Boronic acid compound and use thereof

Abstract

The present application provides a boronic acid compound and a use thereof, the structure of the boronic acid compound being as represented by formula I. The boronic acid compound provided by the present application has excellent proteasome inhibitory activity, and can be used for preparing a medicament for treating or preventing proteasome-related diseases, having excellent therapeutic effects on diseases comprising tumors and autoimmune diseases, while also having better oral drug exposure, and having significant advantages over the existing technology.

Description

A boric acid compound and its application Technical Field

[0001] This application belongs to the field of drug synthesis technology, specifically relating to a boric acid compound and its application. Background Technology

[0002] In eukaryotic cells, protein degradation is primarily mediated via the ubiquitination pathway, in which the protein to be degraded is linked to a polypeptide ubiquitin, and then the 26S proteasome degrades the ubiquitinated protein through three major proteolytic activities. In cells, proteasome-mediated degradation plays a crucial role in many cellular functional processes, such as major histocompatibility complex (MHC) antigen presentation (MHC), apoptosis, growth regulation, NF-κB activation, antigen processing, and pro-inflammatory signal transduction. The proteasome is a multimeric protein composed of seven subunits, existing in cells in two forms: the widely expressed constitutive proteasome and the immunoproteasome, primarily expressed in the immune inflammatory system. The two differ in the composition of their subunits: the constitutive proteasome contains a chymotrypsin-like active subunit (β5c), a caspase-like active subunit (β1c), and a trypsin-like active subunit (β2c); in the immunoproteasome, these three subunits are induced by INF-γ to transform into their corresponding immune subunits (β5i / LMP7, β1i / LMP2, and β2i / MECL1, respectively). Therefore, eukaryotic cells can have two proteasomes in different proportions.

[0003] The proteasome plays a crucial role not only in the presentation of class I MHC antigens but also in a variety of pathological conditions, including malignant tumors, inflammatory diseases, and autoimmune diseases. Current technologies have demonstrated the relationship between the proteasome and the occurrence and progression of these diseases. In particular, proteasome inhibition represents an important new strategy for cancer treatment. For example, King et al. described the important role of the ubiquitin-proteasome pathway in regulating the cell cycle, tumor growth, and metastasis (Science, 274: 1652-1659 (1996)).

[0004] While existing borate proteasome inhibitors have shown good activity against both the β5c and β5i subunits, their oral bioavailability is unsatisfactory. For example, the marketed proteasome inhibitor bortezomib cannot be used orally due to its low bioavailability.

[0005] Therefore, there is an urgent need in the existing technology for a better oral proteasome inhibitor. Summary of the Invention

[0006] This application provides a borate compound and its application. The borate compound provided in this application has excellent proteasome inhibitory activity and better oral drug exposure, which has significant advantages over the prior art.

[0007] In a first aspect, this application provides a boric acid compound or its tautomers, stereoisomers, polymers, solvates, or pharmaceutically acceptable salts, wherein the structure of the boric acid compound is shown in Formula I:

[0008] ;

[0009] R1 is selected from hydrogen, substituted or unsubstituted C. 1~10 Alkyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 6-10 aryl, substituted or unsubstituted 5-12 heteroaryl, substituted or unsubstituted 3-12 heterocyclic, substituted or unsubstituted bridged ring group, wherein the substituent is selected from (=O), -OCF3, -OCHF2, C 1~6 Alkyl, C 1~10 Alkoxy, C 3~6 Cycloalkyl, 3-12 heterocyclic, 6-10 aryl, 5-12 heteroaryl, 6-10 aryloxy, cyano, hydroxyl, sulfhydryl, amino or halogen;

[0010] R2 is selected from hydrogen or C. 1~6 alkyl;

[0011] R1 and R2 exist independently or are connected to each other, forming a substituted or unsubstituted 4- to 12-membered heterocycle together with L1 and the nitrogen atom. The substituents are selected from (=O), halogen, hydroxyl, cyano, amino, mercapto, or -(CO)-(CH2). 1~3 -OH, wherein the 4-12 membered heterocycles are not fused or are fused with benzene rings or 5-6 membered heteroaromatic rings;

