5H),2.27 - 2.48(m,1H),1.56 - 2.21(m,8H),1.37(s,3H),1.33(s,3H),1.24(s,3H),1.22(s,3H),1.19(s,3H),1.12(d,J = 7.2Hz,1H),0.92(s,0.5Hz),0.79(s,2.5H).

[0151] Step N: ((1R)-2-(Benzofuran-3-yl)-1-(((((2R)-1-(N-(tert-butyl)phenylsulfonylimino)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid

[0152]

[0153] Dissolve ((1R)-2-(benzofuran-3-yl)-1-(((((2R)-1-(N-(tert-butyl)phenylsulfonylimino)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (90 mg) in methanol. Add isobutylboronic acid (45 mg), 1 mol / L hydrochloric acid (3 mL) and n-hexane to this solution. Stir at room temperature overnight. Separate and remove the upper n-hexane layer. Wash the methanol phase three times with n-hexane and then concentrate to dryness at 30 °C. Add saturated brine (15 mL), extract three times with dichloromethane. The organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated to dryness. The residue obtained is purified by silica gel preparative plate (1:40 methanol / dichloromethane) to obtain two sulfur atom-based isomers, namely isomer 1 (30 mg) and isomer 2 (20 mg).

[0154] Isomer 1

[0155] 1 H NMR(400MHz,CD 3OD) δ 7.89 (d, J = 7.2 Hz, 2H), 7.49 - 7.60 (m, 5H), 7.40 (d, J = 8.0 Hz, 1H), 7.17 - 7.26 (m, 2H), 4.20 (dd, J = 10.8 Hz, 4.0 Hz, 1H), 4.11 (dd, J = 10.0 Hz, 6.8 Hz, 1H), 3.80 - 3.86 (m, 1H), 3.28 - 3.32 (m, 1H), 3.12 - 3.26 (m, 2H), 2.93 (dd, J = 14.4 Hz, 6.8 Hz, 1H), 2.85 (dd, J = 14.4 Hz, 8.0 Hz, 1H), 1.50 - 1.70 (m, 3H), 1.36 (s, 9H), 1.08 - 1.16 (m, 1H).

[0156] Isomer 2

[0157] 1 H NMR (400 MHz, CD 3 OD) δ 7.82 - 7.90 (m, 2H), 7.44 - 7.58 (m, 5H), 7.41 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 4.20 (dd, J = 10.4 Hz, 2.8 Hz, 1H), 4.04 (dd, J = 10.4 Hz, 7.2 Hz, 1H), 3.91 - 3.98 (m, 1H), 3.22 - 3.30 (m, 2H), 3.10 - 3.15 (m, 1H), 2.91 (dd, J = 14.4 Hz, 7.2 Hz, 1H), 2.83 (dd, J = 14.4 Hz, 7.6 Hz, 1H), 1.61 - 1.86 (m, 4H), 1.32 (s, 9H).

[0158] Example 2

[0159] ((1R)-2-(Benzofuran-3-yl)-1-(((((2R)-1-(N,S-dimethylsulfimido)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid

[0160]

[0161] Step A: N-Sulfinyltriphenylamine

[0162]

[0163] Add triphenylmethylamine (10 g) and triethylamine (7.8 g) to dry ether, protect with nitrogen and cool to 0 °C. Dropwise add thionyl chloride (4.6 g) to the reaction solution. After completion, stir at 0 °C for 2 hours, filter through diatomaceous earth and wash with ether. Evaporate the solvent under reduced pressure at room temperature to obtain a white solid product (11 g).

[0164] Step B: (±)-N-tritylmethanesulfinamide

[0165]

[0166] Dissolve N-sulfinyltriphenylmethylamine (6 g) in anhydrous tetrahydrofuran, protect with nitrogen and cool to 0 °C. Dropwise add 3 mol / L methylmagnesium bromide in tetrahydrofuran solution (5.2 mL) to the reaction solution. After completion, restore to room temperature and stir for 1 hour. Quench the reaction with saturated ammonium chloride and extract with ethyl acetate. Wash the organic phase with saturated brine. After drying the organic phase over anhydrous sodium sulfate, filter and evaporate the solvent. The residue obtained is triturated with petroleum ether and filtered to obtain a solid product (4.5 g).

[0167] 1 H NMR (400 MHz, CDCl 3 ) δ 7.24 - 7.33 (m, 15H), 4.83 (s, 1H), 2.57 (s, 3H).

[0168] Step C: (R)-2-(((tert-butylphenylmethylsilyl)oxy)methyl)pyrrolidine

[0169]

[0170] Add D-prolinol (1 g) and imidazole (1.3 g) to dichloromethane, cool to 0 °C. Dropwise add tert-butyldiphenylchlorosilane (5.7 g) to the reaction solution. After completion, restore to room temperature and stir for 1 hour. Filter to obtain a filtrate. Add saturated ammonium chloride aqueous solution to the filtrate and extract with dichloromethane. After drying the organic phase over anhydrous sodium sulfate, filter and evaporate the solvent. The residue obtained is purified by silica gel column chromatography (1:7 methanol / dichloromethane) to obtain a product (3.1 g).

[0171] 1 H NMR (400 MHz, CDCl 3 ) δ 7.64 - 7.69 (m, 4H), 7.35 - 7.44 (m, 6H), 3.85 (dd, J = 11.2 Hz, 4.8 Hz, 1H), 3.74 (dd, J = 11.2 Hz, 5.6 Hz, 1H), 3.58 - 3.65 (m, 1H), 3.23 (t, J = 7.2 Hz, 2H), 1.85 - 1.99 (m, 3H), 1.67 - 1.75 (m, 1H), 1.06 (s, 9H).

[0172] Step D: (2R)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)-1-(S-methylsulfinyl)pyrrolidine

[0173]

[0174] Add (±)-N-tritylmethanesulfinamide (2 g) to dry dichloromethane, protect with nitrogen and cool to 0 °C. Dropwise add tert-butyl hypochlorite (676 mg) to the reaction solution, stir at 0 °C for 1 hour, and then dropwise add the reaction solution to a dichloromethane solution of (R)-2-(((tert-butylphenylmethylsilyl)oxy)methyl)pyrrolidine (1.4 g) and triethylamine (1.2 g). Stir at room temperature overnight under nitrogen protection, add p-toluenesulfonic acid monohydrate (10.6 g), stir at room temperature for 30 minutes, add 1 mol / L aqueous sodium hydroxide solution to adjust the pH to alkaline, and extract with dichloromethane. Wash the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate, filter and evaporate the solvent. The obtained residue is purified by silica gel column chromatography (pure ethyl acetate) to obtain the product (1.6 g).

[0175] 1 H NMR (400 MHz, CDCl 3 ) δ 7.62 - 7.68 (m, 4H), 7.34 - 7.43 (m, 6H), 3.82 (dd, J = 10.4 Hz, 4.0 Hz, 0.5H), 3.69 - 3.79 (m, 1H), 3.64 (dd, J = 10.4 Hz, 4.0 Hz, 0.5H), 3.51 - 3.59 (m, 1H), 3.22 - 3.42 (m, 2H), 2.78 (s, 3H), 2.17 - 2.21 (m, 1H), 1.78 - 2.13 (m, 4H), 1.05 (s, 9H).

[0176] Step E: (2R)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)-1-(N,S-dimethylsulfinyl)pyrrolidine

[0177]

[0178] Add (2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(S-methylsulfinyl)pyrrolidine (1.2 g) to dry tetrahydrofuran, cool to 0 °C, add sodium hydride (230 mg) to the reaction solution in portions, stir at 0 °C for 30 minutes, dropwise add iodomethane (809 mg), and after completion, restore to room temperature and stir overnight. Quench the reaction with water and extract with ethyl acetate. Wash the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate, filter and evaporate the solvent to obtain the product (1.2 g).

[0179] 1 H NMR (400 MHz, CDCl 3 ) δ 7.62 - 7.67 (m, 4H), 7.35 - 7.44 (m, 6H), 3.77 - 3.82 (m, 1H), 3.67 - 3.72 (m, 1H), 3.53 - 3.62 (m, 1H), 3.16 - 3.30 (m, 2H), 2.76 (s, 1.7H), 2.75 (s, 1.3s), 2.64 (s, 1.3s), 2.51 (s, 1.7H), 2.04 - 2.13 (m, 1H), 1.78 - 1.98 (m, 3H), 1.05 (s, 9H).

[0180] Step F: ((2R)-1-(N,S-Dimethylsulfoximidoyl)pyrrolidin-2-yl)methanol

[0181]

[0182] Dissolve (2R)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)-1-(N,S-dimethylsulfoximidoyl)pyrrolidine (1.2 g) in tetrahydrofuran. Add tetrabutylammonium fluoride monohydrate (1.2 g) to this solution and stir at 40 °C for 2 hours. Evaporate the solvent and purify the resulting residue by silica gel column chromatography (methanol:ethyl acetate 3 / 40) to obtain the product (400 mg).

[0183] 1 H NMR (400 MHz, CDCl 3 ) δ 3.57 - 3.70 (m, 2H), 3.51 - 3.54 (m, 2H), 3.24 - 3.31 (m, 2H), 2.85 (s, 0.6H), 2.80 (s, 2.4H), 2.67 (s, 0.6H), 2.65 (s, 2.4H), 1.97 - 2.06 (m, 1H), 1.66 - 1.95 (m, 3H).

[0184] Step G: ((1R)-2-(Benzofuran-3-yl)-1-(((((2R)-1-(N,S-dimethylsulfoximidoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinanediol ester

[0185]

[0186] 2-(Benzofuran-3-yl)-1-((R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (150 mg) and triethylamine (162 mg) were added to dry dichloromethane, protected by nitrogen and cooled to -60 °C. A dichloromethane solution of bis(trichloromethyl) carbonate (47 mg) was added dropwise to the reaction solution. After completion, the mixture was stirred at -60 °C for 1 hour. A dichloromethane solution of ((2R)-1-(N,S-dimethylsulfinylimino)pyrrolidin-2-yl)methanol (93 mg) was added dropwise to the above solution at -60 °C. The mixture was stirred at -60 °C for 1 hour, quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue obtained was purified by silica gel preparative plate (1:30 methanol / dichloromethane) to obtain the product (25 mg).

[0187] 1 H NMR(400MHz,CDCl 3 )δ7.56(d,J=6.8Hz,1H),7.45(s,1H),7.43(d,J=8.0Hz,1H),7.26(t,J=7.2Hz,1H),7.21(t,J=7.2Hz,1H),4.96(d,J=5.6Hz,1H),4.27-4.30(m,1H),3.96-4.14(m,2H),3.87-3.94(m,0.6H),3.72-3.80(m,0.4H),3.49-3.55(m,1H),3.18-3.28(m,2H),3.10(dd,J=14.8Hz,5.2Hz,1H),2.96(dd,J=14.8Hz,7.2Hz,1H),2.83(s,1.8H),2.80(s,1.2H),2.67(s,1.8H),2.65(s,1.2H),2.06-2.48(m,3H),1.59-2.01(m,6H),1.24(s,3H),1.20(s,3H),1.05(d,J=10.8Hz,1H),0.79(s,3H).

[0188] Step H: ((1R)-2-(Benzofuran-3-yl)-1-(((((2R)-1-(N,S-dimethylsulfinylimino)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid

[0189]

[0190] Dissolve ((1R)-2-(benzofuran-3-yl)-1-(((((2R)-1-(N,S-dimethylsulfimido)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (25 mg) in methanol. Add isobutylboronic acid (14 mg), 1 mol / L hydrochloric acid (0.1 mL) and n-hexane to this solution, stir at room temperature overnight, separate and remove the upper layer of n-hexane, wash the methanol phase with n-hexane three times, then concentrate to dryness at 30 °C, dilute with dichloromethane, and wash the product into the aqueous phase with 2 mol / L aqueous sodium hydroxide solution (5 mL). After washing the aqueous phase with dichloromethane three times, acidify it to acidic pH with 3 mol / L hydrochloric acid, extract with dichloromethane three times, dry the organic phase over anhydrous sodium sulfate, filter and concentrate to remove the solvent at 30 °C to obtain the product (10 mg).

[0191] 1 H NMR(400MHz,CD 3 OD)δ7.59(d,J=8.0Hz,1H),7.54(s,1H),7.42(d,J=7.6Hz,1H),7.26(t,J=7.2Hz,1H),7.21(t,J=7.2Hz,1H),4.17-4.30(m,2H),3.96-4.07(m,1H),3.62(s,1H),3.58(s,2H),3.33-3.50(m,3H),2.83-2.97(m,2H),2.79(s,2H),2.76(s,1H),1.94-2.20(m,4H).

[0192] Example 3

[0193] (R)-(2-(benzofuran-3-yl)-1-(2-(3-dimethylsulfimido)phenyl)acetamido)ethyl)boronic acid

[0194]

[0195] Step A: 2-(3-dimethylsulfimido)phenyl)acetic acid

[0196]

[0197] 3-Bromophenylacetic acid (431 mg) was dissolved in 1,4-dioxane. Tris(dibenzylideneacetone)dipalladium (184 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (230 mg), and cesium carbonate (1.96 g) were successively added. The system was thoroughly purged with nitrogen, heated to 100 °C and reacted overnight. After monitoring that the raw materials were completely converted, water was added for dilution, and the mixture was extracted with dichloromethane. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by silica gel preparative plate (1:10 methanol / dichloromethane) to obtain the product (67 mg).

[0198] 1 H NMR(400MHz,CDCl 3 )δ7.15(t,J=8.0Hz,1H),6.96-6.98(m,2H),6.89(d,J=7.6Hz,1H),3.54(s,2H),3.13(s,6H)。

[0199] Step B: (R)-2-(Benzofuran-3-yl)-1-(2-(3-dimethylsulfinimidylphenyl)acetamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0200]

[0201] 2-(3-Dimethylsulfinimidylphenyl)acetic acid (67 mg), 2-(benzofuran-3-yl)-1-((R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (111 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (146 mg), N,N-diisopropylethylamine (114 mg), and 4-dimethylaminopyridine (36 mg) were added to dry dichloromethane. After completion, the mixture was stirred at room temperature overnight, quenched with water, and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue obtained was purified by silica gel preparative plate (20:1 methanol / dichloromethane) to obtain the product (30 mg).

[0202] 1 H NMR(400MHz,CDCl 3) δ 7.44 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.22 - 7.26 (m, 2H), 7.17 (d, J = 7.2 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.83 (s, 1H), 6.72 (d, J = 7.2 Hz, 1H), 6.21 (s, 1H), 4.24 (d, J = 8.0 Hz, 1H), 3.61 (d, J = 16.8 Hz, 1H), 3.54 (d, J = 16.8 Hz, 1H), 3.08 (s, 6H), 2.92 - 2.99 (m, 2H), 2.73 - 2.80 (m, 1H), 2.30 - 2.35 (m, 1H), 2.11 - 2.16 (m, 1H), 1.99 (t, J = 5.6 Hz, 1H), 1.80 - 1.89 (m, 2H), 1.40 (d, J = 10.4 Hz, 1H), 1.37 (s, 3H), 1.26 (s, 3H), 0.85 (s, 3H).

[0203] Step C: (R)-(2-(Benzofuran-3-yl)-1-(2-(3-dimethylsulfinimidylphenyl)acetamido)ethyl)boronic acid

[0204]

[0205] Dissolve 2(R)-2-(benzofuran-3-yl)-1-(2-(3-dimethylsulfinimidylphenyl)acetamido)ethyl boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (30 mg) in methanol (1 mL). To this solution, add isobutylboronic acid (28 mg), 1 mol / L hydrochloric acid (0.2 mL) and n-hexane (1 mL). Stir at room temperature overnight. Separate and remove the upper n-hexane layer. Wash the methanol phase with n-hexane three times and then concentrate it to dryness at 30 °C to obtain the crude product. Add diethyl ether to make a slurry, filter to collect the solid, and dry the solid to obtain the product (15 mg).

[0206] 1 H NMR (400 MHz, CD 3 OD) δ 7.57 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.42 - 7.47 (m, 2H), 7.24 - 7.33 (m, 4H), 7.21 (t, J = 7.6 Hz, 1H), 3.74 - 3.77 (m, 8H), 3.01 (dd, J = 9.6 Hz, 5.2 Hz, 1H), 2.89 (dd, J = 14.8 Hz, 4.8 Hz, 1H), 2.71 (dd, J = 14.8 Hz, 9.6 Hz, 1H).

[0207] Example 4

[0208] (R)-(1-(3-(6-((Dimethyl(oxo)-λ 6 -sulfanylidenyl)amino)pyridin-2-yl)ureido)-2-phenylethyl)boronic acid

[0209]

[0210] Step A: ((6-Bromopyridin-2-yl)imino)dimethyl-λ 6 -sulfoximine

[0211]

[0212] N 2 Under N protection, a suspension of 2,6-dibromopyridine (6.00 g), dimethylsulfoximine (1.63 g), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthrene (1.50 g), tris(dibenzylideneacetone)dipalladium(0) (0.793 g) and cesium carbonate (8.59 g) in 1,4-dioxane (100 mL) was heated to reflux overnight. After cooling to room temperature, it was filtered and washed with dichloromethane. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (100% AcOEt) to obtain the product (4.0 g).

[0213] 1 H NMR (400 MHz, CDCl 3 ) δ 7.31 - 7.35 (m, 1H), 6.93 (dd, J = 7.6 Hz, 0.8 Hz, 1H), 6.69 (dd, J = 7.6 Hz, 0.8 Hz, 1H), 3.36 (s, 6H).

[0214] Step B: ((6-Aminopyridin-2-yl)imino)dimethyl-λ 6 -sulfoximine

[0215]

[0216] A mixture of ((6-bromopyridin-2-yl)imino)dimethyl-λ 6 -sulfoximine (4.0 g), cuprous oxide (0.230 g), N,N'-dimethylethylenediamine (0.142 g), anhydrous potassium carbonate (4.43 g), 25% aqueous ammonia (20 mL) and ethylene glycol (20 mL) was heated to 60 °C and stirred overnight. After cooling to room temperature, it was filtered through diatomaceous earth and washed with dichloromethane. The aqueous layer was separated and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the product (1.4 g).

[0217] 11H NMR (400 MHz, CDCl 3 ) δ 7.27 - 7.31 (m, 1H), 6.19 (d, J = 7.6 Hz, 1H), 6.04 (d, J = 7.6 Hz, 1H), 4.26 (brs, 2H), 3.35 (s, 6H).

[0218] Step C: Benzylboronic acid pinacol ester

[0219]

[0220] Referring to the method of Step C in Example 1, using benzyl chloride, copper(I) iodide, bis(pinacolato)diboron, triphenylphosphine and lithium tert-butoxide as raw materials, the product (2.5 g) was obtained by reaction.

[0221] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.23 - 7.27 (m, 2H), 7.17 - 7.19 (m, 2H), 7.13 (t, J = 7.6 Hz, 1H), 2.29 (s, 2H), 1.25 (s, 12H).

[0222] Step D: Benzylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0223]

[0224] Referring to the method of Step D in Example 1, using benzylboronic acid pinacol ester and (1S,2S,3R,5S)-(+)-pinane-2,3-diol as the main raw materials, the product (2.0 g) was obtained by reaction.

[0225] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.22 - 7.27 (m, 2H), 7.18 - 7.20 (m, 2H), 7.13 (t, J = 7.6 Hz, 1H), 4.27 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 2.32 (s, 2H), 2.17 - 2.30 (m, 2H), 2.04 (t, J = 6.0 Hz, 1H), 1.80 - 1.90 (m, 2H), 1.37 (s, 3H), 1.25 (s, 3H), 1.06 (d, J = 10.4 Hz, 1H), 0.87 (s, 3H).

[0226] Step E: 1-(S)-chloro-2-phenylethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0227]

[0228] Refer to the method in step E of Example 1. Using benzylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester, dichloromethane, butyllithium and zinc chloride tetrahydrofuran solution as the main raw materials, a pale yellow oily crude product (2.3 g) was obtained and directly used for the next reaction.

[0229] 1 H NMR(400MHz,CDCl 3 )δ7.22 - 7.31(m,3H),7.12 - 7.16(m,1H),4.77(d,J=8.8Hz,1H),3.59 - 3.63(m,1H),3.18 - 3.23(m,1H),3.08 - 3.12(m,1H),2.32 - 2.37(m,1H),2.15 - 2.22(m,2H),2.05(t,J=5.6Hz,1H),1.82 - 1.91(m,2H),1.35(s,3H),1.27(s,3H),1.06(d,J=10.8Hz,1H),0.85(s,3H).

[0230] Step F: 2-phenyl-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride

[0231]

[0232] Refer to the method in step F of Example 1. Using 1-(S)-chloro-2-phenylethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester, lithium bis(trimethylsilyl)amide tetrahydrofuran solution and hydrogen chloride 1,4-dioxane solution as the main raw materials, a product (0.70 g) was obtained.

[0233] 1 H NMR(400MHz,CDCl 3 )δ7.97 - 8.16(brs,3H),7.34 - 7.43(m,3H),7.17 - 7.26(m,2H),4.35(d,J=8.4Hz,1H),2.80 - 3.06(m,3H),2.17 - 2.20(m,1H),1.95 - 2.13(m,2H),1.80 - 1.88(m,2H),1.27(s,3H),1.20(s,3H),1.03 - 1.06(m,1H),0.76(s,3H).

[0234] Step G: (R)-(1-(3-(6-((dimethyl(oxo)-λ 6-Thioalkyl)amino)pyridin-2-yl)ureido)-2-phenylethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0235]

[0236] 2-Phenyl-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (150 mg) and triethylamine (162 mg) were added to dry dichloromethane, protected by nitrogen and cooled to -60 °C. A solution of bis(trichloromethyl) carbonate (48 mg) in dichloromethane was added dropwise to the reaction solution. After completion, the mixture was stirred at -60 °C for 1 hour. At -60 °C, a solution of ((6-aminopyridin-2-yl)imino)dimethyl-λ 6 -sulfinimide (81 mg) in dichloromethane was added dropwise to the above solution. The mixture was stirred at -60 °C for 1 hour, quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue obtained was purified by silica gel preparative plate (1:30 methanol / dichloromethane) to obtain the product (20 mg).

[0237] 1 H NMR (400 MHz, CDCl 3 ) δ 8.97 (s, 1H), 7.48 (s, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 7.2 Hz, 2H), 7.21 (t, J = 7.6 Hz, 2H), 7.11 (t, J = 7.2 Hz, 1H), 6.36 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 8.0 Hz, 1H), 4.18 (d, J = 7.2 Hz, 1H), 3.14 - 3.21 (m, 1H), 3.12 (s, 3H), 2.94 - 3.05 (m, 5H), 2.18 - 2.22 (m, 1H), 1.85 - 1.94 (m, 2H), 1.71 - 1.81 (m, 2H), 1.31 (s, 3H), 1.20 (s, 3H), 1.04 (d, J = 9.2 Hz, 1H), 0.80 (s, 3H).

[0238] Step H: (R)-(1-(3-(6-((Dimethyl(oxo)-λ 6 -Thioalkyl)amino)pyridin-2-yl)ureido)-2-phenylethyl)boronic acid

[0239]

[0240] (R)-(1-(3-(6-((Dimethyl(oxo)-λ 6((1R)-1-(((((2R)-1-(N,S-Dimethylsulfoximino)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (20 mg) was dissolved in methanol (1 mL). Isobutylboronic acid (12 mg), 1 M hydrochloric acid (0.1 mL) and n-hexane (1 mL) were added to this solution, and the mixture was stirred overnight at room temperature. The upper n-hexane layer was separated off, and the methanol phase was washed three times with n-hexane and then concentrated to dryness at 30 °C. The residue was diluted with dichloromethane and the product was washed into the aqueous phase with 2 M aqueous sodium hydroxide solution (5 mL). The aqueous phase was washed three times with dichloromethane and then acidified to acidic pH with 3 M hydrochloric acid. After extraction three times with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated at 30 °C to remove the solvent to give the product (10 mg).

[0241] 1 H NMR(400MHz,CD 3 OD)δ7.81(t,J=8.0Hz,1H),7.15-7.27(m,5H),6.76(d,J=7.6Hz,1H),6.46(d,J=8.4Hz,1H),3.44(s,3H),3.43(s,3H),3.28-3.31(m,1H),2.84-2.94(m,2H).

[0242] Example 5

[0243] ((1R)-1-(((((2R)-1-(N,S-Dimethylsulfoximino)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid

[0244]

[0245] Step A: ((1R)-1-(((((2R)-1-(N,S-Dimethylsulfoximino)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0246]

[0247] 2-Phenyl-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (150 mg) and triethylamine (162 mg) were added to dry dichloromethane, protected by nitrogen and cooled to -60 °C. A dichloromethane solution of bis(trichloromethyl) carbonate (48 mg) was added dropwise to the reaction solution. After completion, the mixture was stirred at -60 °C for 1 hour. A dichloromethane solution of ((2R)-1-(N,S-dimethylsulfimidoyl)pyrrolidin-2-yl)methanol (93 mg) was added dropwise to the above solution at -60 °C. The mixture was stirred at -60 °C for 1 hour, quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue obtained was purified by silica gel preparative plate (1:35 methanol / dichloromethane) to obtain the product (105 mg).

[0248] 1 H NMR(400MHz,CDCl 3 )δ7.24-7.28(m,2H),7.16-7.21(m,3H),4.81(d,J=5.2Hz,1H),4.32(d,J=8.8Hz,1H),4.04-4.14(m,2H),3.86-3.94(m,0.4H),3.73-3.80(m,0.6H),3.38-3.44(m,1H),3.14-3.32(m,2H),3.01(dd,J=14.0Hz,4.8Hz,1H),2.77-2.88(m,4H),2.67(s,1.2H),2.66(s,1.8H),2.29-2.34(m,1H),2.13-2.18(m,1H),1.81-2.01(m,7H),1.31(s,3H),1.26(s,3H),1.11(d,J=11.2Hz,1H),0.82(s,3H).