[0012] R3 is selected from hydrogen or C. 1~6 Alkyl, C 1~10 Alkoxy, C 3~6 Cycloalkyl, 3-12-membered heterocyclic, 6-membered aryl, 5-6-membered heteroaryl, 6-10-membered aryloxy, cyano, hydroxyl, sulfhydryl, amino or halogen;

[0013] L1 is selected from -CH(R4)-, -N(R4)COCH2-, or -OCH2CH2-;

[0014] L2 is -CONH-CH(R5)-;

[0015] R4 and R5 are independently selected from hydrogen, substituted or unsubstituted C4. 1~10 Alkyl, substituted or unsubstituted benzyl, wherein the substituent is selected from cyano, hydroxyl, sulfhydryl, amino or halogen;

[0016] m and n are independently selected from 0, 1 or 2; when m is 0, L1 does not exist, and the two atoms connected to the two ends of L1 are directly connected; when n is 0, L2 does not exist, and the two atoms connected to the two ends of L2 are directly connected.

[0017] The boric acid compounds with the above-mentioned specific structures have excellent proteasome inhibitory activity and better oral drug exposure, which are significant advantages over existing technologies.

[0018] Preferably, n is 1, and the structure of the boric acid compound is shown in Formula II:

[0019] ;

[0020] R5 is selected from hydrogen, substituted or unsubstituted C. 1~10 Alkyl, substituted or unsubstituted benzyl, wherein the substituent is selected from cyano, hydroxy, sulfhydryl, amino or halogen; R1, R2, R3, L1, m have the same limiting range as above;

[0021] Preferably, R5 is selected from hydrogen, isobutyl or benzyl.

[0022] Preferably, n is 0, and the structure of the boric acid compound is shown in Formula III:

[0023] ;

[0024] R1, R2, R3, L1, and m have the same limited range as described above.

[0025] Preferably, R2 is hydrogen;

[0026] Preferably, R1 is selected from hydrogen, substituted or unsubstituted C. 1~6 Alkyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 6-10 aryl, substituted or unsubstituted 5-12 heteroaryl, substituted or unsubstituted 3-12 heterocyclic, substituted or unsubstituted bridged ring group, wherein the substituent is selected from (=O), -OCF3, -OCHF2, C 1~6 Alkyl, C 1~10 Alkoxy, C 3~6 Cycloalkyl, 6-10 aryl, hydroxyl, amino or halogen;

[0027] Preferably, R1 is selected from any of the following structures:

[0028]

[0029] Preferably, R1 and R2 are interconnected and together with L1 and the nitrogen atom form any one of the following structures:

[0030]

[0031] Preferably, R2 is selected from hydrogen, L1 is selected from -CH(R4)-, -N(R4)COCH2- or -OCH2CH2-, and R4 has the same defined range as described above;

[0032] Preferably, L1 is selected from -CH2-, -CH(CH3)-, and -NHCOCH2-.

[0033] Preferably, the boric acid compound is selected from any one of the following structures:

[0034]

[0035]

[0036]

[0037] Secondly, this application provides a pharmaceutical composition comprising, as described above, boric acid compounds or their pharmaceutically acceptable salts.

[0038] Thirdly, this application provides the use of the borate compounds or their pharmaceutically acceptable salts as described above in the preparation of proteasome inhibitors.

[0039] Fourthly, this application also provides the use of the borate compounds or their pharmaceutically acceptable salts as described above in the preparation of medicaments for the treatment or prevention of proteasome-related diseases.

[0040] Preferably, the disease includes tumors and autoimmune diseases.

[0041] Preferably, the diseases include multiple myeloma, acute myeloid leukemia, myeloid cell 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, stomach cancer, thyroid cancer, prostate cancer, bladder cancer, systemic lupus erythematosus (SLE), lupus nephritis (LN), inflammatory bowel disease (IBD), rheumatoid arthritis, multiple sclerosis, scleroderma, adhesive capsulitis, atherosclerosis, Behcet's disease, Crohn's disease, inflammatory bowel disease, ulcerative colitis, autoimmune hepatitis, Sjögren's syndrome, asthma, amyotrophic lateral sclerosis (ALS), psoriasis, immunoglobulin A nephropathy, allergic purpura, or Alzheimer's disease (AD).