[0249] Step B: ((1R)-1-(((((2R)-1-(N,S-dimethylsulfimidoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid

[0250]

[0251] Dissolve ((1R)-1-(((((2R)-1-(N,S-dimethylsulfoximido)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (105 mg) in methanol. Add isobutylboronic acid (62 mg), 1 M hydrochloric acid (0.1 mL) and n-hexane to this solution, stir overnight at room temperature, separate and remove the upper layer of n-hexane, wash the methanol phase three times with n-hexane, then concentrate to dryness at 30 °C, dilute with dichloromethane, and wash the product into the aqueous phase with 2 M aqueous sodium hydroxide solution (5 mL). After washing the aqueous phase three times with dichloromethane, acidify it to acidic pH with 3 M hydrochloric acid, extract three times with dichloromethane, dry the organic phase over anhydrous sodium sulfate, filter and concentrate to remove the solvent at 30 °C to obtain the product (40 mg).

[0252] 1 H NMR(400MHz,CD 3 OD)δ7.16-7.26(m,5H),3.94-4.22(m,3H),3.33-3.43(m,5H),3.20-3.25(m,1H),2.73-2.90(m,5H),1.94-2.18(m,4H).

[0253] Example 6

[0254] ((1R)-2-(Benzofuran-3-yl)-1-(2-((2R)-1-(N-(tert-butyl)phenylsulfoximido)pyrrolidin-2-yl)acetamido)ethyl)boronic acid

[0255]

[0256] Step A: ((R)-2-(Benzofuran-3-yl)-1-(2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0257]

[0258] (R)-Pyrrolidine-2-acetic acid (366 mg), 2-(benzofuran-3-yl)-1-((R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (600 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (912 mg), 4-dimethylaminopyridine (20 mg) and diisopropylethylamine (406 mg) were added to dry dichloromethane (20 mL). After completion, the mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel preparative plate (1:40 methanol / dichloromethane) to obtain the product (180 mg).

[0259] 1 H NMR (400 MHz, CDCl 3 ) δ 8.28 - 8.46 (brs, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 4.16 - 4.26 (m, 1H), 3.94 - 4.03 (m, 1H), 3.22 - 3.37 (m, 2H), 3.06 - 3.17 (m, 1H), 2.94 - 3.04 (m, 1H), 2.63 - 2.88 (m, 2H), 2.39 - 2.52 (m, 1H), 2.27 - 2.38 (m, 1H), 2.04 - 2.15 (m, 1H), 1.90 - 2.04 (m, 2H), 1.73 - 1.89 (m, 5H), 1.40 (d, J = 10.8 Hz, 1H), 1.29 - 1.41 (m, 12H), 1.25 (s, 3H), 0.85 (s, 3H).

[0260] Step B: ((R)-2-(benzofuran-3-yl)-1-(2-((R)-pyrrolidin-2-yl)acetamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester trifluoroacetate

[0261]

[0262] ((R)-2-(Benzofuran-3-yl)-1-(2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (180 mg) was added to dichloromethane (5 mL), and then trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 3 hours, and the solvent was evaporated under reduced pressure to dryness to obtain the product (175 mg).

[0263] Step C: ((1R)-2-(Benzofuran-3-yl)-1-(2-((2R)-1-(N-(tert-butyl)phenylsulfinyl)pyrrolidin-2-yl)acetamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0264]

[0265] Under nitrogen protection, ((R)-2-(Benzofuran-3-yl)-1-(2-((R)-pyrrolidin-2-yl)acetamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester trifluoroacetate (63 mg) and triethylamine (33 mg) were added to dry dichloromethane (5 mL), and the mixture was cooled to 0 °C. A solution of N-(tert-butyl)phenylsulfinyl chloride (37 mg) in dichloromethane (2 mL) was added dropwise to the reaction solution. After completion, the mixture was stirred at room temperature for 2 hours, quenched with water, and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel preparative plate (1:2 ethyl acetate / petroleum ether) to obtain the product (12 mg).

[0266] 1 H NMR(400MHz,CDCl 3)δ8.10 - 8.19(brs, 1H), 7.79(d, J = 7.2Hz, 2H), 7.58(d, J = 6.8Hz, 1H), 7.38 - 7.50(m, 5H), 7.27(td, J = 7.2Hz, 1.2Hz, 1H), 7.22(td, J = 7.6Hz, 1.2Hz, 1H), 4.20(dd, J = 8.8Hz, 2.0Hz, 1H), 3.86 - 3.94(m, 1H), 3.12 - 3.22(m, 2H), 2.96 - 3.09(m, 2H), 2.79 - 2.91(m, 2H), 2.57(dd, J = 16.0Hz, 6.8Hz, 1H), 2.40 - 2.48(m, 1H), 2.16 - 2.35(m, 2H), 1.85 - 2.08(m, 4H), 1.74 - 1.85(m, 2H), 1.58 - 1.64(m, 1H), 1.32(s, 3H), 1.24(s, 3H), 1.22(s, 9H), 0.83(s, 3H).

[0267] Step D: ((1R)-2-(Benzofuran-3-yl)-1-(2-((2R)-1-(N-(tert-butyl)phenylsulfonylimino)pyrrolidin-2-yl)acetamido)ethyl)boronic acid

[0268]

[0269] Dissolve ((1R)-2-(Benzofuran-3-yl)-1-(2-((2R)-1-(N-(tert-butyl)phenylsulfonylimino)pyrrolidin-2-yl)acetamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (12 mg) in methanol (5 mL). Add isobutylboronic acid (10 mg), 1 mol / L hydrochloric acid (1 mL) and n-hexane (5 mL) to this solution. Stir at room temperature overnight. Separate and remove the upper n-hexane layer. Wash the methanol phase with n-hexane, concentrate under reduced pressure, add saturated brine (5 mL), extract with dichloromethane. Dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure. The obtained crude product is purified by trituration with ether to obtain the product (3 mg).

[0270] 1H NMR(400MHz, CD 3OD) δ 8.07 - 8.22 (m, 2H), 7.94 (t, J = 7.2 Hz, 1H), 7.78 - 7.85 (m, 2H), 7.58 - 7.63 (m, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.20 - 7.29 (m, 2H), 4.42 - 4.52 (m, 1H), 3.45 - 3.58 (m, 1H), 3.30 - 3.42 (m, 1H), 3.05 - 3.15 (m, 1H), 2.72 - 2.98 (m, 4H), 1.93 - 2.09 (m, 2H), 1.77 - 1.91 (m, 2H), 1.43 (s, 9H).

[0271] Example 7

[0272] ((1R)-2-(Benzofuran-3-yl)-1-(((((2R)-1-(N-methylpropan-2-ylsulfinyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid

[0273]

[0274] Step A: N-Tritylpropan-2-sulfinamide

[0275]

[0276] Under nitrogen protection, N-sulfinyltritylamine (9.2 g) was dissolved in anhydrous tetrahydrofuran (100 mL), cooled to 0 °C, and a solution of isopropylmagnesium chloride (15 mL, 2 mol / L) in tetrahydrofuran was added dropwise to the reaction solution. After completion, the mixture was stirred at room temperature for 1 hour, quenched with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was triturated with petroleum ether and filtered to obtain a solid product (8.1 g).

[0277] 1 H NMR (400 MHz, CDCl 3 ) δ 7.24 - 7.32 (m, 15H), 4.67 (s, 1H), 2.71 - 2.78 (m, 1H), 1.26 (d, J = 7.2 Hz, 3H), 1.24 (d, J = 7.2 Hz, 3H).

[0278] Step B: (2R)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)-1-(propan-2-ylsulfinyl)pyrrolidine

[0279]

[0280] Under nitrogen protection, N-tritylpropane-2-sulfinamide (8 g) was added to dry dichloromethane (50 mL), cooled to 0 °C, and tert-butyl hypochlorite (2.48 g) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 1 hour, and then the reaction solution was added dropwise to a solution of (R)-2-(((tert-butylphenylmethylsilyl)oxy)methyl)pyrrolidine (3.12 g) and triethylamine (4.6 g) in dichloromethane (50 mL). The mixture was stirred at room temperature overnight under nitrogen protection. p-Toluenesulfonic acid monohydrate (19.8 g) was added, and the mixture was stirred at room temperature for 30 minutes. 1 mol / L aqueous sodium hydroxide solution was added to adjust the pH to 9 - 10, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (pure ethyl acetate) to obtain the product (2.1 g). 1 H NMR(400MHz,CDCl 3 )δ7.62 - 7.68(m,4H),7.34 - 7.44(m,6H),3.94 - 4.02(m,1H),3.75(dd,J=10.0Hz,4.0Hz,0.5H),3.37 - 3.64(m,2.5H),3.11 - 3.29(m,2H),2.07 - 2.56(brs,1H),1.79 - 2.05(m,4H),1.25 - 1.34(m,6H),1.05(s,9H). Step C: (2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(N-methylpropan-2-ylsulfinimidoyl)pyrrolidine

[0281]

[0282] (2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(propyl-2-ylsulfinimidoyl)pyrrolidine (1.0 g) was added to dry tetrahydrofuran (20 mL), cooled to 0 °C, and sodium hydride (180 mg) was added portionwise to the reaction solution. The mixture was stirred at 0 °C for 30 minutes, and iodomethane (480 mg) was added dropwise. After completion, the mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (1.0 g).

[0283] 1 H NMR(400MHz,CDCl 3) δ 7.61 - 7.66 (m, 4H), 7.34 - 7.43 (m, 6H), 4.01 - 4.07 (m, 0.5H), 3.75 - 3.84 (m, 1H), 3.68 - 3.71 (m, 0.5H), 3.53 - 3.59 (m, 1H), 3.35 - 3.41 (m, 0.5H), 3.16 - 3.30 (m, 2H), 3.05 - 3.12 (m, 0.5H), 2.62 (s, 1.5H), 2.60 (s, 1.5H), 1.80 - 2.11 (m, 4H), 1.20 - 1.37 (m, 6H), 1.05 (s, 4.5H), 1.04 (s, 4.5H).

[0284] Step D: ((2R)-1-(N-Methylpropan-2-ylsulfinyl)pyrrolidin-2-yl)methanol

[0285]

[0286] Dissolve (2R)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)-1-(N-methylpropan-2-ylsulfinyl)pyrrolidine (1.0 g) in tetrahydrofuran (20 mL). Add tetrabutylammonium fluoride trihydrate (900 mg) to this solution, raise the temperature to 40 °C and stir for 2 hours. Evaporate the solvent, and purify the obtained residue by silica gel column chromatography (methanol:ethyl acetate 1 / 40) to obtain the product (450 mg).

[0287] 1 H NMR (400 MHz, CDCl 3 ) δ 3.97 - 4.42 (brs, 1H), 3.86 - 3.93 (m, 1H), 3.34 - 3.60 (m, 4H), 3.20 - 3.31 (m, 1H), 2.72 (s, 1.5H), 2.70 (s, 1.5H), 2.04 - 2.14 (m, 1H), 1.78 - 1.98 (m, 2H), 1.60 - 1.69 (m, 1H), 1.39 (d, J = 6.8 Hz, 3H), 1.29 (d, J = 6.8 Hz, 3H).

[0288] Step E: ((1R)-2-(Benzofuran-3-yl)-1-(((((2R)-1-(N-methylpropan-2-ylsulfinyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0289]

[0290] Under nitrogen protection, 2-(benzofuran-3-yl)-1-((R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (100 mg) and triethylamine (60 mg) were added to dry dichloromethane (10 mL), cooled to -60 °C, and a solution of bis(trichloromethyl) carbonate (31 mg) in dichloromethane (5 mL) was added dropwise to the reaction solution. After completion, the mixture was stirred at -60 °C for 1 hour. A solution of ((2R)-1-(N-methylpropan-2-ylsulfinyl)pyrrolidin-2-yl)methanol (60 mg) in dichloromethane (3 mL) was added dropwise to the above solution at -60 °C, and the mixture was stirred at -60 °C for 1 hour. The reaction was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel preparative plate (1:50 methanol / dichloromethane) to obtain the product (68 mg).

[0291] 1 H NMR(400MHz,CDCl 3 )δ7.57(d,J=7.2Hz,1H),7.43-7.45(m,2H),7.27(t,J=7.6Hz,1H),7.21(t,J=7.2Hz,1H),4.94(d,J=5.6Hz,1H),4.28(d,J=7.2Hz,1H),4.02-4.18(m,3H),3.50-3.54(m,1H),3.35-3.41(m,1H),3.08-3.32(m,3H),2.96(dd,J=14.8Hz,6.8Hz,1H),2.65-2.67(m,3H),2.27-2.34(m,1H),2.07-2.14(m,1H),1.78-2.05(m,7H),1.23-1.41(m,9H),1.19(s,3H),1.04(d,J=10.8Hz,1H),0.79(s,3H).

[0292] Step F: ((1R)-2-(benzofuran-3-yl)-1-(((((2R)-1-(N-methylpropan-2-ylsulfinyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid

[0293]

[0294] Dissolve ((1R)-2-(benzofuran-3-yl)-1-(((((2R)-1-(N-methylpropan-2-ylsulfonylimino)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (68 mg) in methanol (5 mL). To this solution, add isobutylboronic acid (35 mg), 1 mol / L hydrochloric acid (0.5 mL), and n-hexane (5 mL). Stir at room temperature overnight. Separate the layers to remove the upper n-hexane layer. Wash the methanol phase with n-hexane, concentrate under reduced pressure. Dilute the residue with dichloromethane and extract with 2 mol / L aqueous sodium hydroxide solution (5 mL). Wash the extract with dichloromethane, acidify to pH 3 - 4 with 3 mol / L hydrochloric acid, extract with dichloromethane. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the product (45 mg).

[0295] 1 H NMR(400MHz,CD 3 OD)δ7.59(d,J=7.6Hz,1H),7.53(s,1H),7.41(d,J=7.6Hz,1H),7.19-7.27(m,2H),4.32-4.38(m,0.5H),3.95-4.19(m,3.5H),3.32-3.48(m,3H),2.75-2.97(m,5H),1.95-2.22(m,4H),1.46-1.51(m,3H),1.39-1.43(m,3H).

[0296] Example 8

[0297] ((1R)-2-(benzofuran-3-yl)-1-(((((2R)-1-(N-methylcyclohexanesulfonylimino)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid

[0298]

[0299] Step A: N-tritylcyclohexanesulfinamide

[0300]

[0301] Under nitrogen protection, dissolve N-sulfinyltritylamine (15 g) in anhydrous tetrahydrofuran (200 mL), cool to 0 °C, and add dropwise a 1 mol / L solution of cyclohexylmagnesium bromide in tetrahydrofuran (50 mL) to the reaction solution. After completion, raise the temperature to 40 °C and stir for 12 hours. Quench the reaction with saturated ammonium chloride aqueous solution and extract with ethyl acetate. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure. Pulverize the obtained residue with methyl tert-butyl ether and filter to obtain the solid product (5.2 g).

[0302] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.22 - 7.32 (m, 15H), 4.70 (s, 1H), 2.45 - 2.53 (m, 1H), 1.22 - 1.90 (m, 10H).

[0303] Step B: (2R)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)-1-(cyclohexanesulfonimido)pyrrolidine

[0304]

[0305] Under nitrogen protection, N-tritylcyclohexanesulfonamide (2 g) was added to dry dichloromethane (50 mL), cooled to 0 °C, and tert-butyl hypochlorite (554 mg) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 1 hour, and then the reaction solution was added dropwise to a solution of (R)-2-(((tert-butylphenylmethylsilyl)oxy)methyl)pyrrolidine (692 mg) and triethylamine (1 g) in dichloromethane (10 mL). The temperature was raised to 40 °C and stirred overnight. p-Toluenesulfonic acid monohydrate (4.0 g) was added, and the mixture was stirred at room temperature for 30 minutes. 1 mol / L aqueous sodium hydroxide solution was added to adjust the pH to 9 - 10, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 2 / 1) to obtain the product (1.1 g).

[0306] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.63 - 7.71 (m, 4H), 7.36 - 7.48 (m, 6H), 4.30 - 4.39 (brs, 0.5H), 3.95 - 4.06 (m, 1H), 3.76 - 3.79 (m, 0.5H), 3.37 - 3.65 (m, 2.7H), 3.22 - 3.31 (m, 1H), 2.87 - 3.01 (m, 1.3H), 1.15 - 2.28 (m, 14H), 1.07 (s, 9H).

[0307] Step C: (2R)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)-1-(N-methylcyclohexanesulfonimido)pyrrolidine

[0308]

[0309] (2R)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)-1-(N-methylcyclohexanesulfonamido)pyrrolidine (1.0 g) was added to dry tetrahydrofuran (30 mL), and the mixture was cooled to 0 °C. Sodium hydride (173 mg, 60%) was added portionwise to the reaction solution, and the mixture was stirred at 0 °C for 30 minutes. Methyl iodide (460 mg) was added dropwise, and after completion, the mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (0.98 g).

[0310] 1 H NMR(400MHz,CDCl 3 )δ7.61-7.65(m,4H),7.34-7.43(m,6H),4.01-4.06(m,0.5H),3.75-3.84(m,1H),3.66-3.69(m,0.5H),3.53-3.58(m,1H),3.33-3.39(m,0.5H),3.15-3.26(m,1.5H),2.80-3.04(m,1H),2.61(s,1.5H),2.59(s,1.5H),1.10-2.28(m,14H),1.05(s,4.5H),1.04(s,4.5H).

[0311] Step D: ((2R)-1-(N-Methylcyclohexanesulfonamido)pyrrolidin-2-yl)methanol

[0312]

[0313] (2R)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)-1-(N-methylcyclohexanesulfonamido)pyrrolidine (1.0 g) was dissolved in tetrahydrofuran (30 mL). Tetrabutylammonium fluoride trihydrate (900 mg) was added to this solution, and the mixture was stirred at 40 °C for 2 hours. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methanol:ethyl acetate 1 / 40) to obtain the product (450 mg).

[0314] 1 H NMR(400MHz,CDCl 3)δ 3.98 - 4.50 (brs, 1H), 3.86 - 3.94 (m, 1H), 3.44 - 3.61 (m, 2.5H), 3.35 - 3.41 (m, 0.5H), 3.21 - 3.31 (m, 1H), 3.06 - 3.16 (m, 1H), 2.72 (s, 1.5H), 2.71 (s, 1.5H), 2.17 - 2.27 (m, 1H), 2.06 - 2.15 (m, 1H), 1.82 - 2.02 (m, 5H), 1.49 - 1.68 (m, 4H), 1.14 - 1.32 (m, 3H).

[0315] Step E: ((1R)-2-(Benzofuran-3-yl)-1-(((((2R)-1-(N-methylcyclohexanesulfonylimino)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0316]

[0317] Under nitrogen protection, 2-(benzofuran-3-yl)-1-(R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (120 mg) and triethylamine (120 mg) were added to dry dichloromethane (10 mL), cooled to -60 °C, and a solution of bis(trichloromethyl) carbonate (38 mg) in dichloromethane (3 mL) was added dropwise to the reaction solution. After completion, the mixture was stirred at -60 °C for 1 hour. A solution of ((2R)-1-(N-methylcyclohexanesulfonylimino)pyrrolidin-2-yl)methanol (83 mg) in dichloromethane (3 mL) was added dropwise to the above solution at -60 °C, and the mixture was stirred at -60 °C for 1 hour. The reaction was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel preparative plate (1:50 methanol / dichloromethane) to obtain the product (80 mg).

[0318] 1 H NMR(400MHz,CDCl 3)δ 7.57 (d, J = 7.2 Hz, 1H), 7.42 - 7.46 (m, 2H), 7.27 (t, J = 7.2 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 4.95 (d, J = 5.6 Hz, 1H), 4.27 (d, J = 8.4 Hz, 1H), 3.86 - 4.18 (m, 3H), 3.48 - 3.56 (m, 1H), 2.85 - 3.38 (m, 5H), 2.66 (s, 2H), 2.65 (s, 1H), 1.76 - 2.34 (m, 14H), 1.44 - 1.66 (m, 2H), 1.02 - 1.34 (m, 10H), 0.79 (s, 3H).

[0319] Step F: ((1R)-2-(Benzofuran-3-yl)-1-(((((2R)-1-(N-methylcyclohexanesulfonimido)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid

[0320]

[0321] Dissolve ((1R)-2-(benzofuran-3-yl)-1-(((((2R)-1-(N-methylcyclohexanesulfonimido)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (80 mg) in methanol (5 mL). To this solution, add isobutylboronic acid (40 mg), 1 mol / L hydrochloric acid (0.5 mL) and n-hexane (5 mL). Stir at room temperature overnight. Separate the layers and remove the upper n-hexane layer. Wash the methanol phase with n-hexane, concentrate under reduced pressure. Dilute the residue with dichloromethane and extract with 2 mol / L aqueous sodium hydroxide solution (5 mL). Wash the extract with dichloromethane, acidify to pH 3 - 4 with 3 mol / L hydrochloric acid, extract with dichloromethane. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the product (45 mg).

[0322] 1 H NMR (400 MHz, CD 3 OD) δ 7.59 (d, J = 7.6 Hz, 1H), 7.53 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.19 - 7.28 (m, 2H), 3.80 - 4.39 (m, 5H), 3.32 - 3.52 (m, 2H), 2.82 - 2.98 (m, 2H), 2.81 (s, 2H), 2.76 (s, 1H), 1.86 - 2.24 (m, 8H), 1.53 - 1.78 (m, 2H), 1.11 - 1.48 (m, 4H).

[0323] Example 9

[0324] (R)-2-(Benzofuran-3-yl)-1-(2-(2-dimethylsulfinimidoyl)acetamido)ethylboronic acid

[0325]

[0326] Step A: Methyl 2-(2-dimethylsulfinimidoyl)acetate

[0327]

[0328] Dissolve methyl 2-bromophenylacetate (1 g) in 1,4-dioxane (20 mL). Sequentially add tris(dibenzylideneacetone)dipalladium (200 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (380 mg), cesium carbonate (2.13 g), and iminodimethyl sulfoxide (490 mg). Bubble nitrogen through the solution and heat it in a microwave at 110 °C for 2 hours. After cooling to room temperature, add water and extract with dichloromethane. Dry the organic phase over anhydrous sodium sulfate and then evaporate the solvent. Purify the residue by silica gel preparative plate (1:30 methanol / dichloromethane) to obtain the product (800 mg).

[0329] 1 H NMR(400MHz,CDCl 3 )δ7.21(d,J=8.0Hz,1H),7.12-7.18(m,2H),6.94(td,J=7.2Hz,1.2Hz,1H),3.65(s,3H),3.62(s,2H),3.09(s,6H).

[0330] Step B: 2-(2-dimethylsulfinimidoyl)acetic acid

[0331]

[0332] Dissolve methyl 2-(2-dimethylsulfinimidoyl)acetate (800 mg) in a mixed solvent of methanol (5 mL) and water (2 mL). Add sodium hydroxide (160 mg), raise the temperature to 70 °C and stir for 4 hours. Cool to room temperature, adjust the pH to 5 - 6 with 1 mol / L dilute hydrochloric acid, directly evaporate the solvent, dry the residue under vacuum, slurry it with 1:10 methanol / dichloromethane, filter, and concentrate the filtrate under reduced pressure to obtain the product (756 mg).

[0333] 1 H NMR(400MHz,CDCl 3 )δ7.14-7.25(m,3H),6.97(t,J=7.6Hz,1H),3.65(s,2H),3.17(s,6H).

[0334] Step C: (R)-2-(Benzofuran-3-yl)-1-(2-(2-dimethylsulfinimidoyl)acetamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0335]

[0336] Dissolve 2-(2-dimethylsulfinimidoyl)acetic acid (756 mg) and 2-(benzofuran-3-yl)-1-(R)-(3-acetylbenzenesulfonamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (1.75 g) in N,N-dimethylformamide (5 mL). Sequentially add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.519 g) and 4-dimethylaminopyridine (620 mg), and stir at room temperature overnight. Add water, extract with dichloromethane, wash the extract with water, concentrate under reduced pressure, and purify the residue by silica gel preparative plate (1:30 methanol / dichloromethane) to obtain the product (640 mg).

[0337] 1 H NMR (400 MHz, CDCl 3 ) δ 7.46 (d, J = 7.2 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.23 - 7.27 (m, 1H), 7.21 (s, 1H), 7.12 - 7.18 (m, 4H), 6.88 - 6.92 (m, 1H), 4.22 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 3.60 (s, 2H), 2.92 - 2.96 (m, 4H), 2.87 - 2.90 (m, 4H), 2.73 (dd, J = 15.2 Hz, 11.2 Hz, 1H), 2.28 - 2.36 (m, 1H), 2.10 - 2.17 (m, 1H), 1.96 - 1.99 (m, 1H), 1.80 - 1.89 (m, 2H), 1.44 (d, J = 10.0 Hz, 1H), 1.35 (s, 3H), 1.26 (s, 3H), 0.85 (s, 3H).

[0338] Step D: (R)-2-(Benzofuran-3-yl)-1-(2-(2-dimethylsulfinimidoyl)acetamido)ethylboronic acid

[0339]

[0340] (R)-2-(Benzofuran-3-yl)-1-(2-(2-dimethylsulfinimidoyl)acetamido)ethyl boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (434 mg) was dissolved in a mixed solvent of methanol (5 mL) and n-hexane (5 mL). Isobutylboronic acid (485 mg) and 1 mol / L dilute hydrochloric acid (0.25 mL) were added, and the mixture was stirred at room temperature overnight. It was washed with n-hexane, the methanol phase was collected, concentrated under reduced pressure, and the residue was purified by silica gel preparative plate (1:4 methanol / dichloromethane) to obtain the product (120 mg).

[0341] 1 H NMR(400MHz,CD 3 OD)δ7.55(d,J=8.0Hz,1H),7.53(s,1H),7.42(d,J=8.0Hz,1H),7.25(t,J=7.6Hz,1H),7.13-7.21(m,4H),6.89-6.93(m,1H),3.66-3.75(m,2H),3.14(s,3H),3.11(s,3H),2.85-2.96(m,2H),2.69(dd,J=14.8Hz,9.6Hz,1H).

[0342] Example 10

[0343] (R)-(2-(Benzofuran-3-yl)-1-(2-(4-dimethylsulfinimidoylphenyl)acetamido)ethyl)boronic acid

[0344]

[0345] Step A: Ethyl 2-(3-dimethylsulfinimidoylphenyl)acetate

[0346]

[0347] Under nitrogen protection, ethyl 4-bromophenylacetate (460 mg) was dissolved in 1,4-dioxane (10 mL). Tris(dibenzylideneacetone)dipalladium (185 mg), cesium carbonate (2.00 g) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (230 mg) were added successively, and the temperature was raised to 105 °C and stirred overnight. It was cooled to room temperature, diluted with water, extracted with dichloromethane, the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel preparative plate (1:10 methanol / dichloromethane) to obtain the product (210 mg).

[0348] 1 H NMR(400MHz,CDCl 3)δ 7.1 - 7.12 (m, 2H), 6.98 - 7.00 (m, 2H), 4.10 (q, J = 7.20 Hz, 2H), 3.51 (s, 2H), 3.10 (s, 6H), 1.21 (d, J = 7.20 Hz, 3H).

[0349] Step B: 2-(3-Dimethylsulfinimidophenyl)acetic acid

[0350]

[0351] Dissolve ethyl 2-(3-dimethylsulfinimidophenyl)acetate (210 mg) in methanol (2 mL), add 1 mol / L aqueous NaOH solution (1 mL), and stir overnight at room temperature. The reaction mixture is acidified to pH 3 - 4 with 1 mol / L hydrochloric acid, and the reaction mixture is directly concentrated to dryness. The residue is washed with dichloromethane, the organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product, which is directly used for the next reaction.

[0352] Step C: (R)-(2-(Benzofuran-3-yl)-1-(2-(4-dimethylsulfinimidophenyl)acetamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0353]

[0354] Add 2-(4-dimethylsulfinimidophenyl)acetic acid (100 mg), 2-(benzofuran-3-yl)-1-((R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (190 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (250 mg), N,N-diisopropylethylamine (130 mg), and 4-dimethylaminopyridine (60 mg) to dry dichloromethane (20 mL), and stir overnight at room temperature. Quench the reaction with water and extract with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel preparative plate (20:1 methanol / dichloromethane) to obtain the product (105 mg).

[0355] 1 H NMR (400 MHz, CDCl 3) δ 7.45 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.16 - 7.27 (m, 3H), 6.96 - 7.01 (m, 3H), 6.12 (brs, 1H), 4.26 (d, J = 7.2 Hz, 1H), 3.60 (d, J = 16.8 Hz, 1H), 3.20 (s, 1H), 3.07 (s, 6H), 2.91 - 2.97 (m, 2H), 2.74 - 2.80 (m, 1H), 2.30 - 2.35 (m, 1H), 2.07 - 2.14 (m, 1H), 1.99 - 2.02 (m, 1H), 1.82 - 1.91 (m, 2H), 1.59 - 1.63 (m, 1H), 1.33 - 1.42 (m, 2H), 1.20 - 1.29 (m, 5H), 0.85 (s, 3H).

[0356] Step D: (R)-(2-(Benzofuran-3-yl)-1-(2-(4-dimethylsulfinimidylphenyl)acetamido)ethyl)boronic acid

[0357]

[0358] Dissolve 2(R)-2-(benzofuran-3-yl)-1-(2-(4-dimethylsulfinimidylphenyl)acetamido)ethyl boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (105 mg) in methanol (2 mL). To this solution, add isobutylboronic acid (100 mg), 1 mol / L hydrochloric acid (0.2 mL), and n-hexane (2 mL). Stir at room temperature overnight. Separate the layers and remove the upper n-hexane layer. Wash the methanol phase with n-hexane, concentrate under reduced pressure to obtain a crude product. Add diethyl ether to slurry, filter to collect the solid, and dry the solid to obtain the product (10 mg).

[0359] 1 H NMR (400 MHz, CD 3 OD) δ 7.55 (d, J = 4.8 Hz, 2H), 7.41 - 7.44 (m, 3H), 7.31 - 7.38 (m, 2H), 7.19 - 7.26 (m, 2H), 3.78 - 3.80 (m, 2H), 3.77 (s, 6H), 2.99 - 3.07 (m, 1H), 2.84 - 2.92 (m, 1H), 2.68 - 2.74 (m, 1H).

[0360] Example 11

[0361] (R)-(2-(Benzofuran-3-yl)-1-(2-(3-chloro-4-dimethylsulfinimidylphenyl)acetamido)ethyl)boronic acid

[0362]

[0363] Step A: 2-(4-Bromo-3-chlorophenyl)acetonitrile

[0364]

[0365] Dissolve 1-bromo-4-(bromomethyl)-2-chlorobenzene (2.84 g) in acetonitrile (100 mL). Sequentially add trimethylsilyl cyanide (990 mg) and tetrabutylammonium fluoride trihydrate (3.15 g). Stir at 30 °C overnight. Add water for dilution, extract with dichloromethane. Wash the organic phase successively with water and saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product (2.9 g).

[0366] 1 H NMR (400 MHz, CDCl 3 ) δ 7.61 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 3.69 (s, 2H).

[0367] Step B: 2-(3-Chloro-4-dimethylsulfinimidoyl)phenylacetonitrile

[0368]

[0369] Under nitrogen protection, dissolve 2-(4-bromo-3-chlorophenyl)acetonitrile (750 mg) in 1,4-dioxane (50 mL). Sequentially add dimethylsulfinimine (329 mg), tris(dibenzylideneacetone)dipalladium (146 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (278 mg), and cesium carbonate (2.1 g). Heat to 110 °C and stir overnight. Cool to room temperature, add water for dilution, extract with dichloromethane. Wash the organic phase successively with water and saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel preparative plate (1:60 methanol / dichloromethane) to obtain the product (150 mg).

[0370] 1 H NMR (400 MHz, CDCl 3 ) δ 7.34 (d, J = 2.4 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.07 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 3.65 (s, 2H), 3.16 (s, 6H).

[0371] Step C: 2-(3-Chloro-4-dimethylsulfinimidoyl)phenylacetic acid

[0372]

[0373] Dissolve 2-(3-chloro-4-(dimethylsulfinylimino)phenyl)acetonitrile (150 mg) in ethanol (5 mL), add 8 mol / L aqueous sodium hydroxide solution (1 mL), and warm to 80 °C with stirring for 2 hours. Cool to room temperature, dilute with water, adjust the pH to 4 - 5 with 1 mol / L hydrochloric acid, extract with dichloromethane, wash the organic phase successively with water and saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the product (130 mg).

[0374] 1 H NMR (400 MHz, CDCl 3 ) δ 7.29 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.03 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 3.55 (s, 2H), 3.16 (s, 6H).

[0375] Step D: (R)-2-(Benzofuran-3-yl)-1-(2-(3-chloro-4-(dimethylsulfinylimino)phenyl)acetamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0376]

[0377] Add 2-(3-chloro-4-(dimethylsulfinylimino)phenyl)acetic acid (131 mg), 2-(benzofuran-3-yl)-1-((R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (226 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (228 mg), and 4-dimethylaminopyridine (74 mg) to dry dichloromethane (5 mL). After completion, stir at room temperature overnight, quench the reaction with water, and extract with dichloromethane. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the resulting residue by silica gel preparative plate (20:1 methanol / dichloromethane) to obtain the product (160 mg).

[0378] 1 H NMR (400 MHz, CDCl 3)δ 7.47 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 7.15 - 7.25 (m, 4H), 6.88 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.19 - 6.23 (brs, 1H), 4.26 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 3.47 - 3.56 (m, 2H), 3.14 (s, 6H), 3.03 - 3.07 (m, 1H), 2.93 - 2.99 (m, 1H), 2.80 - 2.85 (m, 1H), 2.29 - 2.36 (m, 1H), 2.11 - 2.17 (m, 1H), 1.98 - 2.01 (m, 1H), 1.80 - 1.89 (m, 2H), 1.35 - 1.38 (m, 4H), 1.26 (s, 3H), 0.84 (s, 3H).

[0379] Step E: (R)-(2-(Benzofuran-3-yl)-1-(2-(3-chloro-4-(dimethylsulfinylimino)phenyl)acetamido)ethyl)boronic acid

[0380]

[0381] Dissolve (R)-2-(benzofuran-3-yl)-1-(2-(3-chloro-4-(dimethylsulfinylimino)phenyl)acetamido)ethyl boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (160 mg) in methanol (5 mL). To this solution, add isobutylboronic acid (137 mg), 1 mol / L hydrochloric acid (0.2 mL) and n-hexane (5 mL). Stir at room temperature overnight. Separate the layers and remove the upper n-hexane layer. Wash the methanol phase with n-hexane and concentrate under reduced pressure. Purify the residue by silica gel preparative plate (1:10 methanol / dichloromethane) to obtain the product (50 mg).

[0382] 1 H NMR (400 MHz, CD 3 OD), 7.53 - 7.55 (m, 2H), 7.42 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.26 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.18 - 7.23 (m, 2H), 7.05 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 3.62 (s, 2H), 3.20 (s, 6H), 2.97 (dd, J = 10.0 Hz, 5.2 Hz, 1H), 2.85 - 2.90 (m, 1H), 2.68 (dd, J = 15.2 Hz, 10.0 Hz, 1H).

[0383] Example 12

[0384] (R)-(2-(Benzofuran-3-yl)-1-(2-(3-fluoro-4-(dimethylsulfinyl)iminophenyl)acetamido)ethyl)boronic acid

[0385]

[0386] Step A: 2-(4-Bromo-3-fluorophenyl)acetonitrile

[0387]

[0388] Dissolve 1-bromo-4-(bromomethyl)-2-fluorobenzene (2.84 g) in acetonitrile (100 mL), successively add trimethylsilyl cyanide (990 mg) and tetrabutylammonium fluoride trihydrate (3.15 g), stir at 30 °C overnight, add water for dilution, extract with dichloromethane, wash the organic phase successively with water and saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain the crude product (3.03 g) which is directly used for the next reaction part.

[0389] 1 H NMR(400MHz,CDCl 3 )δ7.56(t,J=8.0Hz,1H),7.12(dd,J=8.8Hz,2.0Hz,1H),7.02(d,J=8.0Hz,1H),3.72(s,2H).

[0390] Step B: 2-(3-Fluoro-4-(dimethylsulfinyl)iminophenyl)acetonitrile

[0391]

[0392] Under nitrogen protection, dissolve 2-(4-bromo-3-fluorophenyl)acetonitrile (750 mg) in 1,4-dioxane (50 mL), successively add dimethylsulfinyl imine (329 mg), tris(dibenzylideneacetone)dipalladium(0) (146 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (278 mg) and cesium carbonate (2.1 g), heat to 110 °C and stir overnight. Cool to room temperature, add water for dilution, extract with dichloromethane, wash the organic phase successively with water and saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel preparative plate (1:60 methanol / dichloromethane) to obtain the product (150 mg).

[0393] 1 H NMR(400MHz,CDCl 3)δ 7.22 (t, J = 8.0 Hz, 1H), 7.03 (dd, J = 10.8 Hz, 2.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 3.67 (s, 2H), 3.18 (s, 6H).

[0394] Step C: 2-(3-Fluoro-4-(dimethylsulfinylimino)phenyl)acetic acid

[0395]

[0396] Dissolve 2-(3-fluoro-4-(dimethylsulfinylimino)phenyl)acetonitrile (150 mg) in ethanol (5 mL), add 3 mol / L aqueous sodium hydroxide solution (1 mL), and heat to 80 °C with stirring for 2 hours. Cool to room temperature, dilute with water, adjust the pH to 4 - 5 with 1 mol / L hydrochloric acid, extract with dichloromethane, wash the organic phase successively with water and saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the product (130 mg).

[0397] 1 H NMR (400 MHz, CDCl 3 )δ 7.16 (t, J = 8.4 Hz, 1H), 7.01 (dd, J = 11.2 Hz, 1.6 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 3.57 (s, 2H), 3.18 (s, 6H).

[0398] Step D: (R)-2-(Benzofuran-3-yl)-1-(2-(3-fluoro-4-(dimethylsulfinylimino)phenyl)acetamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0399]

[0400] Add 2-(3-fluoro-4-(dimethylsulfinylimino)phenyl)acetic acid (131 mg), 2-(benzofuran-3-yl)-1-((R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (226 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (228 mg), and 4-dimethylaminopyridine (74 mg) to dry dichloromethane (10 mL). After completion, stir at room temperature overnight, quench the reaction with water, extract with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is purified by silica gel preparative plate (20:1 methanol / dichloromethane) to obtain the product (160 mg).

[0401] 11H NMR (400 MHz, CDCl 3 ) δ 7.46 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.22 - 7.24 (m, 1H), 7.15 - 7.19 (m, 1H), 6.86 (d, J = 11.6 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.39 (brs, 1H), 4.25 (d, J = 7.2 Hz, 1H), 3.50 (d, J = 4.0 Hz, 2H), 3.13 (s, 6H), 3.03 - 3.07 (m, 1H), 2.93 - 2.98 (m, 1H), 2.80 - 2.85 (m, 1H), 2.28 - 2.34 (m, 1H), 2.09 - 2.15 (m, 1H), 1.97 - 1.99 (m, 1H), 1.79 - 1.89 (m, 2H), 1.34 - 1.36 (m, 4H), 1.26 (s, 3H), 0.83 (s, 3H).

[0402] Step E: (R)-(2-(Benzofuran-3-yl)-1-(2-(3-fluoro-4-(dimethylsulfinylimino)phenyl)acetamido)ethyl)boronic acid

[0403]

[0404] Dissolve (R)-2-(Benzofuran-3-yl)-1-(2-(3-fluoro-4-(dimethylsulfinylimino)phenyl)acetamido)ethyl boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (160 mg) in methanol (5 mL). To this solution, add isobutylboronic acid (137 mg), 1 mol / L hydrochloric acid (0.2 mL) and n-hexane (5 mL). Stir at room temperature overnight. Separate the layers and remove the upper n-hexane layer. Wash the methanol phase with n-hexane, concentrate under reduced pressure. The residue is purified by silica gel preparative plate (1:10 methanol / dichloromethane) to obtain the product (50 mg).

[0405] 1 1H NMR (400 MHz, CD 3 OD) δ 7.56 - 7.59 (m, 2H), 7.42 - 7.46 (m, 2H), 7.18 - 7.30 (m, 4H), 3.84 (s, 2H), 3.79 (s, 6H), 3.07 - 3.11 (m, 1H), 2.90 - 2.94 (m, 1H), 2.79 - 2.89 (m, 1H).

[0406] Example 13

[0407] (R)-(2-(Benzofuran-3-yl)-1-(2-(3-methoxy-4-(dimethylsulfinyl)aminophenyl)acetamido)ethyl)boronic acid

[0408]

[0409] Step A: (4-Bromo-3-methoxyphenyl)methanol

[0410]

[0411] (3-Methoxyphenyl)methanol (13.8 g) was dissolved in tetrahydrofuran (150 mL), N-bromosuccinimide (17.8 g) was added, and the mixture was stirred at room temperature overnight. Water was added for dilution, and the mixture was extracted with dichloromethane. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (20.1 g).

[0412] 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 2.8 Hz, 1H), 6.78 (dd, J = 8.8 Hz, 3.2 Hz, 1H), 4.66 (s, 2H), 3.77 (s, 3H).

[0413] Step B: 1-Bromo-4-(bromomethyl)-2-methoxybenzene

[0414]

[0415] (4-Bromo-3-methoxyphenyl)methanol (2.17 g) was dissolved in tetrahydrofuran (100 mL), phosphorus tribromide (813 mg) was added, and the mixture was stirred at room temperature overnight. Water was added for dilution, and the mixture was extracted with dichloromethane. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (2.98 g).

[0416] 1 H NMR (400 MHz, CDCl 3 ) δ 7.43 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 3.2 Hz, 1H), 6.72 (dd, J = 8.4 Hz, 3.2 Hz, 1H), 4.54 (s, 2H), 3.78 (s, 3H).

[0417] Step C: 2-(4-Bromo-3-methoxyphenyl)acetonitrile

[0418]

[0419] Refer to the method in step A of Example 10, using 1-bromo-4-(bromomethyl)-2-methoxybenzene (1.5 g) as the raw material to obtain the product (1.05 g).

[0420] 1 H NMR(400MHz,CDCl 3 )δ7.45(d,J=8.4Hz,1H),7.05(d,J=3.2Hz,1H),6.75(dd,J=8.4Hz,3.2Hz,1H),3.80(s,3H),3.78(s,2H).

[0421] Step D: 2-(3-methoxy-4-dimethylsulfinimidophenyl)acetonitrile

[0422]

[0423] Under nitrogen protection, dissolve 2-(4-bromo-3-methoxyphenyl)acetonitrile (520 mg) in 1,4-dioxane (15 mL), and successively add dimethylsulfinimide (319 mg), tris(dibenzylideneacetone)dipalladium (92 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (197 mg) and cesium carbonate (1.5 g). Heat the microwave reactor to 110 °C and react for 2 hours. Cool to room temperature, add water for dilution, extract with dichloromethane. The organic phase is washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel preparative plate (1:50 methanol / dichloromethane) to obtain the product (210 mg).

[0424] 1 H NMR(400MHz,CDCl 3 )δ7.17(d,J=8.8Hz,1H),6.79(d,J=2.8Hz,1H),6.75(dd,J=8.4Hz,3.2Hz,1H),3.75(s,3H),3.60(s,2H),3.15(s,6H).

[0425] Step E: 2-(3-methoxy-4-dimethylsulfinimidophenyl)acetic acid

[0426]

[0427] Refer to the method in step C of Example 10, using 2-(3-methoxy-4-dimethylsulfinimidophenyl)acetonitrile (210 mg) as the raw material to obtain the product (170 mg).

[0428] 1 H NMR(400MHz,CDCl 3) δ 9.55 - 13.01 (brs, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 3.2 Hz, 1H), 6.73 (dd, J = 8.4 Hz, 3.2 Hz, 1H), 3.75 (s, 3H), 3.64 (s, 2H), 3.18 (s, 6H).

[0429] Step F: (R)-2-(Benzofuran-3-yl)-1-(2-(3-methoxy-4-dimethylsulfinimidophenyl)acetamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0430]

[0431] Refer to the method in Step D of Example 10, using 2-(3-methoxy-4-dimethylsulfinimidophenyl)acetic acid (170 mg) and 2-(benzofuran-3-yl)-1-(R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (230 mg) as raw materials to obtain the product (180 mg).

[0432] 1 H NMR (400 MHz, CDCl 3 ) δ 7.47 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.35 - 7.39 (brs, 1H), 7.21 - 7.26 (m, 2H), 7.16 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.69 - 6.73 (m, 2H), 4.21 - 4.24 (m, 1H), 3.72 (s, 3H), 3.57 (s, 2H), 2.95 - 3.01 (m, 1H), 2.87 - 2.91 (m, 4H), 2.82 (s, 3H), 2.71 - 2.77 (m, 1H), 2.29 - 2.35 (m, 1H), 2.10 - 2.15 (m, 1H), 1.97 (t, J = 5.6 Hz, 1H), 1.79 - 1.88 (m, 2H), 1.43 (d, J = 10.0 Hz, 1H), 1.35 (s, 3H), 1.26 (s, 3H), 0.85 (s, 3H).

[0433] Step G: (R)-(2-(Benzofuran-3-yl)-1-(2-(3-methoxy-4-dimethylsulfinimidophenyl)acetamido)ethylboronic acid

[0434]

[0435] Refer to the method in step E of Example 10, using (R)-2-(benzofuran-3-yl)-1-(2-(3-methoxy-4-dimethylsulfinimidophenyl)acetamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (180 mg) as the raw material to obtain the product (32 mg).

[0436] 1 H NMR(400MHz,CD 3 OD)δ7.53-7.56(m,2H),7.41(d,J=7.6Hz,1H),7.25(td,J=8.0Hz,1.2Hz,1H),7.19(td,J=7.6Hz,1.2Hz,1H),7.09(d,J=8.8Hz,1H),6.81(d,J=2.8Hz,1H),6.75(dd,J=8.8Hz,2.8Hz,1H),3.72(s,3H),3.70(s,2H),3.09(s,3H),3.07(s,3H),2.95(dd,J=9.6Hz,4.8Hz,1H),2.84-2.90(m,1H),2.70(dd,J=14.8Hz,9.6Hz,1H).

[0437] Example 14

[0438] (R)-(2-(benzofuran-3-yl)-1-(2-(2-chloro-4-dimethylsulfinimidophenyl)acetamido)ethylboronic acid

[0439]

[0440] Step A: Methyl 2-(4-bromo-2-chlorophenyl)acetate

[0441]

[0442] Dissolve 2-(4-bromo-2-chlorophenyl)acetic acid (420 mg) in methanol (10 mL), add thionyl chloride (0.2 mL), heat to 60 °C and stir overnight, evaporate the solvent to dryness to obtain the crude product (430 mg).

[0443] 1 H NMR(400MHz,CDCl 3 )δ7.54(d,J=2.0Hz,1H),7.35(dd,J=8.0Hz,2.0Hz,1H),7.15(d,J=8.0Hz,1H),3.72(s,2H),3.70(s,3H).

[0444] Step B: Methyl 2-(2-chloro-4-dimethylsulfinimidophenyl)acetate

[0445]

[0446] Refer to the method in Step B of Example 10, using methyl 2-(2-chloro-4-dimethylsulfinimidophenyl)acetate (430 mg) and iminodimethyl-λ 6 -sulfone (190 mg) as starting materials to obtain the product (250 mg).

[0447] 1 H NMR (400 MHz, CDCl 3 ) δ 7.10 - 7.12 (m, 2H), 6.92 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 3.69 (s, 3H), 3.68 (s, 2H), 3.14 (s, 6H).

[0448] Step C: 2-(2-Chloro-4-dimethylsulfinimidophenyl)acetic acid

[0449]

[0450] Dissolve methyl 2-(2-chloro-4-dimethylsulfinimidophenyl)acetate (250 mg) in 1,4-dioxane (10 mL), add 1 mol / L lithium hydroxide aqueous solution (5 mL), stir at room temperature for 2 hours, adjust the pH to 4 - 5 with 1 mol / L hydrochloric acid, extract with dichloromethane, wash the organic phase successively with water and saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the product (220 mg).

[0451] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.10 - 12.54 (brs, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 3.55 (s, 2H), 3.20 (s, 6H).

[0452] Step D: (R)-2-(Benzofuran-3-yl)-1-(2-(2-chloro-4-dimethylsulfinimidophenyl)acetamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0453]

[0454] Refer to the method in step D of Example 10. Using 2-(2-chloro-4-dimethylsulfinimidophenyl)acetic acid (220 mg) and 2-(benzofuran-3-yl)-1-((R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (210 mg) as starting materials, the product (307 mg) was obtained.

[0455] 1 H NMR(400MHz,CDCl 3 )δ7.48(d,J=7.2Hz,1H),7.37(d,J=8.0Hz,1H),7.22-7.27(m,2H),7.18(td,J=7.6Hz,0.8Hz,1H),7.08(d,J=2.4Hz,1H),7.04(d,J=8.4Hz,1H),6.88(dd,J=8.0Hz,2.4Hz,1H),6.22(s,1H),4.25(dd,J=9.6Hz,1.6Hz,1H),3.71(d,J=16.8Hz,1H),3.64(d,J=16.8Hz,1H),3.13(s,6H),2.94-3.02(m,2H),2.75-2.81(m,1H),2.29-2.35(m,1H),2.11-2.16(m,1H),1.98-2.01(m,1H),1.80-1.89(m,2H),1.36-1.39(m,4H),1.26(s,3H),0.84(s,3H).

[0456] Step G: (R)-(2-(benzofuran-3-yl)-1-(2-(3-methoxy-4-dimethylsulfinimidophenyl)acetamido)ethyl)boronic acid

[0457]

[0458] Refer to the method in step E of Example 10. Using (R)-2-(benzofuran-3-yl)-1-(2-(2-chloro-4-dimethylsulfinimidophenyl)acetamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (280 mg) as the starting material, the product (30 mg) was obtained.

[0459] 1 H NMR(400MHz,CD 3OD) δ 7.56 (d, J = 7.2 Hz, 1H), 7.54 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.25 (td, J = 8.0 Hz, 1.2 Hz, 1H), 7.17 - 7.22 (m, 2H), 7.08 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 3.75 - 3.83 (m, 2H), 3.20 (s, 6H), 2.97 (dd, J = 9.2 Hz, 5.6 Hz, 1H), 2.88 (dd, J = 14.8 Hz, 6.0 Hz, 1H), 2.71 (dd, J = 14.8 Hz, 9.2 Hz, 1H).