[0042] In this document, the compounds in Formula I include either a single stereoisomer or a mixture of isomers in different proportions.

[0043] As is known to those skilled in the art, the salts, solvates, hydrates, and boric acid polymers of a compound are alternative forms of boric acid compounds, and they can all be converted into the compound under certain conditions. Therefore, it is particularly noteworthy that when a compound is mentioned herein, its pharmaceutically acceptable salt is generally also included, and further included, its solvates, hydrates, and boric acid polymers.

[0044] The pharmaceutically acceptable salts described in this application can be formed using, for example, inorganic or organic acids: “Pharmaceutically acceptable salt” means a salt that, within a reasonable medical judgment, is suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and has a reasonable benefit / risk ratio. The salts can be prepared in situ during the final separation and purification of the compounds of this application, or solely by reacting a free base or free acid with a suitable reagent, as outlined below. For example, the free base functional group can react with a suitable acid. Furthermore, when the compounds of this application contain an acidic moiety, suitable pharmaceutically acceptable salts may include metal salts, such as alkali metal salts (e.g., sodium or potassium salts) and alkaline earth metal salts (e.g., calcium or magnesium salts). Examples of pharmaceutically usable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by using other methods in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disaccharide, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-enolate, glyceryl phosphate, gluconate, heptarate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pyrate, pectinate, persulfate, 3-phenylpropionate, phosphate, bitter salts, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Other medicinal salts include (where appropriate) non-toxic ammonium salts, quaternary ammonium salts, and ammonium cations formed by counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0045] In addition, this application also provides a method for preventing and / or treating proteasome-related diseases, which includes administering the compound or pharmaceutical composition of this application to a mammal (including a human) in need of such treatment.

[0046] The term "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group, for example, C 1~3 Alkyl groups refer to straight-chain or branched saturated hydrocarbon groups containing 1 to 3 carbon atoms, C 1~6 Alkyl groups refer to straight-chain or branched saturated hydrocarbon groups containing 1 to 6 carbon atoms, C 1~10 Alkyl groups refer to straight-chain or branched saturated hydrocarbon groups containing 1 to 10 carbon atoms.

[0047] The term "alkoxy" refers to an alkyl-O- group. 1~6 The term "alkoxy" is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. Similarly, "alkylthio" or "thioalkoxy" refers to an alkyl group as defined above that has a specified number of carbon atoms and is linked by a sulfur bridge; for example, methyl-S- and ethyl-S-. Preferred alkoxy groups herein are C1, C2, C3, C4, C5, and C6 alkoxy groups. 1~6 Alkyl group.

[0048] The term "cycloalkyl" refers to a non-aromatic carbocyclic group, including cyclic alkyl groups. Cycloalkyl groups can include monocyclic, bicyclic, or polycyclic systems. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., C 3~6 Cycloalkyl refers to cycloalkyl groups containing 3 to 6 carbon atoms.

[0049] The term "heterocyclic alkyl" or "heterocyclic group" refers to a non-aromatic heterocyclic group in which one, two, or three cyclic carbon atoms are substituted with heteroatoms such as O, N, or S atoms. Heterocyclic alkyl groups preferably have 3, 4, 5, 6, or 7 cyclic atoms. Preferred heterocyclic groups in this document are C16-3 ... 3-8 Heterocyclic group.

[0050] The term "benzyl" refers to benzyl. A substituted benzyl group is one in which at least one hydrogen atom on the benzyl ring is replaced by a non-hydrogen moiety. Substituents for benzyl can be halogens, -CN, -OH, -SH, -NH2, or C. 1-6 alkyl.