[0460] Example 15

[0461] (R)-(2-(Benzofuran-3-yl)-1-(2-(3-(dimethylsulfinimidoyl)-5-methoxyphenyl)acetamido)ethyl)boronic acid

[0462]

[0463] Step A: 2-(3-Bromo-5-methoxyphenyl)acetonitrile

[0464]

[0465] Dissolve 1-bromo-3-(bromomethyl)-5-methoxybenzene (1.0 g) in dry acetonitrile (10 mL). Sequentially add trimethylsilyl cyanide (380 mg) and tetrabutylammonium fluoride trihydrate (0.98 g). Heat to 35 °C and stir overnight. Add water for dilution, extract with dichloromethane. Wash the organic phase successively with water and saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (1:10 ethyl acetate / petroleum ether) to obtain the product (450 mg).

[0466] 1 H NMR (400 MHz, CDCl 3 ) δ 7.04 (s, 1H), 7.00 (s, 1H), 6.79 (s, 1H), 3.79 (s, 3H), 3.68 (s, 2H).

[0467] Step B: 2-(3-Dimethylsulfinimidoyl-5-methoxyphenyl)acetonitrile

[0468]

[0469] Under nitrogen protection, dissolve 2-(3-bromo-5-methoxyphenyl)acetonitrile (400 mg) in 1,4-dioxane (10 mL). Sequentially add iminodimethyl-λ 6-Sulfone (280 mg), tris(dibenzylideneacetone)dipalladium (91 mg), cesium carbonate (1.30 g) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (174 mg) were added. The temperature was raised to 105 °C and stirred overnight. After cooling to room temperature, water was added for dilution, and the mixture was extracted with dichloromethane. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel preparative plate (1:10 methanol / dichloromethane) to obtain the product (200 mg).

[0470] 1 H NMR (400 MHz, CDCl 3 ) δ 6.60 (s, 1H), 6.56 (t, J = 2.0 Hz, 1H), 6.50 (s, 1H), 3.76 (s, 3H), 3.62 (s, 2H), 3.13 (s, 6H).

[0471] Step C: 2-(3-Dimethylsulfinimidyl-5-methoxyphenyl)acetic acid

[0472]

[0473] 2-(3-Dimethylsulfinimidyl-5-methoxyphenyl)acetonitrile (200 mg) was dissolved in methanol (2 mL), 1 mol / L aqueous NaOH solution (1 mL) was added, and the mixture was stirred overnight at room temperature. The reaction solution was acidified to pH 3 - 4 with 1 mol / L hydrochloric acid, and the reaction solution was directly concentrated to dryness. The residue was washed with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product directly used for the next step of reaction.

[0474] 1 H NMR (400 MHz, CDCl 3 ) δ 6.61 (s, 1H), 6.54 (t, J = 2.0 Hz, 1H), 6.48 (s, 1H), 3.52 (s, 2H), 3.46 (s, 3H), 3.13 (s, 6H).

[0475] Step D: (R)-(2-(Benzofuran-3-yl)-1-(2-(3-dimethylsulfinimidyl-5-methoxyphenyl)acetamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0476]

[0477] 2-(3-Dimethylsulfinimidoyl-5-methoxyphenyl)acetic acid (120 mg), 2-(benzofuran-3-yl)-1-((R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (210 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (310 mg), N,N-diisopropylethylamine (183 mg) and 4-dimethylaminopyridine (82 mg) were added to dry dichloromethane (20 mL), and the mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel preparative plate (20:1 methanol / dichloromethane) to obtain the product (128 mg).

[0478] 1 H NMR(400MHz,CDCl 3 )δ7.44(d,J=8.0Hz,1H),7.39(d,J=8.0Hz,1H),7.19-7.24(m,2H),7.15-7.18(m,2H),6.53(t,J=2.0Hz,1H),6.45(s,1H),6.31(s,1H),6.22(brs,1H),4.25(d,J=6.8Hz,1H),3.71(s,3H),3.60(d,J=16.8Hz,1H),3.09(s,6H),2.94-2.99(m,2H),2.73-2.80(m,1H),2.30-2.33(m,1H),2.13-2.16(m,1H),2.00(t,J=5.6Hz,1H),1.81-1.85(m,2H),1.41(t,J=5.2Hz,1H),1.38(s,3H),1.27(s,3H),0.86(s,3H).

[0479] Step E: (R)-(2-(benzofuran-3-yl)-1-(2-(3-(dimethylsulfinimidoyl)-5-methoxyphenyl)acetamido)ethyl)boronic acid

[0480]

[0481] (R)-(2-(Benzofuran-3-yl)-1-(2-(3-dimethylsulfinimidyl-5-methoxyphenyl)acetamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (128 mg) was dissolved in methanol (3 mL). Isobutylboronic acid (120 mg), 1 mol / L hydrochloric acid (0.2 mL) and n-hexane (3 mL) were added to this solution. The mixture was stirred at room temperature overnight. The upper layer of n-hexane was removed by liquid separation. The methanol phase was washed with n-hexane, concentrated under reduced pressure to obtain a crude product. The crude product was slurried with diethyl ether, and the solid was collected by filtration. The solid was dried to obtain the product (25 mg).

[0482] 1 H NMR(400MHz,CD 3 OD)δ7.53-7.57(m,3H),7.40-7.43(m,1H),7.20-7.28(m,2H),6.66-6.69(m,2H),3.78(s,6H),3.71(s,2H),3.47-3.49(m,2H),3.46(s,3H),3.11(s,1H),2.80-2.90(m,1H),2.69-2.73(m,1H).

[0483] Example 16

[0484] (R)-(2-(Benzofuran-3-yl)-1-(4-(2-dimethylsulfinimidylpyridine)acetamido)ethyl)boronic acid

[0485]

[0486] Step A: Ethyl 4-(2-dimethylsulfinimidylpyridine)acetate

[0487]

[0488] Under nitrogen protection, ethyl 4-(2-chloropyridine)acetate (600 mg) was dissolved in 1,4-dioxane (20 mL). Iminodimethyl-λ 6 -sulfone (336 mg), tris(dibenzylideneacetone)dipalladium (137 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthrene (260 mg) and cesium carbonate (1.9 g) were added successively. The temperature was raised to 110 °C and stirred overnight. The mixture was cooled to room temperature, diluted with water, extracted with dichloromethane. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel preparative plate (1:40 methanol / dichloromethane) to obtain the product (150 mg).

[0489] 1 H NMR(400MHz,CDCl3 ) δ 8.12 (s, 1H), 6.62 - 6.80 (m, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.51 (s, 2H), 3.34 (s, 6H), 1.24 (t, J = 7.2 Hz, 3H).

[0490] Step B: 4-(2-Dimethylsulfinimidylpyridine)acetic acid

[0491]

[0492] Dissolve ethyl 4-(2-dimethylsulfinimidylpyridine)acetate (150 mg) in ethanol (5 mL), add 8 mol / L aqueous sodium hydroxide solution (1 mL), and heat to 80 °C with stirring for 2 hours. Cool to room temperature, dilute with water, adjust the pH to 4 - 5 with 1 mol / L hydrochloric acid, concentrate under reduced pressure, and separate the residue by column chromatography (1:5 methanol / dichloromethane) to obtain the product (100 mg).

[0493] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.42 - 13.14 (brs, 1H), 8.13 (d, J = 6.4 Hz, 1H), 7.31 (s, 1H), 7.11 (d, J = 6.4 Hz, 1H), 3.81 (s, 2H), 3.57 (s, 6H).

[0494] Step C: (R)-2-(Benzofuran-3-yl)-1-(4-(2-dimethylsulfinimidylpyridine)acetamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0495]

[0496] Add 4-(2-dimethylsulfinimidylpyridine)acetic acid (100 mg), 2-(benzofuran-3-yl)-1-((R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (160 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (334 mg), 4-dimethylaminopyridine (54 mg), and diisopropylethylamine (114 mg) to dry dichloromethane (15 mL). After completion, stir at room temperature overnight, quench the reaction with water, extract with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the resulting residue by silica gel preparative plate (30:1 methanol / dichloromethane) to obtain the product (73 mg).

[0497] 11H NMR (400 MHz, CDCl 3 ) δ 8.04 - 8.10 (m, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 6.55 - 6.61 (m, 2H), 5.98 (s, 1H), 4.28 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 3.50 (d, J = 16.0 Hz, 1H), 3.46 (d, J = 16.0 Hz, 1H), 3.34 (s, 6H), 3.08 - 3.16 (m, 1H), 2.98 (dd, J = 14.8 Hz, 4.0 Hz, 1H), 2.84 (dd, J = 15.2 Hz, 10.4 Hz, 1H), 2.28 - 2.37 (m, 1H), 2.11 - 2.18 (m, 1H), 2.00 (t, J = 5.6 Hz, 1H), 1.80 - 1.90 (m, 2H), 1.35 (s, 3H), 1.26 - 1.30 (m, 4H), 0.84 (s, 3H).

[0498] Step D: (R)-(2-(Benzofuran-3-yl)-1-(4-(2-dimethylsulfinimidylpyridine)acetamido)ethyl)boronic acid

[0499]

[0500] Dissolve (R)-2-(benzofuran-3-yl)-1-(4-(2-dimethylsulfinimidylpyridine)acetamido)ethyl boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (73 mg) in methanol (5 mL). To this solution, add isobutylboronic acid (43 mg), 1 mol / L hydrochloric acid (0.2 mL), and n-hexane (5 mL). Stir at room temperature overnight. Separate the layers and remove the upper n-hexane layer. Wash the methanol phase with n-hexane, concentrate under reduced pressure to obtain a crude product, and purify by trituration with diethyl ether to obtain the product (25 mg).

[0501] 1 1H NMR (400 MHz, CD 3OD) δ 8.06 (d, J = 6.8 Hz, 1H), 7.56 - 7.59 (m, 2H), 7.48 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.19 - 7.29 (m, 2H), 7.12 (dd, J = 6.4 Hz, 1.2 Hz, 1H), 3.85 - 3.89 (m, 2H), 3.53 - 3.56 (m, 6H), 3.11 (dd, J = 9.2 Hz, 5.6 Hz, 1H), 2.89 - 2.95 (m, 1H), 2.77 (dd, J = 14.8 Hz, 10.0 Hz, 1H).

[0502] Example 17

[0503] (R)-(2-(Benzofuran-3-yl)-1-(2-(5-(dimethylsulfinylimino)pyridin-2-yl)acetamido)ethyl)boronic acid

[0504]

[0505] Step A: Methyl 2-(5-dimethylsulfinylimino-pyridin-2-yl)acetate

[0506]

[0507] Under nitrogen protection, methyl 2-(5-bromo-pyridin-2-yl)acetate (0.5 g) was dissolved in 1,4-dioxane (20 mL), and iminodimethyl-λ 6 -sulfone (150 mg), tris(dibenzylideneacetone)dipalladium (50 mg), cesium carbonate (0.70 g) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthrene (88 mg) were added in sequence. The temperature was raised to 105 °C and stirred overnight. After cooling to room temperature, it was diluted with water and extracted with dichloromethane. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel preparative plate (1:10 methanol / dichloromethane) to obtain the product (300 mg).

[0508] 1 H NMR (400 MHz, CDCl 3 ) δ 8.40 (d, J = 2.8 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.49 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 3.97 (s, 3H), 3.48 (s, 2H), 3.23 (s, 6H).

[0509] Step B: 2-(5-Dimethylsulfinylimino-pyridin-2-yl)acetic acid

[0510]

[0511] Dissolve methyl 2-(5-dimethylsulfinylimidoyl-pyridin-2-yl)acetate (300 mg) in methanol (5 mL), add 1 mol / L aqueous NaOH solution (3 mL), and stir overnight at room temperature. The reaction solution was acidified to pH 5 - 6 with 1 mol / L hydrochloric acid, and the reaction solution was directly concentrated to dryness. The residue was purified by silica gel preparative plate (1:10 methanol / dichloromethane) to obtain the product (180 mg).

[0512] 1 H NMR(400MHz,CDCl 3 )δ8.27(d,J=1.6Hz,1H),8.08 - 8.10(m,1H),7.76(d,J=8.8Hz,1H),4.05(s,2H),3.38(s,6H).

[0513] Step C: (R)-(2-(Benzofuran-3-yl)-1-(2-(5-(dimethylsulfinylimino)pyridin-2-yl)acetamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0514]

[0515] Add 2-(5-dimethylsulfinylimino-pyridin-2-yl)acetic acid (180 mg), 2-(benzofuran-3-yl)-1-((R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (300 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (455 mg), N,N-diisopropylethylamine (248 mg) and 4-dimethylaminopyridine (123 mg) to dry dichloromethane (15 mL), and stir overnight at room temperature. Quench the reaction with water, extract with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the obtained residue by silica gel preparative plate (20:1 methanol / dichloromethane) to obtain the product (150 mg).

[0516] 1 H NMR(400MHz,CDCl 3)δ8.38(brs,1H),8.05(s,1H),7.53(d,J=7.6Hz,1H),7.44(d,J=8.0Hz,1H),7.30 - 7.40(m,1H),7.18 - 7.28(m,2H),7.16 - 7.20(m,1H),7.02(d,J=8.0Hz,1H),4.25(d,J=8.4Hz,1H),3.61 - 3.77(m,1H),3.15(s,6H),2.98 - 3.10(m,2H),2.78 - 2.84(m,1H),2.30 - 2.35(m,1H),2.08 - 2.17(m,2H),2.00(t,J=5.6Hz,1H),1.82 - 1.91(m,2H),1.40(d,J=10.4Hz,1H),1.37(s,3H),1.27(s,3H),0.85(s,3H).

[0517] Step D: (R)-(2-(Benzofuran-3-yl)-1-(2-(5-(dimethylsulfinimidoyl)pyridin-2-yl)acetamido)ethyl)boronic acid

[0518]

[0519] Dissolve (R)-(2-(Benzofuran-3-yl)-1-(2-(5-(dimethylsulfinimidoyl)pyridin-2-yl)acetamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (145 mg) in methanol (2 mL). To this solution, add isobutylboronic acid (130 mg), 1 mol / L hydrochloric acid (0.2 mL) and n-hexane (2 mL). Stir at room temperature overnight. Separate the layers to remove the upper n-hexane layer. Wash the methanol layer with n-hexane, concentrate under reduced pressure to obtain a crude product. Add ether for slurrying, filter to collect the solid, and dry the solid to obtain the product (10 mg).

[0520] 1 H NMR(400MHz,CD 3 OD)δ7.68(d,J=8.4Hz,2H),7.43 - 7.48(m,2H),7.22 - 7.34(m,4H),3.76(s,2H),3.58 - 3.73(m,1H),3.29(s,6H),2.83 - 2.92(m,1H),2.68 - 2.71(m,1H).

[0521] Example 18

[0522] (R)-(2-(Benzofuran-3-yl)-1-(3-(dimethylsulfinimidoylphenyl)propanamido)ethyl)boronic acid

[0523]

[0524] Step A: Methyl 3-(dimethylsulfinimidoyl)phenylpropionate

[0525]

[0526] Under nitrogen protection, dissolve methyl 3-bromo-3-phenylpropionate (600 mg) in 1,4-dioxane (15 mL), and successively add dimethylsulfinimide (276 mg), tris(dibenzylideneacetone)dipalladium(0) (112 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (200 mg) and cesium carbonate (1.6 g). Heat the mixture to 110 °C and stir overnight. Cool to room temperature, add water for dilution, extract with dichloromethane. Wash the organic phase successively with water and saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel preparative plate (1:60 methanol / dichloromethane) to obtain the product (500 mg).

[0527] 1 H NMR (400 MHz, CDCl 3 ) δ 7.14 (t, J = 7.6 Hz, 1H), 6.89 - 6.92 (m, 2H), 6.81 (d, J = 7.6 Hz, 1H), 3.66 (s, 3H), 3.14 (s, 6H), 2.88 (t, J = 8.0 Hz, 2H), 2.61 (t, J = 8.0 Hz, 2H).

[0528] Step B: 3-(Dimethylsulfinimidoyl)phenylpropionic acid

[0529]

[0530] Dissolve methyl 3-(dimethylsulfinimidoyl)phenylpropionate (500 mg) in ethanol (10 mL), add 8 mol / L aqueous sodium hydroxide solution (1 mL), heat to 80 °C and stir for 2 hours. Cool to room temperature, add water for dilution, adjust the pH to 3 - 4 with 1 mol / L hydrochloric acid, concentrate under reduced pressure, and separate the residue by column chromatography (1:5 methanol / dichloromethane) to obtain the product (300 mg).

[0531] Step C: (R)-2-(Benzofuran-3-yl)-1-(3-(dimethylsulfinimidoyl)phenylpropionamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0532]

[0533] 3-(Dimethylsulfinimidylphenyl)propanoic acid (150 mg), 2-(benzofuran-3-yl)-1-((R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (233 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (471 mg), 4-dimethylaminopyridine (76 mg) and diisopropylethylamine (160 mg) were added to dry dichloromethane (10 mL). After completion, the mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel preparative plate (1:40 methanol / dichloromethane) to obtain the product (60 mg).

[0534] 1 H NMR(400MHz,CDCl 3 )δ7.51(d,J=7.6Hz,1H),7.44(d,J=8.4Hz,1H),7.26-7.30(m,2H),7.21(t,J=7.6Hz,1H),7.10(t,J=8.0Hz,1H),6.91(d,J=7.6Hz,1H),6.84(s,1H),6.74(d,J=8.0Hz,1H),6.19(s,1H),4.26(d,J=7.2Hz,1H),3.11(s,6H),3.01-3.06(m,1H),2.92-2.97(m,1H),2.86(t,J=7.6Hz,2H),2.76(dd,J=15.2Hz,11.2Hz,1H),2.52-2.56(m,2H),2.31-2.38(m,1H),2.12-2.18(m,1H),2.01(t,J=5.6Hz,1H),1.81-1.90(m,2H),1.42(d,J=10.8Hz,1H),1.38(s,3H),1.27(s,3H),0.86(s,3H).

[0535] Step D: (R)-(2-(Benzofuran-3-yl)-1-(3-(dimethylsulfinimidylphenyl)propanamido)ethyl)boronic acid

[0536]

[0537] (R)-2-(Benzofuran-3-yl)-1-(3-(dimethylsulfinimidoylphenyl)propanamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (60 mg) was dissolved in methanol (5 mL). Isobutylboronic acid (47 mg), 1 mol / L hydrochloric acid (0.2 mL) and n-hexane (5 mL) were added to this solution. The mixture was stirred at room temperature overnight. The upper layer of n-hexane was removed by liquid separation. The methanol phase was washed with n-hexane and concentrated under reduced pressure to obtain a crude product, which was purified by trituration with diethyl ether to obtain the product (32 mg).

[0538] 1 H NMR(400MHz,CD 3 OD)δ8.51(d,J=8.0Hz,1H),7.40-7.42(m,2H),7.14-7.26(m,3H),6.89-6.93(m,2H),6.85(d,J=7.6Hz,1H),3.17(s,6H),2.79-2.92(m,4H),2.64-2.70(m,2H),2.54(dd,J=15.2Hz,10.4Hz,1H).

[0539] Example 19

[0540] (R)-(2-(Benzofuran-3-yl)-1-(4-(dimethylsulfinimidoylphenyl)propanamido)ethylboronic acid

[0541]

[0542] Step A: Methyl 4-(dimethylsulfinimidoylphenyl)propionate

[0543]

[0544] Under nitrogen protection, methyl 4-bromophenylpropionate (600 mg) was dissolved in 1,4-dioxane (50 mL). Dimethylsulfinimide (276 mg), tris(dibenzylideneacetone)dipalladium (112 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthrene (200 mg) and cesium carbonate (1.6 g) were added successively. The temperature was raised to 110 °C and stirred overnight. After cooling to room temperature, water was added for dilution, and the mixture was extracted with dichloromethane. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel preparative plate (1:60 methanol / dichloromethane) to obtain the product (480 mg).

[0545] 1 H NMR(400MHz,CDCl 3)δ 7.02 - 7.07 (m, 2H), 6.96 - 6.99 (m, 2H), 3.65 (s, 3H), 3.12 (s, 6H), 2.87 (t, J = 7.6 Hz, 2H), 2.58 (t, J = 7.6 Hz, 2H).

[0546] Step B: 4-(Dimethylsulfinimidylphenyl)propionic acid

[0547]

[0548] Dissolve methyl 4-(dimethylsulfinimidylphenyl)propionate (410 mg) in ethanol (10 mL), add 8 mol / L aqueous sodium hydroxide solution (1 mL), heat to 80 °C and stir for 2 hours. Cool to room temperature, dilute with water, adjust the pH to 3 - 4 with 1 mol / L hydrochloric acid, concentrate under reduced pressure, and separate the residue by column chromatography (1:5 methanol / dichloromethane) to obtain the product (300 mg).

[0549] Step C: (R)-2-(Benzofuran-3-yl)-1-(4-(dimethylsulfinimidylphenyl)propanamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0550]

[0551] Add 4-(dimethylsulfinimidylphenyl)propionic acid (150 mg), 2-(benzofuran-3-yl)-1-((R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (233 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (471 mg), 4-dimethylaminopyridine (76 mg) and diisopropylethylamine (160 mg) to dry dichloromethane (10 mL). After completion, stir at room temperature overnight, quench the reaction with water, extract with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the obtained residue by silica gel preparative plate (1:40 methanol / dichloromethane) to obtain the product (120 mg).

[0552] 1 H NMR (400 MHz, CDCl 3)δ 7.51 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.25 - 7.30 (m, 2H), 7.20 (t, J = 7.6 Hz, 1H), 6.94 - 6.99 (m, 4H), 4.26 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 3.09 (s, 6H), 3.02 - 3.08 (m, 1H), 2.93 - 2.98 (m, 1H), 2.84 (t, J = 7.6 Hz, 2H), 2.74 - 2.80 (m, 1H), 2.46 - 2.55 (m, 2H), 2.31 - 2.37 (m, 1H), 2.12 - 2.18 (m, 1H), 2.01 (t, J = 5.6 Hz, 1H), 1.81 - 1.90 (m, 2H), 1.42 (d, J = 10.0 Hz, 1H), 1.38 (s, 3H), 1.27 (s, 3H), 0.86 (s, 3H).

[0553] Step D: (R)-(2-(Benzofuran-3-yl)-1-(4-(dimethylsulfinimidylphenyl)propanamido)ethyl)boronic acid

[0554]

[0555] Dissolve (R)-2-(benzofuran-3-yl)-1-(4-(dimethylsulfinimidylphenyl)propanamido)ethyl boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (120 mg) in methanol (5 mL). Add isobutylboronic acid (65 mg), 1 mol / L hydrochloric acid (0.5 mL) and n-hexane (5 mL) to this solution. Stir at room temperature overnight. Separate and remove the upper n-hexane layer. Wash the methanol phase with n-hexane, concentrate under reduced pressure to obtain a crude product, and purify by trituration with diethyl ether to obtain the product (40 mg).

[0556] 1 H NMR (400 MHz, CD 3 OD) δ 7.49 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.37 (s, 1H), 7.17 - 7.26 (m, 2H), 7.08 - 7.11 (m, 2H), 6.97 - 7.01 (m, 2H), 3.14 (s, 6H), 2.79 - 2.92 (m, 4H), 2.57 - 2.71 (m, 2H), 2.52 (dd, J = 14.8 Hz, 10.4 Hz, 1H).

[0557] Example 20

[0558] (R)-(2-(Benzofuran-3-yl)-1-((((2-(N,S-dimethylsulfamoylimino)benzyl)oxy)carbonyl)amino)ethyl)boronic acid

[0559]

[0560] Step A: 2-(Methylthio)benzoic acid

[0561]

[0562] At 0 °C, dissolve 2-mercaptobenzoic acid (8 g) in methanol (100 mL), slowly add 8 mol / L aqueous sodium hydroxide solution (19.5 mL), keep at 0 °C for 10 minutes, then add methyl iodide (1.8 g). Raise the temperature to room temperature and stir for 5 hours. Adjust the pH to 3 - 4 with 1 mol / L dilute hydrochloric acid. After evaporating the solvent, disperse the residue in methanol (50 mL), filter the solid, wash the solid thoroughly with methanol, and obtain the product (4.1 g) after evaporating methanol.

[0563] 1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 2.49 (s, 3H).

[0564] Step B: Methyl 2-(methylthio)benzoate

[0565]

[0566] At 0 °C, add 2-(methylthio)benzoic acid (4 g) to methanol (150 mL), slowly add thionyl chloride (8.5 g), stir at room temperature for 10 minutes, then reflux overnight. Obtain the product (4.7 g) after evaporating the solvent. 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.46 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 3.90 (s, 3H), 2.45 (s, 3H).

[0567] Step C: (2-(Methylthio)phenyl)methanol

[0568]

[0569] Under nitrogen protection, methyl 2-(methylthio)benzoate (4.7 g) was dissolved in tetrahydrofuran (150 mL), and a toluene solution of 1 mol / L diisobutylaluminum hydride (78 mL) was slowly added under ice bath cooling, and the mixture was stirred at room temperature overnight. The reaction was quenched by slowly adding a saturated aqueous sodium sulfate solution, the solid was filtered, washed thoroughly with dichloromethane, the organic phase was collected by liquid separation, and the solvent was evaporated to obtain the product (3.5 g).

[0570] 1 H NMR(400MHz,CDCl 3 )δ7.36(d,J=7.6Hz,1H),7.24-7.28(m,2H),7.14-7.19(m,1H),4.74(s,2H),2.47(s,3H),2.22-2.29(brs,1H).

[0571] Step D: 2-((2-(methylthio)benzyl)oxy)tetrahydro-2H-pyran

[0572]

[0573] (2-(Methylthio)phenyl)methanol (1.95 g) was dissolved in 3,4-dihydropyran (50 mL), pyridinium p-toluenesulfonate (0.975 g) was added, and the mixture was stirred at room temperature overnight. An aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. After the organic phase was washed with a saturated sodium chloride solution, the organic phase was evaporated to obtain the product (2.7 g).