[0051] Term "C" 1~3 "Alkyl heterocyclic group" refers to an aromatic heterocyclic group or a non-aromatic heterocyclic group that has been substituted onto a saturated hydrocarbon group containing 1 to 3 carbon atoms, including cyclic alkyl groups, wherein one or more cyclic carbon atoms are substituted with heteroatoms such as O, N, or S atoms. Heterocyclic alkyl groups preferably have 3, 4, 5, 6, or 7 cyclic atoms.

[0052] “C 1~10 "Alkoxy" refers to an -O-alkyl group. Alkyl groups include straight-chain, branched, and cyclic alkyl groups, with 1 to 10 carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy, isopropoxy, and cyclopropoxy), tert-butoxy, etc.

[0053] "Aryl" refers to an aromatic carbocyclic group, including monocyclic, bicyclic, tricyclic, or polycyclic aromatic hydrocarbons, such as phenyl, naphthyl, anthracene, phenanthrene, etc. Aryl groups are preferably monocyclic, bicyclic, or tricyclic ring systems having 5 to 12 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. "Substituted aryl" refers to an aryl group in which at least one hydrogen atom on the benzene ring is replaced by a non-hydrogen moiety; the substituents in the aryl group can be halogens, carbonyl groups ... 1~10 Alkoxy, -CN, -OH, -SH, -NH2, C 1~6 Alkyl groups. Preferred aryl groups include phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, etc. Fused aryl groups can be attached to another group at a suitable position on a cycloalkyl ring or aromatic ring. Example: Dashed lines drawn from a ring system indicate that the bond can be attached to any suitable ring atom.

[0054] The term "heteroaryl" refers to a stable 5-12 membered aromatic monocyclic, bicyclic, or polycyclic heterocycle that is fully or partially unsaturated and contains a carbon atom and one, two, three, or four heteroatoms independently selected from N, O, and S. It includes 5-, 6-, or 7-membered aromatic monocyclic rings or 8-, 9-, 10-, 11-, or 12-membered aromatic bicyclic or polycyclic heterocycles; preferably, any heterocycle defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or, if defined, another substituent). The heterocycle may be attached to its side group at any heteroatom or carbon atom to obtain a stable structure. If the resulting compound is stable, the heterocyclic group described herein may be substituted at the carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other.Examples of aromatic heteroyl groups include, but are not limited to, acridine, aziridine, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophene, benzooxazolyl, benzooxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisooxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazole, 4aH-carbazole, carbolinyl, chromanyl, chromenyl, cenyl, decahydroquinolinyl, dihydrofurano[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazoalkyl, imidazolinyl, imidazolyl, 1H-indazole, imidazopyridyl, dihydroindole, indazinyl, indoleyl, 3H-indoleyl. Isobenzofuranyl, isochoryl, isoindazole, isodihydroindole, isoindole, isoquinolinyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, diazanaphthyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolylalkyl, oxazolyl, oxazolopyridyl, oxazolyl, naphthalene-intercalated diazaphenyl, hydroxyindoleyl, pyrimidinyl, phenanthidyl, phenanthrololinyl, phenazinyl, phenothiazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, piperazine, piperidinyl, piperidine Keto, 4-piperidinone, piperin, pteridin, purine, pyran, pyrazin, pyrazolyl, pyrazolinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridinium-imidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrololinyl, 2-pyrrolidone, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quininecycloyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl Diazolyl, thiazolyl, thiazolyl, thienyl, thiazopyridyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthonyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, 1H-inzolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 2,3-dihydro-benzofuranyl, 1,2,3,4-tetrahydroquinoxalinyl and 1,2,3,4-tetrahydroquinazolinyl. The term "heteroaryl" may also include biaryl structures formed by an "aryl" as defined above and a monocyclic "heteroaryl", such as, but not limited to, "-phenylbipyridinyl-", "-phenylbipyrimidinyl", "-pyridylbiphenyl", "-pyridylbipyrimidinyl-", and "-pyrimidinylbiphenyl-".

[0055] "Aryloxy group" refers to -O-aryl, and the concept of aryl is as described above. The most preferred example of aryloxy group is phenoxy group.