[0574] 1 H NMR(400MHz,CDCl 3 )δ7.40(d,J=7.2Hz,1H),7.21-7.28(m,2H),7.12-7.16(m,1H),4.82(d,J=12.4Hz,1H),4.79(t,J=3.6Hz,1H),4.57(d,J=12.4Hz,1H),3.91-3.96(m,1H),3.52-3.57(m,1H),2.44(s,3H),1.81-1.93(m,1H),1.62-1.78(m,2H),1.48-1.62(m,3H).

[0575] Step E: Imino(methyl)(2-((((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)-λ 6 -sulfone

[0576]

[0577] Dissolve 2-((2-(methylthio)benzyl)oxy)tetrahydro-2H-pyran (2.7 g) in methanol (200 mL), and successively add iodobenzene diacetate (10.9 g) and ammonium carbamate (4.4 g). Stir at room temperature overnight. Concentrate under reduced pressure to remove the solvent, and purify the residue by silica gel column chromatography (5% methanol / dichloromethane) to obtain the product (1.1 g). 1 H NMR(400MHz,CDCl 3 )δ8.11(td,J=8.0Hz,1.2Hz,1H),7.56-7.68(m,2H),7.44-7.49(m,1H),5.02-5.21(m,2H),4.74-4.77(m,1H),3.84-3.90(m,1H),3.50-3.57(m,1H),3.26(s,3H),1.68-1.88(m,2H),1.46-1.65(m,4H).

[0578] Step F: Methyl(methylimino)(2-((((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)-λ 6 -sulfone

[0579]

[0580] Dissolve imino(methyl)(2-((((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)-λ 6 -sulfone (170 mg) in tetrahydrofuran (10 mL), add sodium hydride (51 mg) under ice-bath cooling, add iodomethane (135 mg) after 10 minutes, and stir at room temperature overnight. Filter, add water and extract with dichloromethane. Concentrate the extract under reduced pressure to remove the solvent to obtain the product (180 mg).

[0581] 1 H NMR(400MHz,CDCl 3 )δ7.95-7.99(m,1H),7.64-7.68(m,1H),7.53-7.58(m,1H),7.42-7.47(m,1H),4.94-5.09(m,2H),4.70-4.75(m,1H),3.82-3.89(m,1H),3.48-3.55(m,1H),3.16(s,3H),2.61-2.62(m,3H),1.68-1.84(m,2H),1.45-1.64(m,4H).

[0582] Step G: 2-(N,S-Dimethylsulfimidoyl)benzyl alcohol

[0583]

[0584] Methyl (methylimino)(2 - ((((tetrahydro - 2H - pyran - 2 - yl)oxy)methyl)phenyl)-λ 6 -sulfone (180 mg) was dissolved in methanol (10 mL), p - toluenesulfonic acid (12 mg) was added, and the mixture was heated to 45 °C and stirred overnight. Water was added and the mixture was extracted with dichloromethane. The extract was concentrated under reduced pressure, and the residue was purified by silica gel preparative plate (1:30 methanol / dichloromethane) to obtain the product (100 mg).

[0585] 1 H NMR (400 MHz, CDCl 3 ) δ 7.93 (d, J = 7.6 Hz, 1H), 7.49 - 7.57 (m, 2H), 7.44 (td, J = 7.6 Hz, 2.0 Hz, 1H), 4.76 - 4.83 (m, 2H), 3.13 (s, 3H), 2.69 (s, 3H).

[0586] Step H: 2 - (Benzofuran - 3 - yl)-1-(R)-(3 - acetylbenzenesulfonamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane - 2,3 - diol ester

[0587]

[0588] 2 - (Benzofuran - 3 - yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane - 2,3 - diol ester hydrochloride (104 mg) was dissolved in dichloromethane (10 mL), cooled to - 60 °C, dry triethylamine (112 mg) was added, and after keeping warm for 15 minutes, a solution of triphosgene (33 mg) in dichloromethane (5 mL) was added dropwise. After keeping warm at - 60 °C for 30 minutes, a solution of 2-(N,S - dimethylsulfimidoyl)benzyl alcohol (55 mg) in dichloromethane (5 mL) was added dropwise, and the mixture was kept warm at - 60 °C for 1 hour. The temperature was raised to room temperature and stirred overnight. Saturated brine was added and the mixture was extracted with dichloromethane. The extract was purified by silica gel preparative plate (1:30 methanol / dichloromethane) to obtain the product (90 mg). 1 H NMR (400 MHz, CDCl 3)δ 7.98 (d, J = 8.4 Hz, 1H), 7.55 - 7.62 (m, 2H), 7.45 - 7.52 (m, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.23 - 7.28 (m, 1H), 7.13 - 7.18 (m, 1H), 5.46 - 5.62 (m, 2H), 5.10 (d, J = 4.8 Hz, 1H), 4.26 (d, J = 8.4 Hz, 1H), 3.48 - 3.52 (m, 1H), 3.17 (s, 3H), 3.10 (dd, J = 14.8 Hz, 5.2 Hz, 1H), 2.95 (dd, J = 14.8 Hz, 6.8 Hz, 1H), 2.66 (s, 3H), 2.24 - 2.31 (m, 1H), 2.04 - 2.11 (m, 1H), 1.94 (t, J = 5.6 Hz, 1H), 1.82 - 1.87 (m, 1H), 1.73 - 1.79 (m, 1H), 1.23 (s, 3H), 1.15 (s, 1.5H), 1.14 (s, 1.5H), 1.04 (d, J = 11.2 Hz, 1H), 0.78 (s, 3H).

[0589] Step I: (R)-(2-(Benzofuran-3-yl)-1-((((2-(N,S-dimethylsulfimido)benzyl)oxy)carbonyl)amino)ethyl)boronic acid

[0590]

[0591] Dissolve 2-(Benzofuran-3-yl)-1-(R)-(3-acetylbenzenesulfonamido)ethyl boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (90 mg) in a mixed solvent of methanol (5 mL) and n-hexane (5 mL), add isobutylboronic acid (98 mg), 1 mol / L dilute hydrochloric acid (0.2 mL), and stir at room temperature overnight. Separate the methanol phase, wash it with n-hexane, collect the methanol phase, concentrate it under reduced pressure, and purify the residue by silica gel preparative plate (1:10 methanol / dichloromethane) to obtain the product (29 mg).

[0592] 1 H NMR(400MHz,CD 3OD) δ 7.93 - 7.96 (m, 1H), 7.65 - 7.69 (m, 2H), 7.52 - 7.59 (m, 2H), 7.48 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.21 - 7.26 (m, 1H), 7.16 (t, J = 7.6 Hz, 1H), 5.40 - 5.54 (m, 2H), 3.31 - 3.34 (m, 1H), 3.17 (s, 3H), 2.90 - 2.98 (m, 1H), 2.84 (dd, J = 14.8 Hz, 8.0 Hz, 1H), 2.59 (s, 3H).

[0593] Example 21

[0594] (R)-2-(Benzofuran-3-yl)-1-N-(3-(S-methylsulfinylimino)phenylmethoxyoxo)aminoethylboronic acid

[0595]

[0596] Step A: 3-(Methylthio)benzyl alcohol

[0597]

[0598] Under nitrogen protection, methyl 3-(methylthio)benzoate (1.82 g) was dissolved in anhydrous tetrahydrofuran (50 mL), cooled to 0 °C, and a toluene solution of 1 mol / L diisobutylaluminum hydride (30 mL) was added dropwise. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched with water, then 1 mol / L aqueous sodium hydroxide solution (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with 1 mol / L hydrochloric acid and saturated brine respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a colorless oily product (1.50 g), which was directly used in the next step.

[0599] 1 H NMR (400 MHz, CDCl 3 ) δ 7.22 - 7.28 (m, 2H), 7.16 (d, J = 7.2 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H), 4.65 (s, 2H), 2.47 (s, 3H).

[0600] Step B: 2-((3-(Methylthio)benzyl)oxy)tetrahydro-2H-pyran

[0601]

[0602] Dissolve 3-(methylthio)benzyl alcohol (1.50 g) in 3,4-dihydro-2H-pyran (20 mL), add pyridinium p-toluenesulfonate (100 mg), and stir overnight at room temperature. The reaction solution is directly concentrated to dryness, and the residue is purified by silica gel column chromatography (1:5 ethyl acetate / petroleum ether) to obtain the product (2.2 g).

[0603] 1 H NMR(400MHz,CDCl 3 )δ7.23 - 7.29(m,2H),7.13(d,J=7.6Hz,1H),7.11(d,J=7.6Hz,1H),4.62(s,2H),4.78 - 4.83(m,1H),3.75 - 3.96(m,1H),3.66 - 3.69(m,1H),2.44(s,3H),1.85 - 1.99(m,2H),1.67 - 1.78(m,3H),1.55 - 1.63(m,1H).

[0604] Step C: Imino(3 - ((((tetrahydro - 2H - pyran - 2 - yl)oxy)methyl)phenyl)-λ 6 -methyl sulfone

[0605]

[0606] Add 2 - ((3-(methylthio)benzyl)oxy)tetrahydro - 2H - pyran (1.5 g), iodobenzene diacetate (3.1 g), and ammonium carbamate (1.6 g) to methanol (100 mL), stir at room temperature for 2 hours, evaporate the solvent, and the residue is purified by silica gel column chromatography (1:10 methanol / dichloromethane) to obtain the product (1.3 g).

[0607] 1 H NMR(400MHz,CDCl 3 )δ8.07(d,J=8.0Hz,1H),7.98 - 8.03(m,1H),7.48(t,J=8.0Hz,1H),7.30(t,J=8.0Hz,1H),4.77 - 4.86(m,1H),4.45 - 4.71(m,2H),3.70 - 3.90(m,1H),3.55(t,J=5.6Hz,1H),3.46(s,3H),3.08 - 3.13(m,1H),1.84 - 1.98(m,2H),1.66 - 1.79(m,3H),1.55 - 1.63(m,1H).

[0608] Step D: Imino(3 - hydroxymethylphenyl)-λ 6 -methyl sulfone

[0609]

[0610] Imino(3 - ((((tetrahydro - 2H - pyran - 2 - yl)oxy)methyl)phenyl)-λ 6 -methylsulfone (1.0 g) and p - toluenesulfonic acid (100 mg) were dissolved in methanol (10 mL). After heating under reflux overnight, the solvent was removed by evaporation. The residue was dissolved in dichloromethane and washed with saturated NaHCO 3 aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:10 methanol / dichloromethane) to obtain the product (510 mg).

[0611] 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 4.77 (s, 2H), 3.11 (s, 3H).

[0612] Step E: (R)-2-(Benzofuran - 3 - yl)-1 - N-(3-(S - methylsulfonylimino)phenylmethoxyoxo)aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane - 2,3 - diol ester

[0613]

[0614] 2-(Benzofuran - 3 - yl)-1-(R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane - 2,3 - diol ester hydrochloride (300 mg) was dissolved in dichloromethane (5 mL). The solution was cooled to -78 °C, and triphosgene (100 mg) was added to the reaction solution. The mixture was stirred at this temperature for 30 minutes, and then a dichloromethane (2 mL) solution of imino(3 - hydroxymethylphenyl)-λ 6 -methylsulfone (200 mg) was added. The reaction was stirred at room temperature overnight. The reaction was quenched by adding water, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel preparative plate (1:20 methanol / dichloromethane) to obtain the product (208 mg).

[0615] 1 H NMR (400 MHz, CDCl 3)δ 7.98 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.50 - 7.59 (m, 3H), 7.41 - 7.44 (m, 2H), 7.16 - 7.20 (m, 1H), 5.10 - 5.21 (m, 3H), 4.28 (d, J = 8.0 Hz, 1H), 3.54 - 3.59 (m, 1H), 3.14 - 3.17 (m, 1H), 3.11 (s, 3H), 2.95 - 2.99 (m, 1H), 2.67 - 2.74 (m, 1H), 2.27 - 2.33 (m, 1H), 2.05 - 2.15 (m, 1H), 1.95 - 2.01 (m, 2H), 1.79 - 1.87 (m, 2H), 1.55 (s, 3H), 1.17 (s, 3H), 1.03 (d, J = 10.8 Hz, 1H), 0.79 (s, 3H).

[0616] Step F: (R)-2-(Benzofuran-3-yl)-1-N-(3-(S-methylsulfinylimino)phenylmethoxyoxo)aminoethylboronic acid

[0617]

[0618] Dissolve (R)-2-(benzofuran-3-yl)-1-N-(3-(S-methylsulfinylimino)phenylmethoxyoxo)aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (200 mg) in methanol (5 mL). Add isobutylboronic acid (215 mg), 1 mol / L hydrochloric acid (0.2 mL) and n-hexane (5 mL) to the reaction solution. Stir at room temperature overnight. Separate and remove the upper layer of n-hexane. Wash the methanol phase with n-hexane, concentrate under reduced pressure to obtain a crude product. Add ether for pulping, filter and collect the solid. Dry the solid to obtain the product (25 mg).

[0619] 1 H NMR (400 MHz, CD 3 OD) δ 8.11 - 8.5 (m, 2H), 7.90 (d, J = 8.0 Hz, 1H), 7.79 - 7.83 (m, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.17 - 7.27 (m, 2H), 5.21 (s, 2H), 3.90 (s, 3H), 3.28 - 3.25 (m, 3H), 2.92 - 2.98 (m, 1H), 2.83 - 2.88 (m, 1H).

[0620] Example 22

[0621] (R)-(2-(Benzofuran-3-yl)-1-(4-(2-methoxy-(dimethylsulfinimidyl)phenyl))acetamido)ethylboronic acid

[0622]

[0623] Step A: 4-(2-Methoxy-(dimethylsulfinimidyl)phenyl)acetonitrile

[0624]

[0625] Under nitrogen protection, dissolve 4-bromo-2-methoxyphenylacetonitrile (620 mg) in 1,4-dioxane (50 mL), and successively add dimethylsulfinimine (308 mg), tris(dibenzylideneacetone)dipalladium (125 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (238 mg) and cesium carbonate (1.7 g). Heat to 110 °C and stir overnight. Cool to room temperature, add water for dilution, extract with dichloromethane. The organic phase is washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel preparative plate (1:100 methanol / dichloromethane) to obtain the product (300 mg).

[0626] Step B: 4-(2-Methoxy-(dimethylsulfinimidyl)phenyl)acetic acid

[0627]

[0628] Dissolve 4-(2-methoxy-(dimethylsulfinimidyl)phenyl)acetonitrile (200 mg) in ethanol (10 mL), add 8 mol / L aqueous sodium hydroxide solution (1 mL), heat to 80 °C and stir for 2 hours. Cool to room temperature, add water for dilution, adjust the pH to 5 - 6 with 1 mol / L hydrochloric acid, extract with dichloromethane. The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the product (150 mg).

[0629] 1 H NMR(400MHz,DMSO-d 6 )δ11.68 - 12.28(brs,1H),6.91(d,J=7.6Hz,1H),6.42 - 6.47(m,2H),3.66(s,3H),3.35(s,2H),3.17(s,6H).

[0630] Step C: (R)-2-(Benzofuran-3-yl)-1-(4-(2-methoxy-(dimethylsulfinimidyl)phenyl))acetamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0631]

[0632] 4-(2-Methoxy-(dimethylsulfinimidophenyl))acetic acid (150 mg), 2-(benzofuran-3-yl)-1-((R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (219 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (332 mg), 4-dimethylaminopyridine (71 mg) and diisopropylethylamine (150 mg) were added to dry dichloromethane (20 mL). After completion, the mixture was stirred at room temperature overnight, quenched with water, and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel preparative plate (1:40 methanol / dichloromethane) to obtain the product (80 mg).

[0633] 1 H NMR (400 MHz, CDCl 3 ) δ 7.51 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.28 (td, J = 8.4 Hz, 1.2 Hz, 1H), 7.19 - 7.24 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 6.65 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.57 - 6.61 (brs, 1H), 6.54 (d, J = 1.6 Hz, 1H), 4.27 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 3.54 - 3.63 (m, 5H), 3.17 (s, 6H), 2.92 - 2.98 (m, 2H), 2.76 (dd, J = 15.6 Hz, 12.0 Hz, 1H), 2.32 - 2.40 (m, 1H), 2.12 - 2.19 (m, 1H), 2.03 (t, J = 5.6 Hz, 1H), 1.83 - 1.92 (m, 2H), 1.47 (d, J = 10.8 Hz, 1H), 1.40 (s, 3H), 1.29 (s, 3H), 0.88 (s, 3H).

[0634] Step D: (R)-(2-(Benzofuran-3-yl)-1-(4-(2-methoxy-(dimethylsulfinimidophenyl))acetamido)ethyl)boronic acid

[0635]

[0636] (R)-2-(Benzofuran-3-yl)-1-(4-(2-methoxy-(dimethylsulfinylimino)phenyl))acetamidoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (20 mg) was dissolved in methanol (5 mL). Isobutylboronic acid (55 mg), 1 mol / L hydrochloric acid (0.5 mL) and n-hexane (5 mL) were added to this solution. The mixture was stirred at room temperature overnight. The upper layer of n-hexane was removed by liquid separation. The methanol phase was washed with n-hexane and concentrated under reduced pressure to obtain a crude product, which was purified by trituration with diethyl ether to obtain the product (9 mg).

[0637] 1 H NMR(400MHz,CD 3 OD)δ7.55(d,J=8.0Hz,1H),7.52(s,1H),7.42(d,J=8.0Hz,1H),7.25(t,J=7.6Hz,1H),7.20(t,J=7.6Hz,1H),7.05-7.08(m,1H),6.64-6.69(m,2H),3.73(s,3H),3.54-3.66(m,2H),3.25(s,6H),2.84-2.96(m,2H),2.69(dd,J=14.8Hz,9.6Hz,1H).

[0638] Example 23

[0639] (R)-(2-(Benzofuran-3-yl)-1-(4-(3-chloro-(dimethylsulfinylimino)phenyl))propanamido)ethylboronic acid

[0640]

[0641] Step A: Methyl 4-(3-chloro-(dimethylsulfinylimino)phenyl)propionate

[0642]

[0643] Under nitrogen protection, methyl 4-(3-chloro-(dimethylsulfinylimino)phenyl)propionate (1.0 g) was dissolved in 1,4-dioxane (50 mL). Dimethylsulfinylimine (340 mg), tris(dibenzylideneacetone)dipalladium (165 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (313 mg) and cesium carbonate (2.3 g) were added successively. The temperature was raised to 110 °C and stirred overnight. After cooling to room temperature, water was added for dilution, and the mixture was extracted with dichloromethane. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel preparative plate (1:100 methanol / dichloromethane) to obtain the product (900 mg).

[0644] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.06 - 7.08 (m, 2H), 6.88 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 3.66 (s, 3H), 3.13 (s, 6H), 2.97 (t, J = 8.0 Hz, 2H), 2.60 (t, J = 8.0 Hz, 2H).

[0645] Step B: 4-(3-chloro-(dimethylsulfinimidoyl)phenyl)propanoic acid

[0646]

[0647] Dissolve methyl 4-(3-chloro-(dimethylsulfinimidoyl)phenyl)propionate (333 mg) in ethanol (10 mL), add 8 mol / L aqueous sodium hydroxide solution (1 mL), heat to 80 °C and stir for 2 hours. Cool to room temperature, dilute with water, adjust the pH to 5 - 6 with 1 mol / L hydrochloric acid, extract with dichloromethane, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the product (305 mg).

[0648] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 11.90 - 12.44 (brs, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 3.18 (s, 6H), 2.78 (t, J = 7.6 Hz, 2H), 2.45 (t, J = 7.6 Hz, 2H).

[0649] Step C: (R)-2-(benzofuran-3-yl)-1-(4-(3-chloro-(dimethylsulfinimidoyl)phenyl)propanamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0650]

[0651] 4-(3-chloro-(dimethylsulfinimidylphenyl))propanoic acid (100 mg), 2-(benzofuran-3-yl)-1-(R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (136 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (205 mg), 4-dimethylaminopyridine (44 mg) and diisopropylethylamine (93 mg) were added to dry dichloromethane (15 mL). After completion, the mixture was stirred at room temperature overnight, quenched with water, and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel preparative plate (1:40 methanol / dichloromethane) to obtain the product (80 mg).

[0652] 1 H NMR(400MHz,CDCl 3 )δ7.50(d,J=7.2Hz,1H),7.44(d,J=8.4Hz,1H),7.26-7.31(m,2H),7.21(t,J=8.0Hz,1H),7.04-7.07(m,2H),6.87(dd,J=8.0Hz,2.0Hz,1H),6.24(s,1H),4.27(dd,J=8.4Hz,2.0Hz,1H),3.04-3.14(m,7H),2.92-2.99(m,3H),2.75-2.82(m,1H),2.52(t,J=7.2Hz,2H),2.31-2.38(m,1H),2.12-2.20(m,1H),2.01(t,J=5.6Hz,1H),1.82-1.92(m,2H),1.42(d,J=10.8Hz,1H),1.38(s,3H),1.27(s,3H),0.86(s,3H).

[0653] Step D: (R)-(2-(benzofuran-3-yl)-1-(4-(3-chloro-(dimethylsulfinimidylphenyl))propanamido)ethyl)boronic acid

[0654]

[0655] (R)-2-(Benzofuran-3-yl)-1-(4-(3-chloro-(dimethylsulfoximidyl)phenyl)propanamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (80 mg) was dissolved in methanol (5 mL). Isobutylboronic acid (55 mg), 1 mol / L hydrochloric acid (0.5 mL) and n-hexane (5 mL) were added to this solution. The mixture was stirred overnight at room temperature. The upper n-hexane layer was separated off by liquid separation. The methanol phase was washed with n-hexane and concentrated under reduced pressure to obtain a crude product, which was purified by trituration with diethyl ether to give the product (40 mg).

[0656] 1 H NMR(400MHz,CD 3 OD)δ7.49(d,J=6.8Hz,1H),7.39-7.41(m,2H),7.17-7.27(m,2H),7.15(d,J=8.0Hz,1H),7.07(d,J=2.4Hz,1H),6.94(dd,J=8.0Hz,2.4Hz,1H),3.17(s,6H),2.98-3.07(m,2H),2.80-2.91(m,2H),2.67(t,J=7.2Hz,2H),2.56(dd,J=14.8Hz,10.0Hz,1H).

[0657] Example 24

[0658] (1R)-2-(Benzofuran-3-yl)-1-(2-(3-(N,S-dimethylsulfoximidyl)phenyl)acetamido)ethylboronic acid

[0659]

[0660] Step A: Methyl 3-(methylthio)benzoate

[0661]

[0662] 3-Mercaptobenzoic acid (5.0 g) was dissolved in anhydrous N,N-dimethylformamide (80 mL). The solution was cooled to 0 °C, and anhydrous potassium carbonate (22.5 g) and methyl iodide (18.5 g) were successively added thereto. After returning to room temperature, the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate (200 mL) and filtered through diatomaceous earth. The filtrate was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography (5% ethyl acetate / petroleum ether mixture) to give the product (5.6 g).

[0663] 1 H NMR(400MHz,CDCl 3)δ 7.89 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.30 - 7.34 (m, 1H), 3.89 (s, 3H), 2.50 (s, 3H).

[0664] Step B: 3-(Methylthio)benzyl alcohol

[0665]

[0666] Dissolve methyl 3-(methylthio)benzoate (1.82 g) in anhydrous tetrahydrofuran (50 mL). Under nitrogen protection, cool to 0 °C. Dropwise add a toluene solution of 1 mol / L diisopropylaluminum hydride (30 mL) to the system. After restoring to room temperature, stir for 3 hours. Slowly add ethyl acetate (150 mL) and 1 mol / L aqueous sodium hydroxide solution (70 mL) to the system in sequence. Separate the organic phase, dry it over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to evaporate the solvent to obtain the target product (1.51 g).

[0667] 1 H NMR (400 MHz, CDCl 3 )δ 7.47 - 7.50 (m, 1H), 7.24 - 7.26 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 4.65 (s, 2H), 2.47 (s, 3H).

[0668] Step C: (3-(Chloromethyl)phenyl)methyl sulfide

[0669]

[0670] Dissolve 3-(methylthio)benzyl alcohol (1.0 g) in dichloromethane (30 mL). Cool to 0 °C. Add phosphorus pentachloride (2.8 g) to the reaction system in batches. After restoring to room temperature, stir for 1 hour. Carefully add water (50 mL) to quench the reaction. Extract with dichloromethane. Separate the organic phase, dry it over anhydrous sodium sulfate, filter, and evaporate the solvent. Purify the residue by silica gel column chromatography (10% ethyl acetate / petroleum ether mixture) to obtain the product (1.3 g).

[0671] 1 H NMR (400 MHz, CDCl 3 )δ 7.35 - 7.32 (m, 1H), 7.28 - 7.30 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 4.67 (s, 2H), 2.49 (s, 3H).

[0672] Step D: 2-(3-(Methylthio)phenyl)acetonitrile

[0673]

[0674] Add (3-(Chloromethyl)phenyl)methyl sulfide (1.0 g), trimethylsilyl cyanide (0.7 g) and tetrabutylammonium fluoride trihydrate (1.86 g) to acetonitrile (10 mL), heat to 40 °C and stir overnight. After returning to room temperature, quench the reaction with water and extract with dichloromethane. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to evaporate the solvent, and purify the obtained residue by silica gel column chromatography (10% ethyl acetate / petroleum ether mixture) to obtain the product (1.1 g).

[0675] 1 H NMR (400 MHz, CDCl 3 ) δ 7.26 - 7.30 (m, 1H), 7.18 - 7.20 (m, 2H), 7.07 (d, J = 7.6 Hz, 1H), 3.71 (s, 2H), 2.48 (s, 3H).

[0676] Step E: 2-(3-(S-Methylsulfinyl)phenyl)acetonitrile

[0677]

[0678] Add 2-(3-(Methylthio)phenyl)acetonitrile (1.0 g), iodobenzene diacetate (0.8 g) and ammonium carbamate (0.25 g) to methanol (10 mL), and stir overnight at room temperature under an air atmosphere. Evaporate the solvent, and purify the obtained residue by silica gel column chromatography (2% - 10% methanol / dichloromethane mixture) to obtain the product (0.95 g).

[0679] 1 H NMR (400 MHz, CDCl 3 ) δ 9.23 (brs, 1H), 7.90 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.51 - 7.57 (m, 2H), 3.74 (s, 2H), 2.59 (s, 3H).

[0680] Step F: 2-(3-(N,S-Dimethylsulfinyl)phenyl)acetic acid

[0681]

[0682] 2-(3-(S-methylsulfinylimino)phenyl)acetonitrile (0.9 g) and paraformaldehyde (0.88 g) were mixed in formic acid (50 mL), and the mixture was heated to 105 °C and reacted for 72 hours. The solvent was evaporated to dryness, and the resulting residue was purified by silica gel column chromatography (10% methanol / dichloromethane mixture) to obtain the product (0.35 g).

[0683] 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (s, 1H), 7.83 - 7.92 (m, 1H), 7.54 - 7.61 (m, 2H), 3.77 (s, 2H), 3.21 (s, 3H), 2.63 (s, 3H).

[0684] Step G: (1R)-2-(benzofuran-3-yl)-1-(2-(3-(N,S-dimethylsulfinylimino)phenyl)acetamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0685]

[0686] 2-(3-(N,S-dimethylsulfinylimino)phenyl)acetic acid (100 mg) was dissolved in dichloromethane (10 mL), and 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (189 mg), N,N-diisopropylethylamine (89 mg), and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (165 mg) were added. The mixture was stirred at room temperature for 2 hours, quenched with water (20 mL), and extracted with dichloromethane. 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 resulting residue was purified by silica gel preparative plate (1:2 ethyl acetate / petroleum ether) to obtain the product (87 mg).

[0687] 1 H NMR (400 MHz, CDCl 3)δ 7.76 - 7.79 (m, 2H), 7.48 - 7.52 (m, 3H), 7.40 - 7.44 (m, 1H), 7.25 - 7.33 (m, 2H), 7.16 - 7.22 (m, 1H), 6.26 (s, 1H), 4.27 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 3.63 (s, 2H), 3.57 (s, 3H), 3.21 - 3.26 (m, 1H), 3.06 - 3.10 (m, 1H), 2.97 - 3.03 (m, 1H), 2.87 - 2.90 (m, 1H), 2.62 (s, 3H), 2.28 - 2.35 (m, 1H), 2.09 - 2.16 (m, 1H), 1.98 (t, J = 5.2 Hz, 1H), 1.79 - 1.87 (m, 1H), 1.31 (s, 3H), 1.26 (d, J = 12.4 Hz, 1H), 1.26 (s, 3H), 0.83 (s, 3H).

[0688] Step H: (1R)-2-(Benzofuran-3-yl)-1-(2-(3-(N,S-dimethylsulfoximidoyl)phenyl)acetamido)ethylboronic acid

[0689]

[0690] Dissolve (1R)-2-(benzofuran-3-yl)-1-(2-(3-(N,S-dimethylsulfoximidoyl)phenyl)acetamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (80 mg) in methanol (5 mL). Add isobutylboronic acid (80 mg), 1 mol / L hydrochloric acid (0.05 mL) and n-hexane (5 mL) to this solution. Stir at room temperature overnight. Separate and remove the upper layer of n-hexane. Wash the methanol phase with n-hexane, concentrate under reduced pressure, and recrystallize the residue from a dichloromethane / ether system to obtain the product (21 mg).

[0691] 1 H NMR (400 MHz, CD 3 OD) δ 7.91 (s, 1H), 7.87 (d, J = 6.8 Hz, 1H), 7.55 - 7.66 (m, 4H), 7.42 (d, J = 8.0 Hz, 1H), 7.25 - 7.28 (m, 1H), 7.18 - 7.24 (m, 1H), 3.89 (s, 2H), 3.31 (s, 3H), 3.02 - 3.06 (m, 1H), 2.90 (dd, J = 14.4 Hz, 4.8 Hz, 1H), 2.73 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 2.58 (s, 3H).

[0692] Example 25

[0693] (R)-2-(Benzofuran-3-yl)-1-(3-(4-(dimethylsulfinylimino)-3-chlorophenyl)propylamino)ethylboronic acid

[0694]

[0695] Step A: 3-(4-Bromo-3-chlorophenyl)acrylic acid

[0696]

[0697] 4-Bromo-3-chlorobenzaldehyde (2.2 g) and cyclopropylidenemalonic acid (2.16 g) were added to triethylamine (10.5 mL). After completion, the temperature was lowered to 0 °C, and formic acid (8.5 mL) was slowly added dropwise. After the addition was complete, the temperature was raised to 100 °C and the reaction was carried out overnight. The reaction solution was poured into ice water, and a large amount of solid precipitated. It was filtered, the filter cake was washed with ice water, the solid was collected, and dried under vacuum to obtain the product (1.9 g).

[0698] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.22 - 12.66 (br, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.52 (d, J = 16.0 Hz, 1H), 6.64 (d, J = 16.0 Hz, 1H).

[0699] Step B: Methyl 3-(4-bromo-3-chlorophenyl)acrylate

[0700]

[0701] 3-(4-Bromo-3-chlorophenyl)acrylic acid (1.9 g) was added to methanol (20 mL). The temperature was lowered to 0 °C, and thionyl chloride (2.6 g) was slowly added dropwise. After completion, the temperature was raised to 60 °C and the reaction was carried out for 2 hours. The reaction solution was distilled under reduced pressure to remove the solvent to obtain the product (1.9 g).

[0702] 1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 16.0 Hz, 1H), 7.24 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.42 (d, J = 16.0 Hz, 1H), 3.80 (s, 3H).

[0703] Step C: Methyl (4-(dimethylsulfinylimino)-3-chlorophenyl)acrylate

[0704]

[0705] Methyl 3-(4-bromo-3-chlorophenyl)acrylate (1.7 g), dimethylsulfoximide (846 mg), tris(dibenzylideneacetone)dipalladium (283 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (354 mg) and cesium carbonate (4.06 g) were added to 1,4-dioxane (20 mL). After purging with nitrogen, the temperature was raised to 100 °C and the reaction was carried out overnight. After cooling to room temperature, the insoluble matters were removed by filtration through diatomaceous earth. The filtrate was collected, and the solvent was removed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 3:4) to obtain the product (2 g). The product was confirmed by mass spectrometry, [M+H] + Signal 288.

[0706] Step D: Methyl (4-dimethylsulfoximidoyl-3-chlorophenyl)propionate

[0707]

[0708] Methyl (4-dimethylsulfoximidoyl-3-chlorophenyl)acrylate (1.7 g) and 5% platinum on carbon (500 mg) were added to methanol (20 mL). After that, hydrogen was purged six times, and the mixture was stirred at room temperature for 1 hour. The insoluble matters were removed by filtration through diatomaceous earth. The filtrate was collected, and the solvent was evaporated to dryness to obtain the product (1.7 g).

[0709] 1 H NMR (400 MHz, CDCl 3 ) δ 7.19 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.95 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 3.66 (s, 3H), 3.14 (s, 6H), 2.85 (t, J = 7.6 Hz, 2H), 2.58 (t, J = 7.6 Hz, 2H).

[0710] Step E: (4-Dimethylsulfoximidoyl-3-chlorophenyl)propionic acid

[0711]

[0712] Methyl (4-dimethylsulfoximidoyl-3-chlorophenyl)propionate (320 mg) and sodium hydroxide (133 mg) were added to methanol (10 mL) and water (3 mL). The temperature was raised to 60 °C and the reaction was carried out for 1 hour. The solvent was removed by concentration under reduced pressure. Water was added to adjust the pH to 5. The aqueous phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (220 mg).

[0713] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.21 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H), 6.96 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 3.15 (s, 6H), 2.87 (t, J = 7.6 Hz, 2H), 2.64 (t, J = 7.6 Hz, 2H).

[0714] Step F: (R)-2-(Benzofuran-3-yl)-1-(3-(4-dimethylsulfinimidoyl-3-chlorophenyl)propylamino)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0715]

[0716] Dissolve (4-dimethylsulfinimidoyl-3-chlorophenyl)propanoic acid (220 mg) in dry dichloromethane (15 mL), add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (394 mg), N,N-diisopropylethylamine (150 mg) and 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (450 mg), stir at room temperature for 2 hours, add water (20 mL), extract with dichloromethane, wash the organic phase with 1 mol / L hydrochloric acid and saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the obtained residue by silica gel preparative plate (30% ethyl acetate / dichloromethane) to obtain the product (100 mg).

[0717] 1 1H NMR (400 MHz, CDCl 3) δ 7.50 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.25 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.16 - 7.21 (m, 1H), 7.13 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.84 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 6.66 - 6.74 (br, 1H), 4.24 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 3.02 - 3.11 (m, 7H), 2.91 - 2.98 (m, 1H), 2.76 - 2.83 (m, 3H), 2.43 - 2.48 (m, 2H), 2.27 - 2.37 (m, 1H), 2.10 - 2.17 (m, 1H), 1.97 - 2.01 (m, 1H), 1.78 - 1.90 (m, 2H), 1.40 (d, J = 10.4 Hz, 1H), 1.36 (s, 3H), 1.25 (s, 3H), 0.84 (s, 3H).

[0718] Step G: (R)-2-(Benzofuran-3-yl)-1-(3-(4-dimethylsulfinimidoyl-3-chlorophenyl)propylamino)ethylboronic acid

[0719]

[0720] Dissolve (R)-2-(benzofuran-3-yl)-1-(3-(4-dimethylsulfinimidoyl-3-chlorophenyl)propylamino)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (100 mg) in methanol (10 mL). Add isobutylboronic acid (88 mg), 1 mol / L hydrochloric acid (0.3 mL) and n-hexane (10 mL) to this solution. Stir at room temperature overnight. Separate the layers and remove the upper n-hexane layer. Wash the methanol phase with n-hexane, concentrate under reduced pressure, and purify the residue by silica gel preparative plate (1:6 methanol / dichloromethane) to obtain the product (22 mg).

[0721] 1 H NMR (400 MHz, CD 3 OD) δ 7.49 (d, J = 7.6 Hz, 1H), 7.39 - 7.42 (m, 2H), 7.17 - 7.28 (m, 4H), 7.02 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 3.16 (s, 6H), 2.80 - 2.92 (m, 4H), 2.58 - 2.72 (m, 2H), 2.53 (dd, J = 14.8 Hz, 10.4 Hz, 1H).

[0722] Example 26

[0723] (R)-(2-(Benzofuran-3-yl)-1-(2-(4-(N,S-dimethylsulfamoylamino)phenyl)acetamido)ethyl)boronic acid

[0724]

[0725] Step A: Methyl 2-(4-(methylthio)phenyl)acetate

[0726]

[0727] At room temperature, 2-(4-(methylthio)phenyl)acetic acid (4 g) was dissolved in methanol (40 mL), thionyl chloride (1 mL) was added, and the mixture was refluxed overnight. The solvent was evaporated to dryness to obtain the product (4.1 g).

[0728] 1 H NMR (400 MHz, CDCl 3 ) δ 7.16 - 7.22 (m, 4H), 3.67 (s, 3H), 3.57 (s, 2H), 2.45 (s, 3H).

[0729] Step B: Methyl 2-(4-(S-methylsulfamoylamino)phenyl)acetate

[0730]

[0731] At room temperature, methyl 2-(4-(methylthio)phenyl)acetate (3.92 g), iodobenzene diacetate (19.3 g), and ammonium carbamate (7.8 g) were added to methanol (100 mL), and the mixture was stirred overnight with an open mouth. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column (1:20 methanol / dichloromethane) to obtain the product (3.1 g).

[0732] 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 3.70 - 3.75 (m, 5H), 3.12 (s, 3H).

[0733] Step C: 2-(4-(N,S-dimethylsulfamoylamino)phenyl)acetic acid

[0734]

[0735] At room temperature, methyl 2-(4-(S-methylsulfamoylamino)phenyl)acetate (1 g) and aqueous formaldehyde solution (2 mL) were added to formic acid (10 mL), and the mixture was heated to 105 °C and stirred overnight. The solvent was evaporated to dryness to obtain the product (900 mg).

[0736] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.73 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 3.68 (s, 2H), 3.07 (s, 3H), 2.42 (s, 3H).

[0737] Step D: (R)-2-(Benzofuran-3-yl)-1-(2-(4-(N,S-dimethylsulfamoylamino)phenyl)acetamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0738]

[0739] Referring to the method in Step D of Example 10, using 2-(4-(N,S-dimethylsulfamoylamino)phenyl)acetic acid (228 mg) and 2-(benzofuran-3-yl)-1-((R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (376 mg) as raw materials to obtain the product (100 mg).

[0740] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.77 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 7.2 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1H), 7.25 (s, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.03 (s, 1H), 4.29 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 3.61 (s, 2H), 3.20 - 3.27 (m, 1H), 2.97 - 3.07 (m, 4H), 2.88 (dd, J = 14.8 Hz, 10.0 Hz, 1H), 2.60 (s, 3H), 2.29 - 2.37 (m, 1H), 2.10 - 2.19 (m, 1H), 1.99 (t, J = 5.2 Hz, 1H), 1.79 - 1.92 (m, 2H), 1.32 (s, 3H), 1.27 (d, J = 12.4 Hz, 1H), 1.26 (s, 3H), 0.83 (s, 3H).

[0741] Step E: (R)-2-(Benzofuran-3-yl)-1-(2-(4-(N,S-dimethylsulfamoylamino)phenyl)acetamido)ethylboronic acid

[0742]

[0743] Refer to the method in Step E of Example 10, using (R)-2-(benzofuran-3-yl)-1-(2-(4-(N,S-dimethylsulfamoylamino)phenyl)acetamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (100 mg) as the raw material to obtain the product (30 mg).

[0744] 1 H NMR(400MHz,CD 3 OD)δ7.87(d,J=8.4Hz,2H),7.54-7.60(m,4H),7.43(d,J=8.0Hz,1H),7.24-7.29(m,1H),7.19-7.24(m,1H),3.85(s,2H),3.24(s,3H),3.02(dd,J=10.0Hz,5.2Hz,1H),2.89(dd,J=14.8Hz,5.2Hz,1H),2.72(dd,J=14.8Hz,10.0Hz,1H),2.58(s,3H).

[0745] Example 27

[0746] (((1R)-2-(benzofuran-3-yl)-1-((((3-(N,S-dimethylsulfamoylamino)benzyl)oxy)carbonyl)amino)ethyl)boronic acid

[0747]

[0748] Step A: Methyl 3-(S-methylsulfamoylamino)benzoate

[0749]

[0750] Add methyl 3-(methylthio)benzoate (1.0 g), iodobenzene diacetate (5.3 g) and ammonium carbamate (1.72 g) to methanol (20 mL), and stir overnight at room temperature under an air atmosphere. Evaporate the solvent, and purify the obtained residue by silica gel column chromatography (2%-10% methanol / dichloromethane mixture) to obtain the product (1.1 g).

[0751] 1 H NMR(400MHz,CDCl 3 )δ8.65(t,J=1.6Hz,1H),8.27(d,J=8.0Hz,1H),8.20(dd,J=8.0Hz,1.6Hz,1H),7.64(t,J=8.0Hz,1H),5.04(brs,1H),3.95(s,3H),3.13(s,3H).

[0752] Step B: Methyl 3-(N,S-dimethylsulfamoyl)benzoate

[0753]

[0754] Methyl 3-(S-methylsulfamoyl)benzoate (500 mg) and paraformaldehyde (210 mg) were mixed in formic acid (10 mL), and the mixture was heated to 105 °C and reacted for 72 hours. The solvent was evaporated to dryness, and the resulting residue was purified by silica gel column chromatography (10% methanol / dichloromethane mixture) to obtain the product (0.31 g).

[0755] 1 H NMR (400 MHz, CDCl 3 ) δ 8.53 (t, J = 1.6 Hz, 1H), 8.26 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 3.95 (s, 3H), 3.09 (s, 3H), 2.64 (s, 3H).

[0756] Step C: (3-(Hydroxymethyl)phenyl)(methyl)(methylimino)-λ 6 -sulfone

[0757]

[0758] Methyl 3-(N,S-dimethylsulfamoyl)benzoate (300 mg) was dissolved in anhydrous tetrahydrofuran (10 mL), and the solution was cooled to 0 °C under nitrogen protection. A toluene solution of 1 mol / L diisopropylaluminum hydride (4.0 mL) was added dropwise to the system. After returning to room temperature, the mixture was stirred until the reaction was complete. Ethyl acetate (50 mL) and 1 mol / L aqueous sodium hydroxide solution (30 mL) were slowly added to the system in sequence. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to evaporate the solvent to obtain the target product (105 mg).

[0759] 1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 4.79 (s, 2H), 3.08 (s, 3H), 2.62 (s, 3H), 1.83 (brs, 1H).

[0760] Step D: ((1R)-2-(Benzofuran-3-yl)-1-((((3-(N,S-dimethylsulfamoylamino)benzyl)oxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0761]

[0762] Under nitrogen protection, dissolve 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (200 mg) in dichloromethane (10 mL), cool to -60 °C, add a solution of triphosgene (63 mg) in dichloromethane (1 mL), slowly dropwise add a solution of triethylamine (214 mg) in dichloromethane (1 mL), maintain low-temperature stirring for 30 minutes, add (3-(hydroxymethyl)phenyl)(methyl)(methylimino)-λ 6 -sulfone (105 mg), warm back to room temperature, and stir for 1 hour. Quench the reaction with water and extract with dichloromethane. Wash the organic phase with 1 mol / L hydrochloric acid and saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the obtained residue by silica gel preparative plate (1:3 ethyl acetate / petroleum ether) to obtain the product (25 mg).

[0763] 1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (s, 1H), 7.52 - 7.60 (m, 4H), 7.42 - 7.44 (m, 2H), 7.23 - 7.27 (m, 1H), 7.18 (t, J = 7.6 Hz, 1H), 5.12 - 5.22 (m, 3H), 4.28 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 3.57 (q, J = 6.0 Hz, 1H), 3.12 - 3.17 (m, 1H), 3.08 (s, 3H), 2.95 - 3.01 (m, 1H), 2.64 (s, 3H), 2.27 - 2.33 (m, 1H), 2.08 - 2.14 (m, 1H), 1.96 (t, J = 6.0 Hz, 1H), 1.78 - 1.95 (m, 2H), 1.24 (s, 3H), 1.18 (s, 3H), 1.02 (d, J = 11.2 Hz, 1H), 0.79 (s, 3H).

[0764] Step E: ((1R)-2-(Benzofuran-3-yl)-1-((((3-(N,S-dimethylsulfamoylamino)benzyl)oxy)carbonyl)amino)ethyl)boronic acid

[0765]

[0766] Dissolve ((1R)-2-(benzofuran-3-yl)-1-((((3-(N,S-dimethylsulfamoylamino)benzyl)oxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (25 mg) in methanol (5 mL). Add isobutylboronic acid (37 mg), 1 mol / L hydrochloric acid (0.1 mL) and n-hexane (5 mL) to this solution. Stir at room temperature overnight. Separate the layers to remove the upper n-hexane layer, and wash the methanol phase with n-hexane. Concentrate under reduced pressure at 30 °C to obtain the product (11 mg).

[0767] 1 H NMR(400MHz,CD 3 OD)δ7.88(s,1H),7.83(d,J=7.6Hz,1H),7.60 - 7.64(m,2H),7.56(d,J=7.6Hz,1H),7.49(s,1H),7.40(d,J=7.6Hz,1H),7.16 - 7.26(m,2H),5.17(s,2H),3.32 - 3.34(m,1H),3.15(s,3H),2.92 - 2.97(m,1H),2.82 - 2.87(m,1H),2.56(s,3H).

[0768] Example 28

[0769] (R)-(2-(benzofuran-3-yl)-1-(2-(4-((dimethyl(oxy)-λ 6 -sulfamoyl)amino)-3-(dimethylamino)phenyl)acetamido)ethyl)boronic acid

[0770]

[0771] Step A: Methyl 4-bromo-3-(dimethylamino)benzoate

[0772]

[0773] Dissolve methyl 3-amino-4-bromobenzoate (5 g), paraformaldehyde (15.6 g), and sodium triacetoxyborohydride (23 g) in acetic acid (100 mL). Stir at room temperature for 96 hours. Dilute the reaction mixture with dichloromethane (800 mL) and wash the mixture with water (100 mL) three times. Wash the organic phase successively with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the resulting residue by silica gel column chromatography (1:5 ethyl acetate / petroleum ether) to obtain the product (3.56 g).

[0774] 1 H NMR(400MHz,CDCl 3) δ 7.72 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 3.89 (s, 3H), 2.82 (s, 6H).

[0775] Step B: (4-Bromo-3-(dimethylamino)phenyl)methanol

[0776]

[0777] Dissolve methyl 4-bromo-3-(dimethylamino)benzoate (1 g) in a mixed solvent of tetrahydrofuran (30 mL) and ethanol (1 mL). Slowly add a 4 mol / L solution of lithium borohydride in tetrahydrofuran (3.4 mL) at 0 °C. Raise the temperature to room temperature and stir overnight. Quench the reaction with methanol. Concentrate the mixed solution under reduced pressure. The resulting residue is purified by silica gel column (1:3 ethyl acetate / petroleum ether) to obtain the product (0.9 g).

[0778] 1 H NMR (400 MHz, CDCl 3 ) δ 7.51 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.86 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 4.63 (s, 2H), 2.79 (s, 6H), 1.68 - 1.79 (br, 1H).

[0779] Step C: 2-Bromo-5-(bromomethyl)-N,N-dimethylaniline

[0780]

[0781] Dissolve (4-bromo-3-(dimethylamino)phenyl)methanol (0.72 g) in dichloromethane (50 mL). Slowly add triphenylphosphine (1.05 g) and carbon tetrabromide (1.33 g) in sequence at 0 °C. Raise the temperature to room temperature and stir overnight. Concentrate the mixed solution under reduced pressure. The resulting residue is purified by silica gel column (1:30 ethyl acetate / petroleum ether) to obtain the product (476 mg).

[0782] 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 4.40 (s, 2H), 2.79 (s, 6H).

[0783] Step D: 2-(4-Bromo-3-(dimethylamino)phenyl)acetonitrile

[0784]

[0785] Dissolve 2-bromo-5-(bromomethyl)-N,N-dimethylaniline (0.72 g) in acetonitrile (35 mL). Sequentially and slowly add trimethylsilyl cyanide (0.27 mL) and tetrabutylammonium fluoride trihydrate (668 mg) at room temperature. Then raise the temperature to room temperature and stir overnight. Dilute the reaction solution with dichloromethane (150 mL), wash the mixed solution with water (50 mL) three times. The organic phase is successively washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel column (ethyl acetate / petroleum ether = 1:20) to obtain the product (290 mg).

[0786] 1 H NMR (400 MHz, CDCl 3 ) δ 7.52 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.81 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 3.68 (s, 2H), 2.80 (s, 6H).

[0787] Step E: 2-(4-((dimethyl(oxo)-λ 6 -sulfinylimino)amino)-3-(dimethylamino)phenyl)acetonitrile

[0788]

[0789] N 2 Under N protection, sequentially add 2-(4-bromo-3-(dimethylamino)phenyl)acetonitrile (100 mg), dimethylsulfinamide (80 mg), tris(dibenzylideneacetone)dipalladium(0) (20 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (37 mg) and cesium carbonate (280 mg) into 1,4-dioxane (10 mL). Raise the temperature to 110 °C and stir overnight. After returning to room temperature, filter through diatomaceous earth, concentrate the filtrate under reduced pressure. The obtained residue is purified by silica gel column (methanol / dichloromethane = 1:35) to obtain the crude product (83 mg).

[0790] 1 H NMR (400 MHz, CDCl 3 ) δ 7.18 (d, J = 7.6 Hz, 1H), 6.90 (s, 1H), 6.85 (d, J = 7.6 Hz, 1H), 3.65 (s, 2H), 3.21 (s, 6H), 2.84 (s, 6H).

[0791] Step F: 2-(4-((dimethyl(oxo)-λ 6 -sulfinylimino)amino)-3-(dimethylamino)phenyl)acetic acid

[0792]

[0793] 2-(4-((Dimethyl(oxo)-λ 6 -sulfinylimino)amino)-3-(dimethylamino)phenyl)acetonitrile (83 mg) was added to ethanol (10 mL), and an 8 mol / L aqueous sodium hydroxide solution (0.8 mL) was slowly added. The temperature was raised to 80 °C and stirred overnight. The pH was adjusted to 3 with 1 mol / L hydrochloric acid solution, and the mixture was extracted three times with dichloromethane (50 mL). The organic phases were combined, washed successively with saturated brine and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (100 mg) which was directly used in the next reaction.

[0794] Step G: (R)-(2-(Benzofuran-3-yl)-1-(2-(4-((dimethyl(oxy)-λ 6 -sulfonamido)amino)-3-(dimethylamino)phenyl)acetamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0795]

[0796] 2-(4-((Dimethyl(oxo)-λ 6 -sulfinylimino)amino)-3-(dimethylamino)phenyl)acetic acid (100 mg), (2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (138 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (210 mg), and N,N-diisopropylethylamine (0.13 mL) were successively added to dichloromethane (15 mL), and the mixture was stirred at room temperature for 0.5 h. The reaction was quenched with 1 mol / L hydrochloric acid (30 mL), and the mixed solution was washed with dichloromethane (50 mL). The layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel preparative plate (1:30 methanol / dichloromethane) to obtain the product (20 mg).

[0797] 1 H NMR (400 MHz, CDCl 3)δ 7.60 (s, 1H), 7.53 - 7.57 (m, 3H), 7.44 (d, J = 7.6 Hz, 1H), 7.21 - 7.29 (m, 3H), 5.65 (d, J = 5.2 Hz, 1H), 4.39 (d, J = 7.2 Hz, 1H), 3.12 - 3.16 (m, 2H), 2.60 - 2.94 (m, 15H), 2.28 - 2.38 (m, 1H), 2.15 - 2.23 (m, 1H), 2.01 (t, J = 5.6 Hz, 1H), 1.88 - 1.95 (m, 2H), 1.35 (s, 3H), 1.23 (s, 3H), 1.02 (d, J = 10.8 Hz, 1H), 0.80 (s, 3H).

[0798] Step H: (R)-(2-(Benzofuran-3-yl)-1-(2-(4-((Dimethyl(oxy)-λ 6 -Sulfonamido)amino)-3-(dimethylamino)phenyl)acetamido)ethyl)boronic acid

[0799]

[0800] Dissolve (R)-(2-(Benzofuran-3-yl)-1-(2-(4-((Dimethyl(oxy)-λ 6 -Sulfonamido)amino)-3-(dimethylamino)phenyl)acetamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (20 mg) in methanol (8 mL). Add isobutylboronic acid (21 mg), 1 mol / L hydrochloric acid (0.3 mL) and n-hexane (8 mL) to this solution. Stir at room temperature overnight. Separate and remove the upper n-hexane layer. Wash the methanol phase with n-hexane (20 mL). Concentrate under reduced pressure. Recrystallize the residue from n-hexane / dichloromethane to obtain the product (4 mg).

[0801] 1 H NMR (400 MHz, CD 3 OD) δ 7.57 - 7.64 (m, 4H), 7.44 (d, J = 7.6 Hz, 1H), 7.19 - 7.30 (m, 3H), 3.29 - 3.33 (m, 8H), 3.09 (dd, J = 8.8 Hz, 6.4 Hz, 1H), 2.99 (dd, J = 14.8 Hz, 6.0 Hz, 1H), 2.77 - 2.86 (m, 7H).

[0802] Example 29

[0803] (R)-2-(Benzofuran-3-yl)-1-(3-(2-(dimethylsulfinimidoyl)phenyl)propanamido)ethylboronic acid

[0804]

[0805] Step A: Ethyl 3-(2-(methylthio)phenyl)acrylate

[0806]

[0807] Under nitrogen protection, at 0 °C, triethyl phosphonoacetate (1.77 g) was dissolved in anhydrous tetrahydrofuran (50 mL). 60% sodium hydride (379 mg) was added portionwise. After stirring at room temperature for 30 minutes, a solution of 2-(methylthio)benzaldehyde (800 mg) in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched by slowly adding water (100 mL). The aqueous phase was extracted three times with dichloromethane (200 mL). The organic phase was then washed with saturated brine and concentrated to dryness under reduced pressure. The residue was purified by silica gel preparative plate (1:1 petroleum ether / dichloromethane) to obtain the product (1.3 g).

[0808] 1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (d, J = 16.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.29 - 7.34 (m, 2H), 7.15 - 7.19 (m, 1H), 6.36 (d, J = 16.0 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 2.46 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H).

[0809] Step B: Ethyl 3-(2-(methylthio)phenyl)propionate

[0810]

[0811] Under a hydrogen atmosphere, ethyl 3-(2-(methylthio)phenyl)acrylate (1.3 g) and Raney nickel (650 mg) were mixed in ethanol (30 mL) and stirred overnight at room temperature. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the product (1.28 g).

[0812] 1 H NMR (400 MHz, CDCl 3 ) δ 7.18 - 7.20 (m, 2H), 7.15 (d, J = 7.2 Hz, 1H), 7.06 - 7.10 (m, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.01 - 3.05 (m, 2H), 2.61 - 2.65 (m, 2H), 2.45 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H).

[0813] Step C: Ethyl 3-(2-(S-methylsulfinyl)phenyl)propionate

[0814]

[0815] Under an air atmosphere, ethyl 3-(2-(methylthio)phenyl)propionate (1.28 g), iodobenzene diacetate (5.61 g) and ammonium carbamate (2.26 g) were dissolved in ethanol (50 mL), and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by slowly adding water (200 mL), and the aqueous phase was extracted three times with dichloromethane. The organic phase was washed with saturated brine and concentrated to dryness under reduced pressure. The residue was purified by silica gel column (1:1 petroleum ether / ethyl acetate) to obtain the product (1.0 g).

[0816] 1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.36 - 7.40 (m, 2H), 4.11 (t, J = 7.2 Hz, 2H), 3.41 (t, J = 7.6 Hz, 2H), 3.17 (s, 3H), 2.67 - 2.80 (m, 2H), 1.22 (t, J = 7.6 Hz, 3H).

[0817] Step D: Ethyl 3-(2-(dimethylsulfinyl)phenyl)propionate

[0818]

[0819] Under nitrogen protection, ethyl 3-(2-(S-methylsulfinyl)phenyl)propionate (1.0 g) and paraformaldehyde (558 mg) were dissolved in formic acid (10 mL), and the mixture was heated to 105 °C and stirred for 5 hours. The reaction was quenched by slowly adding water (100 mL), and the aqueous phase was extracted three times with dichloromethane (100 mL). The organic phase was washed with saturated brine and concentrated to dryness under reduced pressure to obtain the product (507 mg).

[0820] 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (d, J = 7.6 Hz, 1H), 7.49 - 7.53 (m, 1H), 7.35 - 7.40 (m, 2H), 4.11 (q, J = 7.2 Hz, 2H), 3.40 - 3.48 (m, 1H), 3.30 - 3.38 (m, 1H), 3.13 (s, 3H), 2.63 - 2.79 (m, 5H), 1.21 (t, J = 7.2 Hz, 3H).

[0821] Step E: 3-(2-(dimethylsulfinyl)phenyl)propionic acid

[0822]

[0823] Ethyl 3-(2-(dimethylsulfonimidoyl)phenyl)propionate (234 mg) and sodium hydroxide (42 mg) were dissolved in a mixed solvent of tetrahydrofuran (12 mL) and water (3 mL), and the mixture was heated to 65 °C and stirred for 1 hour. After returning to room temperature, 1 mol / L dilute hydrochloric acid (5 mL) was added, and the reaction solution was extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the product (211 mg).

[0824] 1 H NMR (400 MHz, CDCl 3 ) δ 11.68 (brs, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.75 (t, J = 7.2 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 3.99 (s, 3H), 3.43 - 3.54 (m, 1H), 3.10 - 3.19 (m, 1H), 2.87 (t, J = 5.2 Hz, 2H), 2.78 (s, 3H).

[0825] Step F: (R)-2-(Benzofuran-3-yl)-1-(3-(2-(dimethylsulfinimidoyl)phenyl)propanamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0826]

[0827] 3-(2-(Dimethylsulfonimidoyl)phenyl)propanoic acid (152 mg) and (R)-2-(benzofuran-3-yl)-1-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (285 mg) were dissolved in dichloromethane (20 mL). 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (288 mg) and 4-dimethylaminopyridine (94 mg) were added successively, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding water (100 mL). The aqueous phase was extracted three times with dichloromethane, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel preparative plate (21:1 dichloromethane / methanol) to obtain the product (179 mg).

[0828] 1 H NMR (400 MHz, CDCl 3) δ 7.84 - 7.93 (m, 1H), 7.35 - 7.55 (m, 6H), 7.16 - 7.28 (m, 2H), 4.20 - 4.26 (m, 1H), 3.30 - 3.41 (m, 1H), 3.14 - 3.25 (m, 1H), 2.99 - 3.09 (m, 2.5H), 2.92 - 2.98 (m, 2.5H), 2.84 - 2.90 (m, 1H), 2.60 - 2.79 (m, 2H), 2.53 (s, 1.5H), 2.42 (s, 1.5H), 2.28 - 2.36 (m, 1H), 2.09 - 2.16 (m, 1H), 1.97 - 2.01 (m, 1H), 1.78 - 1.88 (m, 2H), 1.22 - 1.26 (m, 7H), 0.85 (s, 3H).

[0829] Step G: (R)-2-(Benzofuran-3-yl)-1-(3-(2-(dimethylsulfinimidoyl)phenyl)propanamido)ethylboronic acid

[0830]

[0831] (R)-2-(Benzofuran-3-yl)-1-(3-(2-(dimethylsulfinimidoyl)phenyl)propanamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (179 mg) was dissolved in a mixed solvent of methanol (10 mL) and n-hexane (10 mL). Isobutylboronic acid (163 mg) and 1 mol / L dilute hydrochloric acid (0.5 mL) were added successively, and the mixture was stirred at room temperature overnight. The reaction solution was extracted with methanol (20 mL), washed three times with n-hexane (20 mL), the methanol phase was collected, and concentrated under reduced pressure. The residue was purified by silica gel preparative plate (1:10 methanol / dichloromethane) to obtain the product (32 mg).

[0832] 1 H NMR (400 MHz, CD 3 OD) δ 7.92 (d, J = 8.0 Hz, 1H), 7.60 - 7.65 (m, 1H), 7.44 - 7.55 (m, 4H), 7.41 (d, J = 8.8 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 3.38 - 3.54 (m, 2H), 3.17 (s, 3H), 2.91 - 2.96 (m, 1H), 2.78 - 2.89 (m, 3H), 2.59 - 2.67 (m, 4H).

[0833] Example 30

[0834] ((1R)-2-(Benzofuran-3-yl)-1-((((6-(S-methylsulfinyl)pyridin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid

[0835]

[0836] Step A: 6-(Methylthio)picolonic acid

[0837]

[0838] Methyl 6-chloropicolinate (1.0 g), S-methylisothiourea sulfate (2.14 g) and cesium carbonate anhydrous (7.43 g) were mixed in dimethyl sulfoxide (25 mL). Under nitrogen protection, the mixture was heated to 85 °C and reacted overnight. After the reaction solution was restored to room temperature, water (30 mL) was added to quench the reaction, the pH was adjusted to 5 with 1 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (50% ethyl acetate / petroleum ether mixture) to obtain the product (0.8 g).

[0839] 1 H NMR (400 MHz, CDCl 3 ) δ 7.88 - 7.91 (m, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 2.62 (s, 3H).

[0840] Step B: (6-(Methylthio)pyridin-2-yl)methanol

[0841]

[0842] 6-(Methylthio)picolonic acid (750 mg) was dissolved in anhydrous tetrahydrofuran (20 mL). Under nitrogen protection, the solution was cooled to 0 °C. A toluene solution of 1 mol / L diisobutylaluminum hydride (14 mL) was added dropwise to the system. After restoring to room temperature, the mixture was stirred until the reaction was complete. Ethyl acetate (100 mL) and 1 mol / L aqueous sodium hydroxide solution (50 mL) were slowly added to the system in sequence. The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain the target product (320 mg).

[0843] 1 H NMR (400 MHz, CDCl 3 ) δ 7.43 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.65 (s, 2H), 3.92 (brs, 1H), 2.50 (s, 3H).

[0844] Step C: (6-(Hydroxymethyl)pyridin-2-yl)(imino)(methyl)-λ 6 -sulfone

[0845]

[0846] (6-(Methylthio)pyridin-2-yl)methanol (160 mg), iodobenzene diacetate (1.0 g) and ammonium carbamate (402 mg) were added to methanol (20 mL), and the mixture was stirred overnight at room temperature under an air atmosphere. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (2%-10% methanol / dichloromethane mixture) to obtain the product (182 mg).

[0847] 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 (d, J = 7.6 Hz, 1H), 7.92 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 4.84 (s, 2H), 3.24 (s, 3H), 2.98 (brs, 2H).

[0848] Step D: ((1R)-2-(Benzofuran-3-yl)-1-((((6-(S-Methylsulfinimido)pyridin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0849]

[0850] Under nitrogen protection, 2-(Benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (450 mg) was dissolved in dichloromethane (20 mL), cooled to -60 °C, and a solution of triphosgene (118 mg) in dichloromethane (5 mL) was added. A solution of triethylamine (404 mg) in dichloromethane (5 mL) was slowly added dropwise, and the mixture was stirred at low temperature for 30 minutes. (6-(Hydroxymethyl)pyridin-2-yl)(imino)(methyl)-λ 6 -sulfone (180 mg) was added, and the mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with water and extracted with dichloromethane. 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 resulting residue was purified by silica gel preparative plate (1:3 ethyl acetate / petroleum ether) to obtain the product (121 mg).

[0851] 1 H NMR (400 MHz, CDCl 3)δ8.01(d, J = 7.6 Hz, 1H), 7.89(t, J = 7.6 Hz, 1H), 7.56(d, J = 7.6 Hz, 1H), 7.43 - 7.49(m, 3H), 7.28(d, J = 8.0 Hz, 1H), 7.18 - 7.21(m, 1H), 5.23 - 5.34(m, 2H), 5.19(d, J = 6.0 Hz, 1H), 4.29(d, J = 8.8 Hz, 1H), 3.58(q, J = 6.4 Hz, 1H), 3.24(s, 3H), 3.12 - 3.17(m, 1H), 2.96 - 3.02(m, 1H), 2.27 - 2.34(m, 1H), 2.08 - 2.14(m, 1H), 1.97(t, J = 6.0 Hz, 1H), 1.79 - 1.89(m, 3H), 1.25(s, 3H), 1.19(s, 3H), 1.04(d, J = 11.2 Hz, 1H), 0.79(s, 3H).

[0852] Step E: ((1R)-2-(Benzofuran-3-yl)-1-((((6-(S-methylsulfinyl)pyridin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid

[0853]

[0854] Dissolve ((1R)-2-(Benzofuran-3-yl)-1-((((6-(S-methylsulfinyl)pyridin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (120 mg) in methanol (5 mL). Add isobutylboronic acid (115 mg), 1 mol / L hydrochloric acid (0.1 mL) and n-hexane (5 mL) to this solution. Stir at room temperature overnight. Separate and remove the upper layer of n-hexane. Wash the methanol phase with n-hexane and concentrate it at 30 °C to obtain the product (21 mg).

[0855] 1 H NMR(400 MHz, CD 3 OD)δ8.01 - 8.08(m, 2H), 7.59(d, J = 7.6 Hz, 1H), 7.54(d, J = 7.6 Hz, 1H), 7.53(s, 1H), 7.41(d, J = 8.0 Hz, 1H), 7.17 - 7.26(m, 2H), 5.21(s, 2H), 4.54 - 4.56(m, 1H), 3.36 - 3.40(m, 1H), 3.23(s, 3H), 2.94 - 2.99(m, 1H), 2.85 - 2.91(m, 1H).

[0856] Example 31

[0857] (R)-2-(Benzofuran-3-yl)-1-((((2-(S-methylsulfinimidoyl)benzyl)oxy)carbonyl)amino)ethylboronic acid

[0858]

[0859] Step A: 2-(S-methylsulfinimidoyl)benzyl alcohol

[0860]

[0861] Under nitrogen protection, imino(methyl)(2-((((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)-λ 6 -sulfone (2.16 g) and p-toluenesulfonic acid (207 mg) were dissolved in methanol (30 mL), and the mixture was stirred at 45 °C overnight. The reaction was quenched by adding water (100 mL), and the aqueous phase was extracted three times with dichloromethane (100 mL). The organic phase was washed with saturated brine (100 mL), concentrated under reduced pressure, and purified by silica gel preparative plate (1:30 methanol / dichloromethane) to obtain the product (130 mg).

[0862] Step B: (R)-2-(Benzofuran-3-yl)-1-((((2-(S-methylsulfinimidoyl)benzyl)oxy)carbonyl)amino)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0863]

[0864] (R)-2-(Benzofuran-3-yl)-1-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (330 mg) was dissolved in anhydrous dichloromethane, cooled to -60 °C, and a solution of triphosgene (104 mg) in dichloromethane (5 mL) and a solution of triethylamine (354 mg) in dichloromethane (5 mL) were added dropwise in sequence. After stirring at -60 °C for 30 minutes, a solution of 2-(S-methylsulfinimidoyl)benzyl alcohol (130 mg) in dichloromethane (5 mL) was added dropwise, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by adding water, and the aqueous phase was extracted three times with dichloromethane (100 mL). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel preparative plate (2:1 petroleum ether / ethyl acetate) to obtain the product (20 mg).

[0865] 1 H NMR(400MHz,CDCl 3)δ8.10(d,J=8.4Hz,1H),7.38-7.60(m,6H),7.14-7.28(m,2H),5.48-5.70(m,2H),5.11(d,J=6.0Hz,1H),4.24-4.29(m,1H),3.47-3.53(m,1H),3.24(s,3H),3.08-3.16(m,1H),2.92-2.98(m,1H),2.25-2.32(m,1H),2.06-2.11(m,1H),1.72-2.02(m,3H),1.29(s,3H),1.25(s,3H),1.04(d,J=11.2Hz,1H),0.78(s,3H).

[0866] Step C: (R)-2-(Benzofuran-3-yl)-1-((((2-(S-methylsulfinylimino)benzyl)oxy)carbonyl)amino)ethylboronic acid

[0867]

[0868] Dissolve (R)-2-(benzofuran-3-yl)-1-((((2-(S-methylsulfinylimino)benzyl)oxy)carbonyl)amino)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (20 mg) in a mixed solvent of methanol (5 mL) and n-hexane (5 mL). Successively add isobutylboronic acid (19 mg) and 1 mol / L dilute hydrochloric acid (0.25 mL), and stir at room temperature overnight. Separate the methanol phase by liquid separation, wash it three times with n-hexane (20 mL), and concentrate it under reduced pressure to dryness. The residue is purified by a silica gel preparative plate (1:10 methanol / dichloromethane) to obtain the product (3 mg).

[0869] 1 H NMR(400MHz,CD 3 OD)δ8.05-8.09(m,1H),7.59-7.67(m,2H),7.47-7.56(m,3H),7.39(d,J=7.6Hz,1H),7.23(t,J=7.6Hz,1H),7.16(t,J=7.6Hz,1H),5.46-5.62(m,2H),3.27-3.33(m,1H),3.18(s,3H),2.90-2.97(m,1H),2.81-2.87(m,1H).

[0870] Example 32

[0871] (((1R)-2-(Benzofuran-3-yl)-1-((((6-(N,S-dimethylsulfinylimino)pyridin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid

[0872]

[0873] Step A: (6-(Hydroxymethyl)pyridin-2-yl)(methylimino)(methyl)-λ 6 -sulfone

[0874]

[0875] Dissolve (6-(Hydroxymethyl)pyridin-2-yl)(imino)(methyl)-λ 6 -sulfone (50 mg) and paraformaldehyde (35 mg) in formic acid (10 mL), heat to reflux and stir overnight. Evaporate the solvent to dryness, and the resulting residue is purified by silica gel column chromatography (2%-10% methanol / dichloromethane mixture) to obtain the product (33 mg).

[0876] 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 (d, J = 7.2 Hz, 1H), 7.93 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 4.80 - 4.91 (m, 2H), 3.23 (s, 3H), 2.61 (s, 3H), 1.61 - 2.20 (br, 1H).

[0877] Step B: ((1R)-2-(Benzofuran-3-yl)-1-((((6-(N,S-Methylsulfinimidyl)pyridin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0878]

[0879] Under nitrogen protection, dissolve 2-(Benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (50 mg) in dichloromethane (5 mL), cool to -60 °C, add a solution of triphosgene (22 mg) in dichloromethane (5 mL), slowly dropwise add a solution of triethylamine (24 mg) in dichloromethane (5 mL), maintain low temperature and stir for 30 minutes, add (6-(Hydroxymethyl)pyridin-2-yl)(methylimino)(methyl)-λ 6 -sulfone (30 mg), warm to room temperature and stir for 1 hour. Quench the reaction with water, extract with dichloromethane, wash the organic phase with 1 mol / L hydrochloric acid and saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and the resulting residue is purified by silica gel preparative plate (1:3 ethyl acetate / petroleum ether) to obtain the product (25 mg).

[0880] 1 1H NMR (400 MHz, CDCl 3 ) δ 8.00 (d, J = 7.6 Hz, 1H), 7.90 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 6.8 Hz, 1H), 7.43 - 7.46 (m, 3H), 7.28 (d, J = 7.6 Hz, 1H), 7.18 - 7.27 (m, 1H), 5.24 - 5.34 (m, 2H), 4.29 (d, J = 8.0 Hz, 1H), 3.97 (d, J = 8.8 Hz, 1H), 3.57 - 3.59 (m, 1H), 3.24 (s, 3H), 3.14 - 3.16 (m, 1H), 2.97 - 3.02 (m, 1H), 2.61 (s, 3H), 2.42 - 2.47 (m, 1H), 2.28 - 2.34 (m, 1H), 2.16 - 2.30 (m, 1H), 1.97 - 1.99 (m, 1H), 1.79 - 1.91 (m, 1H), 1.26 (s, 3H), 1.20 (s, 3H), 1.03 (d, J = 11.2 Hz, 1H), 0.79 (s, 3H).

[0881] Step C: ((1R)-2-(Benzofuran-3-yl)-1-((((6-(N,S-dimethylsulfimido)pyridin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid

[0882]

[0883] Dissolve ((1R)-2-(benzofuran-3-yl)-1-((((6-(N,S-methylsulfimido)pyridin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (20 mg) in methanol (3 mL). Add isobutylboronic acid (25 mg), 1 mol / L hydrochloric acid (0.1 mL) and n-hexane (3 mL) to this solution. Stir at room temperature overnight. Separate and remove the upper n-hexane layer, and wash the methanol phase with n-hexane and then concentrate it at 30 °C to obtain the product (9 mg).

[0884] 1 1H NMR (400 MHz, CD 3OD) δ 8.27 (d, J = 4.4 Hz, 2H), 7.77 - 7.79 (m, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.54 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.17 - 7.27 (m, 2H), 5.25 (s, 2H), 3.93 - 3.98 (m, 1H), 3.30 - 3.33 (m, 1H), 3.23 (s, 3H), 2.85 - 2.96 (m, 1H), 2.74 (s, 3H).

[0885] Example 33

[0886] ((1R)-2-(Benzofuran-3-yl)-1-((((5-chloro-2-(N-methyl-ethylsulfonylimino)benzyl)oxy)carbonyl)amino)ethyl)boronic acid

[0887]

[0888] Step A: Methyl 5-chloro-2-(methylthio)-benzoate

[0889]

[0890] Dissolve methyl 5-chloro-2-mercapto-benzoate (1.0 g) in methanol (20 mL). After cooling to 0 °C, add sodium hydroxide (580 mg) and methyl iodide (1.03 g). Restore to room temperature and stir overnight. Quench the reaction with water (20 mL) and extract with dichloromethane. The organic phase is dried over anhydrous sodium sulfate and the solvent is evaporated to obtain the product (0.7 g).

[0891] 1 H NMR (400 MHz, CDCl 3 ) δ 7.96 (d, J = 1.6 Hz, 1H), 7.42 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H), 2.43 (s, 3H).

[0892] Step B: (5-Chloro-2-(methylthio)phenyl)methanol

[0893]

[0894] Dissolve methyl 5-chloro-2-(methylthio)benzoate (750 mg) in anhydrous tetrahydrofuran (20 mL), and cool it to 0 °C under nitrogen protection. Dropwise add a toluene solution of 1 mol / L diisopropylaluminum hydride (10 mL) to the system. After restoring to room temperature, stir until the reaction is complete, and then slowly add ethyl acetate (80 mL) and 1 mol / L aqueous sodium hydroxide solution (40 mL) to the system in sequence. Separate the organic phase, dry it with anhydrous sodium sulfate, and evaporate the solvent to obtain the target product (205 mg).

[0895] 1 H NMR(400MHz,CDCl 3 )δ7.39(d,J=1.6Hz,1H),7.21-7.24(m,1H),7.16(s,1H),4.69(s,2H),2.45(s,3H),2.20(brs,1H).

[0896] Step C: (4-Chloro-2-(hydroxymethyl)phenyl)(imino)(methyl)-λ 6 -sulfone

[0897]

[0898] Add (5-chloro-2-(methylthio)phenyl)methanol (170 mg), iodobenzene diacetate (870 mg) and ammonium carbamate (352 mg) to methanol (20 mL), and stir overnight at room temperature under an air atmosphere. The residue obtained by evaporating the solvent is purified by silica gel column chromatography (2%-10% methanol / dichloromethane mixture) to obtain the product (111 mg).

[0899] 1 H NMR(400MHz,CDCl 3 )δ7.82(d,J=8.4Hz,1H),7.43(dd,J=8.4Hz,2.0Hz,1H),7.36(d,J=2.0Hz,1H),4.61-4.74(m,2H),4.00(brs,1H),2.74(s,3H).

[0900] Step D: (4-Chloro-2-(hydroxymethyl)phenyl)(methylimino)(ethyl)-λ 6 -sulfone

[0901]

[0902] Add (4-chloro-2-(hydroxymethyl)phenyl)(imino)(methyl)-λ 6- Sulfone (110 mg) and anhydrous potassium carbonate (215 mg) were mixed in N,N-dimethylformamide (10 mL). After cooling to 0 °C, methyl iodide (230 mg) was added. The mixture was restored to room temperature and stirred overnight. The reaction was quenched by adding water (50 mL), and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue obtained was purified by silica gel column chromatography (10% methanol / dichloromethane mixture) to give the product (115 mg).

[0903] 1 H NMR(400MHz,CDCl 3 )δ7.84(d,J=8.4Hz,1H),7.52(d,J=2.0Hz,1H),7.46(dd,J=8.4Hz,2.0Hz,1H),4.73-4.82(m,2H),4.38(brs,1H),3.23-3.33(m,2H),2.76(s,3H),1.24(t,J=7.2Hz,3H).

[0904] Step E: ((1R)-2-(Benzofuran-3-yl)-1-((((5-chloro-2-(N-methyl-ethylsulfonylimino)benzyl)oxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester

[0905]

[0906] Under nitrogen protection, 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (145 mg) was dissolved in dichloromethane (10 mL). After cooling to -60 °C, a solution of triphosgene (38 mg) in dichloromethane (1 mL) was added, and a solution of triethylamine (130 mg) in dichloromethane (1 mL) was slowly added dropwise. The mixture was stirred at low temperature for 30 minutes, and (4-chloro-2-(hydroxymethyl)phenyl)(methylimino)(ethyl)-λ 6 - sulfone (80 mg) was added. The mixture was restored to room temperature and stirred for 1 hour. The reaction was quenched with water, and the mixture was extracted with dichloromethane. 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 obtained was purified by silica gel preparative plate (1:3 ethyl acetate / petroleum ether) to give the product (112 mg).

[0907] 1 H NMR(400MHz,CDCl 3)δ 7.84 (d, J = 8.4 Hz, 1H), 7.58 - 7.59 (m, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.41 - 7.45 (m, 3H), 7.18 - 7.28 (m, 2H), 5.39 - 5.55 (m, 2H), 5.16 (d, J = 6.4 Hz, 1H), 4.27 (d, J = 7.2 Hz, 1H), 3.49 - 3.54 (m, 1H), 3.45 (s, 2H), 3.27 (q, J = 7.6 Hz, 2H), 3.08 - 3.13 (m, 1H), 2.94 - 2.99 (m, 1H), 2.65 (s, 3H), 2.26 - 2.32 (m, 1H), 2.06 - 2.12 (m, 1H), 1.96 (t, J = 6.0 Hz, 1H), 1.76 - 1.86 (m, 3H), 1.23 (s, 3H), 1.16 (s, 3H), 1.04 (d, J = 10.8 Hz, 1H), 0.78 (s, 3H).

[0908] Step F: ((1R)-2-(Benzofuran-3-yl)-1-((((5-chloro-2-(N-methyl-ethylsulfonimidyl)benzyl)oxy)carbonyl)amino)ethyl)boronic acid

[0909]

[0910] Dissolve ((1R)-2-(benzofuran-3-yl)-1-((((5-chloro-2-(N-methyl-ethylsulfonimidyl)benzyl)oxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (112 mg) in methanol (5 mL). Add isobutylboronic acid (89 mg), 1 mol / L hydrochloric acid (0.3 mL) and n-hexane (5 mL) to this solution. Stir at room temperature overnight. Separate and remove the upper n-hexane layer. Wash the methanol phase with n-hexane and concentrate it at 30 °C to obtain the product (41 mg).

[0911] 1 H NMR (400 MHz, CD 3 OD) δ 7.83 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.67 (s, 1H), 7.53 - 7.56 (m, 2H), 7.48 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.13 - 7.23 (m, 2H), 5.35 - 5.46 (m, 2H), 3.29 - 3.33 (m, 2H), 2.95 - 3.01 (m, 1H), 2.82 - 2.88 (m, 1H), 2.58 (s, 3H), 2.56 - 2.57 (m, 1H), 1.12 - 1.17 (m, 3H).

[0912] Example 34

[0913] ((1R)-2-(Benzofuran-3-yl)-1-((((5-cyclopropyl-2-(N,S-dimethylsulfamoylamino)benzyl)oxy)carbonyl)amino)ethyl)boronic acid

[0914]

[0915] Step A: (5-Bromo-2-(methylthio)phenyl)methanol

[0916]

[0917] Dissolve methyl 5-bromo-2-(methylthio)benzoate (5.0 g) in anhydrous tetrahydrofuran (100 mL), cool to 0 °C, and add lithium aluminum hydride (1.1 g) portionwise to the reaction solution. After restoring to room temperature, stir for 1 hour. Carefully add ethyl acetate (100 mL) and 1 mol / L hydrochloric acid (150 mL) dropwise to the reaction solution. Separate the organic phase and dry it over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue is purified by silica gel column chromatography (10%-50% ethyl acetate / petroleum ether mixture) to obtain the product (4.1 g).

[0918] 1 H NMR (400 MHz, CDCl 3 ) δ 7.54 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 4.71 (s, 2H), 2.45 (s, 3H).

[0919] Step B: 2-((5-Bromo-2-(methylthio)benzyl)oxy)tetrahydro-2H-pyran

[0920]

[0921] Dissolve (5-bromo-2-(methylthio)phenyl)methanol (4.0 g), 3,4-dihydro-2H-pyran (10 mL), and p-toluenesulfonic acid monohydrate (15 mg) in tetrahydrofuran (50 mL), stir overnight at room temperature, and add ethyl acetate (100 mL) and 1 mol / L aqueous sodium hydroxide solution (70 mL) to the system. Separate the organic phase and dry it over anhydrous sodium sulfate. Evaporate the solvent, and the obtained residue is purified by silica gel column chromatography (10%-20% ethyl acetate / petroleum ether mixture) to obtain the target product (4.6 g).

[0922] 1 H NMR (400 MHz, CDCl 3)δ 7.56 (d, J = 1.6 Hz, 1H), 7.36 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 4.73 - 4.79 (m, 2H), 4.49 - 4.52 (m, 1H), 3.87 - 3.93 (m, 1H), 3.53 - 3.58 (m, 1H), 2.43 (s, 3H), 1.84 - 1.89 (m, 1H), 1.41 - 1.78 (m, 5H).

[0923] Step C: 2 - ((5 - cyclopropyl - 2 - (methylthio)benzyl)oxy)tetrahydro - 2H - pyran

[0924]

[0925] Mix 2 - ((5 - bromo - 2 - (methylthio)benzyl)oxy)tetrahydro - 2H - pyran (1.0 g), cyclopropylboronic acid (0.54 g), tetrakis(triphenylphosphine)palladium (0.36 g) and potassium carbonate (1.3 g) in toluene (50 mL). After thoroughly displacing nitrogen, heat under reflux overnight. After returning to room temperature, filter the reaction solution through diatomaceous earth, and purify the residue obtained by evaporating the solvent from the filtrate by silica gel column chromatography (10% - 20% ethyl acetate / petroleum ether mixture) to obtain the product (0.71 g).

[0926] 1 H NMR (400 MHz, CDCl 3 )δ 7.31 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.96 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 4.73 - 4.79 (m, 2H), 4.55 - 4.58 (m, 1H), 3.92 - 3.97 (m, 1H), 3.54 - 3.57 (m, 1H), 2.41 (s, 3H), 1.84 - 1.88 (m, 2H), 1.52 - 1.74 (m, 5H), 0.90 - 0.95 (m, 2H), 0.64 - 0.68 (m, 2H).

[0927] Step D: (4 - cyclopropyl - 2 - (((tetrahydro - 2H - pyran - 2 - yl)oxy)methyl)phenyl)(imino)(methyl)-λ 6 - sulfone

[0928]

[0929] 2-((5-Cyclopropyl-2-(methylthio)benzyl)oxy)tetrahydro-2H-pyran (700 mg), iodobenzene diacetate (2.43 g), and ammonium carbamate (982 mg) were added to methanol (20 mL), and the mixture was stirred overnight at room temperature under an air atmosphere. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (2%-10% methanol / dichloromethane mixture) to give the product (374 mg).

[0930] 1 H NMR(400MHz,CDCl 3 )δ7.97(dd,J=8.0Hz,6.0Hz,1H),7.30(d,J=10.8Hz,1H),7.08(dt,J=8.0Hz,2.4Hz,1H),4.99-5.16(m,2H),4.73-4.76(m,1H),3.86-3.91(m,1H),3.52-3.56(m,1H),3.17-3.18(m,3H),1.91-1.98(m,2H),1.53-1.73(m,5H),1.04-1.09(m,2H),0.75-0.79(m,2H).

[0931] Step E: (4-Cyclopropyl-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)(methylimino)(methyl)-λ 6 -sulfone

[0932]

[0933] (4-Cyclopropyl-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)(imino)(methyl)-λ 6 -sulfone (300 mg) was dissolved in anhydrous tetrahydrofuran (10 mL) and N,N-dimethylformamide (5 mL), cooled to 0 °C, 60% NaH solid (60 mg) was added to the system, and the mixture was stirred at 0 °C for half an hour. Methyl iodide (150 mg) was added. After the reaction solution was restored to room temperature, it was stirred overnight. The reaction was quenched by adding water (10 mL), and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to dryness, and the residue obtained was purified by silica gel column chromatography (2%-10% methanol / dichloromethane mixture) to give the product (213 mg).

[0934] 1 H NMR(400MHz,CDCl 3)δ 7.88 (t, J = 8.0 Hz, 1H), 7.34 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 4.93 - 5.06 (m, 2H), 4.73 - 4.74 (m, 1H), 3.86 - 3.91 (m, 1H), 3.53 - 3.57 (m, 1H), 3.12 - 3.26 (m, 3H), 2.63 - 2.65 (m, 3H), 1.92 - 1.98 (m, 2H), 1.54 - 1.85 (m, 5H), 1.04 - 1.09 (m, 2H), 0.75 - 0.80 (m, 2H).

[0935] Step F: (4 - cyclopropyl - 2 - (hydroxymethyl)phenyl)(methylimino)(methyl)-λ 6 -sulfone

[0936]

[0937] (4 - cyclopropyl - 2 - ((((tetrahydro - 2H - pyran - 2 - yl)oxy)methyl)phenyl)(methylimino)(methyl)-λ 6 -sulfone (210 mg) and p - toluenesulfonic acid monohydrate (20 mg) were mixed in methanol (15 mL) and stirred overnight at room temperature. The reaction was quenched by adding 1 mol / L aqueous sodium hydroxide solution (5 mL), and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to evaporate the solvent. The resulting residue was purified by silica gel preparative plate (5% methanol / dichloromethane mixture) to obtain the product (130 mg).

[0938] 1 H NMR (400 MHz, CDCl 3 )δ 7.82 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 7.11 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 4.69 - 4.85 (m, 2H), 3.12 (s, 3H), 2.75 (s, 3H), 1.89 - 1.95 (m, 1H), 1.03 - 1.08 (m, 2H), 0.75 - 0.79 (m, 2H).

[0939] Step G: ((1R)-2-(benzofuran - 3 - yl)-1-((((5 - cyclopropyl - 2-(N,S - dimethylsulfimido)benzyl)oxy)carbonyl)amino)ethyl)boronic acid - (1S,2S,3R,5S)-(+)-pinane - 2,3 - diol ester

[0940]

[0941] Under nitrogen protection, dissolve 2-(benzofuran-3-yl)-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester hydrochloride (245 mg) in dichloromethane (15 mL), cool to -60 °C, add a solution of triphosgene (64 mg) in dichloromethane (2 mL), slowly dropwise add a solution of triethylamine (220 mg) in dichloromethane (5 mL), maintain low-temperature stirring for 30 minutes, add (4-chloro-2-(hydroxymethyl)phenyl)(methylimino)(ethyl)-λ 6 -sulfone (130 mg), warm back to room temperature, and stir for 1 hour. Quench the reaction with water and extract with dichloromethane. Wash the organic phase with 1 mol / L hydrochloric acid and saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the resulting residue by silica gel preparative plate (1:3 ethyl acetate / petroleum ether) to obtain the product (55 mg).

[0942] 1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.39 - 7.43 (m, 2H), 7.19 - 7.22 (m, 1H), 7.14 - 7.16 (m, 1H), 5.09 - 5.27 (m, 3H), 4.46 (t, J = 11.2 Hz, 1H), 4.21 - 4.29 (m, 2H), 3.49 - 3.56 (m, 1H), 3.44 (s, 3H), 3.08 - 3.14 (m, 1H), 2.89 - 2.98 (m, 1H), 2.25 - 2.31 (m, 1H), 1.90 - 1.96 (m, 2H), 1.84 - 1.86 (m, 1H), 1.74 - 1.82 (m, 2H), 1.31 (d, J = 10.0 Hz, 1H), 1.23 (s, 3H), 1.17 (s, 3H), 0.99 - 1.06 (m, 3H), 0.78 (s, 3H), 0.74 - 0.76 (m, 2H).

[0943] Step H: ((1R)-2-(benzofuran-3-yl)-1-((((5-cyclopropyl-2-(N,S-dimethylsulfimidoyl)benzyl)oxy)carbonyl)amino)ethyl)boronic acid

[0944]

[0945] Dissolve ((1R)-2-(benzofuran-3-yl)-1-(((5-cyclopropyl-2-(N,S-dimethylsulfimido)benzyl)oxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester (50 mg) in methanol (5 mL). Add isobutylboronic acid (40 mg), 1 mol / L hydrochloric acid (0.1 mL) and n-hexane (5 mL) to this solution. Stir at room temperature overnight. Separate the layers and remove the upper n-hexane layer. Wash the methanol phase with n-hexane and concentrate under reduced pressure to obtain the product (11 mg).

[0946] 1H NMR(400MHz,CD 3 OD)δ7.92-7.96(m,1H),7.39-7.56(m,5H),7.22-7.26(m,1H),7.16-7.18(m,1H),5.25-5.43(m,2H),3.92(s,3H),2.85-2.91(m,3H),2.82(s,3H),2.08-2.12(m,1H),1.18-1.20(m,2H),0.86-0.89(m,2H).

[0947] Biological assay

[0948] 1. Determination of the enzymatic inhibitory activity of the compound against LMP7:

[0949] LMP7 is a catalytic subunit of the immunoproteasome. In this experiment, an enzymatic detection method platform was established using its hydrolase activity and used for the activity detection of the compound. Ac-ANW-AMC (Bonston Biochem, Cat#S-320) was used as the substrate for LMP7, and the amount of the fluorescent group AMC (7-Amino-4-methylcoumarin) released after hydrolysis could reflect the enzymatic activity. MOLT-4 cells are human acute lymphoblastic leukemia cells, which were identified as cells with high expression of LMP7. We established an enzymatic detection method for the compound against LMP7 using the MOLT-4 cell lysate as the enzyme source and detected the inhibitory activity (half inhibitory concentration, IC 50 ) of the compound.

[0950] MOLT-4 cells were cultured in RPMI-1640 (Biological Industries) medium containing 10% fetal bovine serum (Biological Industries) and 1% Pen Strep (Gibco) in a 75 cm 2 cell culture flask (Corning) (37 °C, 95% air and 5% CO 2) Passage 2 - 3 times a week. Collect 1x10 7 MOLT-4 cells, resuspend with 1 ml PBS (Solarbio), centrifuge at 3000 rpm for 5 minutes. Aspirate the supernatant. Resuspend the cells with 500 μl lysis buffer (20 mM Tris, pH 8.0, 5 mM EDTA, add Protease inhibitor (1:1000) and Phosphatase Inhibitor (1:100) when in use), and place on ice for 30 minutes. Sonicate the cells, 0.5S on, 0.5S off, sonication time 2.5S. Centrifuge at 12000 rpm, 4°C for 10 minutes. The supernatant is the cell lysate, and protein quantification is performed using the BCA method (Thermo, #23225).

[0951] The compound is serially diluted 5-fold with 100% DMSO, with a total of 9 concentrations. Take 2 μl of each concentration and add it to 48 μl of reaction buffer (20 mM Tris, pH 8.0, 0.5 mM EDTA) and mix well to be used as 4* compound (final concentrations are 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256, 0 nM). Prepare 4* MOLT-4 cell lysate with the reaction buffer, with a final concentration of 20 ng / μl, and 2* Ac-ANW-AMC, with a final concentration of 100 μM. Take 5 μl of the 4* compound and add it to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), add 5 μl of 4* cell lysate, centrifuge, and react in an incubator at 23°C for 1 hour. Add 10 μl of 2* Ac-ANW-AMC, centrifuge to start the reaction, and react in the dark at 23°C for 2 hours. After the reaction, read the signal value (excitation wavelength 345 nm / emission wavelength 445 nm) on a CLARIOstar Plus (purchased from BMG LRBTECH). The enzyme activity of each compound is measured at 9 concentrations, and the data is processed using GraphPad Prism software to calculate the half-inhibitory concentration of the compound against LMP7, that is, the IC 50 value.

[0952] 2. Determination of the enzymatic inhibitory activity of the compound against β5 enzyme:

[0953] β5 is a catalytic subunit of the proteasome. In this experiment, an enzymatic assay method platform was established using its hydrolase activity and was used for the activity detection of compounds. Ac-WLA-AMC (BonstonBiochem, Cat#S-330) was used as the substrate for β5, and the amount of the fluorescent group AMC (7-Amino-4-methylcoumarin) released after hydrolysis could reflect the enzymatic activity. HEK-293 is a human embryonic kidney cell line that constitutively expresses the proteasome and does not express the immunoproteasome. We established an enzymatic assay method for compounds against β5 using the HEK-293 cell lysate as the enzyme source and detected the inhibitory activity (half inhibitory concentration, IC 50 ) of the compounds. The enzymatic inhibitory activity of the compounds against β5 was used as a detection index for compound selectivity.

[0954] HEK-293 cells were cultured in a 75 cm 2 cell culture flask (Corning) with DMEM (Biological Industries) medium containing 10% fetal bovine serum (Biological Industries) and 1% Pen Strep (Gibco) at 37 °C in an atmosphere of 95% air and 5% CO 2 . The cells were passaged 2-3 times a week. 1 x 10 7 HEK-293 cells were collected, resuspended in 1 ml PBS (Solarbio), centrifuged at 3000 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, supplemented with Protease inhibitor (1:1000) and Phosphatase Inhibitor (1:100) when in use), and placed on ice for 30 minutes. The cells were sonicated with 0.5S on, 0.5S off for a total sonication time of 2.5S. Then centrifuged at 12000 rpm at 4 °C for 10 minutes. The supernatant was the cell lysate, and the protein concentration was quantified by the BCA method (Thermo, #23225).

[0955] The compound was serially diluted 5-fold with 100% DMSO to a total of 9 concentrations. For each concentration, 2 μl was taken and added to 48 μl of reaction buffer (20 mM Tris, pH 8.0, 0.5 mM EDTA) and mixed well to obtain 4× compound (final concentrations of 100000, 20000, 4000, 800, 160, 32, 6.4, 1.28, 0 nM) for later use. 4× HEK-293 cell lysate was prepared with the reaction buffer at a final concentration of 25 ng / μl, and 2× Ac-WLA-AMC at a final concentration of 20 μM. 5 μl of the 4× compound was added to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), 5 μl of 4× HEK-293 cell lysate was added, centrifuged, and reacted in an incubator at 23 °C for 1 hour. 10 μl of 2× Ac-WLA-AMC was added, centrifuged to initiate the reaction, and reacted in the dark at 23 °C for 2 hours. After the reaction, the signal value (excitation wavelength 345 nm / emission wavelength 445 nm) was read on a CLARIO star Plus (purchased from BMG LRBTECH). The enzyme activity was measured for each compound at 9 concentrations, and the data was processed using GraphPad Prism software to calculate the half-inhibitory concentration of the compound against β5, i.e., the IC 50 value.

[0956] The aforementioned "*" refers to multiplication, indicating a multiple.

[0957] The test results of some of the above compounds are shown in Table 1.

[0958] Table 1: In vitro activity test results of compounds

[0959]

[0960] 3. Determination of the cell activity of the compound:

[0961] MOLT-4 is a human acute lymphoblastic leukemia cell line, which has been identified as a cell line with high expression of LMP7. In this experiment, the compound was pre-incubated with MOLT-4, and Ac-ANW-AMC (BonstonBiochem, Cat# S-320) was used as the substrate of LMP7 to establish a method for detecting the enzyme activity of LMP7 in cells and to detect the inhibitory activity (half-inhibitory concentration, IC 50 ) of the compound.

[0962] Cells were seeded in 24-well plates (Corning) at a concentration of 1.5 x 105 cells / ml per well. The next day, the compounds were prepared. Starting from 2 mM, 5-fold serial dilutions were made with 100% DMSO, resulting in 8 concentrations. For each concentration of the compound, 2 μl was added to 1 ml of cell culture medium, and 1 ml of RPMI-1640 only (final FBS concentration 5%, v / v) was added to make up the volume. The compound and the cells were mixed well. After incubation in the incubator for 2 hours, the mixture was centrifuged at 2000 rpm for 8 minutes. The supernatant was discarded, and the cells were washed once with 2 ml of PBS (Solarbio) and centrifuged again to discard the supernatant. 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 just before use) and placed in the refrigerator at 4 °C for 45 minutes. Then, it was centrifuged at 2000 rpm for 2 min. The lysate from the 24-well plate was transferred to a 96-well plate and centrifuged at 2000 rpm at 4 °C for 15 min. The supernatant was the lysate. Protein quantification was performed using the BCA method (Thermo, #23225). 2* lysate was prepared with reaction buffer (20 mM Tris, pH 8.0, 0.5 mM EDTA) to a final concentration of 20 ng / μl. 2* Ac-ANW-AMC was prepared with reaction buffer to a final concentration of 100 μM. 10 μl of the 2* lysate was added to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), and 10 μl of 2* Ac-ANW-AMC was added. After centrifugation to start the reaction, the reaction was carried out at 23 °C in the dark for 1 hour. After the reaction, the signal value was read on a CLARIO starPlus (purchased from BMG LRBTECH) (excitation wavelength 345 nm / emission wavelength 445 nm). The enzyme activity was measured for each compound at 8 concentrations, and the data was processed using GraphPad Prism software to calculate the half-inhibitory concentration of the compound on the LMP7 hydrolase in MOLT-4 cells, i.e., the IC 50 value.

[0963] The aforementioned "*" refers to multiplication, indicating a multiple

[0964] Table 2: Results of cell activity tests of compounds

[0965]

[0966] 4. Pharmacokinetic studies of the compound in animals:

[0967] For the animal pharmacokinetic experiment, 3 healthy adult male rats, sourced from Beijing Vital River Laboratory Animal Technology Co., Ltd., were used. The compound was suspended in a 20% solution of sulfobutyl ether-β-cyclodextrin (W / W / V) with a solution concentration of 1 mg / mL. The administration volume was 5 mL / kg, and a single intragastric administration was performed at a dose of 5 mg / kg. The animals were fasted overnight before the experiment, with the fasting period ranging from 10 hours before dosing to 4 hours after dosing. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. The animals were lightly 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 heparin anticoagulant tube. The samples were centrifuged at 4200 rpm for 5 min at 4°C, and the plasma was transferred to a centrifuge tube and stored at -80°C until analysis. The plasma samples were analyzed using an acetonitrile protein precipitation method to extract the compound to be measured and the internal standard (warfarin or propranolol) from the rat plasma. The extract was analyzed by LC / MS / MS. The measured plasma concentration-time data of individual animals were analyzed using a non-compartmental model with WinNonlin (version 5.2.1; Pharsight Corporation) software to obtain the following pharmacokinetic parameters: maximum (peak) plasma drug concentration C max ; time to peak concentration T max ; half-life T 1 / 2 and the area under the plasma concentration-time curve extrapolated to infinite time AUC 0-inf .

[0968]

[0969] Industrial Applicability

[0970] The present invention relates to boric acid derivatives; the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, a pharmaceutical composition comprising these compounds, and the use of such compounds in the treatment of diseases related to lmp7, having good economic value and application prospects.

[0971]

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt or isomer thereof, wherein, R a and R b is H; X is a bond, -O-, or -NR 4 -; Y is a key or -(CR 4 R 5 ) m -; and X and Y are not simultaneously a bond; R 4 and R 5 is H; m is 1 or 2; R 2 is H; R 3 selected from C 6-10 aryl and C 5-10 heteroaryl; R 1 selected from C 3-8 heterocycloalkyl, C 6-10 aryl, and C 5-10 heteroaryl, wherein the heterocycloalkyl, aryl, and heteroaryl are each substituted with one of and are optionally substituted with halogen, -O-C 1-6 alkyl, -NR 9 R 8 or R 10 ; R 6a and R 6b each independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, and C 6-10 aryl; R 7 selected from H and C 1-6 alkyl; R 8 selected from C 1-6 alkyl; R 9 selected from H and C 1-6 alkyl; R 10 Selected from C 3-8 cycloalkyl group.

2. The following compound or a pharmaceutically acceptable salt or isomer thereof.

3. The following compound or a pharmaceutically acceptable salt or isomer thereof.

4. A pharmaceutical composition comprising the compound according to any one of claims 1 - 3, or a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable carrier.

5. Use of the compound according to any one of claims 1 - 3, or a pharmaceutically acceptable salt or isomer thereof, or the composition according to claim 4, in the manufacture of a medicament for the treatment of a disease associated with lmp7 activity.

6. The use according to claim 5, wherein the disease associated with lmp7 activity is multiple myeloma, acute myeloid leukemia, myelocytic leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, diffuse large B - cell lymphoma, plasmacytoma, follicular lymphoma, immunocytoma, breast cancer, liver cancer, colorectal cancer, ovarian cancer, esophageal cancer, lung cancer, head and neck cancer, pancreatic cancer, kidney cancer, gastric cancer, thyroid cancer, prostate cancer, bladder cancer, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, scleroderma, ankylosing 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 - Schönlein purpura, Alzheimer's disease (AD).

Images