[0056] The term "bridged cycloalkyl" refers to polycyclic compounds sharing two or more carbon atoms, including bicyclic bridged cycloalkyls and polycyclic bridged cycloalkyls. The former consists of two alicyclic rings sharing two or more carbon atoms; the latter is a bridged cycloalkyl composed of three or more rings. Preferred bridged cycloalkyls in this document are selected from adamantylalkyl and adamantane-1-yl-methyl.

[0057] Halogens include fluorine, chlorine, bromine, and iodine.

[0058] Compared with the prior art, this application has the following beneficial effects:

[0059] This application provides a boric acid compound with a specific structure that exhibits excellent proteasome inhibition and better oral drug exposure, demonstrating significant advantages over existing technologies. Detailed Implementation

[0060] To further illustrate the technical means and effects adopted in this application, the following describes the technical solution of this application in conjunction with preferred embodiments, but this application is not limited to the scope of the embodiments.

[0061] Compound Synthesis

[0062] The following examples provide the structures and synthetic methods of borate compounds.

[0063] Key intermediate fragment BB1: (R)-2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)ethyl-1-amine hydrochloride

[0064]

[0065]

[0066] Implementation steps:

[0067] Step 1: (R,E)-2-methyl-N-(2-phenylethylidene)propane-2-sulfinamide

[0068]

[0069] Phenylacetaldehyde (4.40 g, 20.0 mmol) and (R)-2-methylpropane-2-sulfinamide (2.43 g, 20.0 mmol) were dissolved in dry tetrahydrofuran (40 mL), followed by the slow addition of tetraethyl titanate (7.7 mL, 40.0 mmol). The reaction mixture was stirred at 20 °C for 6 hours. After the reaction was complete, water (60 mL) was added to the reaction mixture, and stirring was continued for 30 minutes. The insoluble matter was filtered off, and the filtrate was extracted with ethyl acetate (60 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (eluent: 10% ethyl acetate in petroleum ether) to give a colorless liquid (3.50 g, 78%).

[0070]

[0071]

[0072] Step 2: (R)-2-methyl-N-((R)-2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)ethyl)propane-2-sulfinamide

[0073]

[0074] (R,E)-2-methyl-N-(2-phenylethylene)propane-2-sulfinamide (3.50 g, 15.7 mmol) was dissolved in 1,4-dioxane (35 mL), followed by the addition of 4-methoxybenzylamine (107 mg, 0.78 mmol), tricyclohexylphosphine tetrafluoroborate (69 mg, 0.19 mmol), and an aqueous solution of copper sulfate (6.3 mL, 0.03 M, 0.19 mmol). After the reaction mixture was cooled to 0°C, pinacol diborate (5.97 g, 23.5 mmol) was added in portions. The reaction mixture was slowly heated to 20°C under nitrogen protection and stirred for 8 hours. After the reaction was complete, the reaction mixture was poured into water (40 mL), extracted with ethyl acetate (30 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (elution buffer: petroleum ether solution of 35% dichloromethane) to give a colorless liquid (3.30 g, 60%).

[0075]

[0076] Step 3: (R)-2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)ethyl-1-amine hydrochloride

[0077]

[0078] (R)-2-methyl-N-((R)-2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)ethyl)propane-2-sulfinamide (250 mg, 0.72 mmol) was dissolved in methanol (5 mL), and then a dioxane solution of hydrogen chloride (0.9 mL, 4 M, 3.55 mmol) was added. The reaction mixture was stirred at 20 °C for 10 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the crude product was slurried with tert-butyl methyl ether (2 mL) to give a yellow solid (210 mg, 99%).

[0079]

[0080]

[0081] Key intermediate fragment BB2: (R)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-2-(p-tolyl)ethyl-1-amine hydrochloride

[0082]

[0083]

[0084] Implementation steps:

[0085] Step 1: 2-(p-Tolyl)acetaldehyde

[0086]

[0087] 2-(p-Tolyl)ethanol-1-ol (1.36 g, 10.0 mmol) was dissolved in dichloromethane (25 mL), and then Dysmart reagent (4.67 g, 11.0 mmol) was added in three portions at 0 °C. The reaction mixture was stirred at 20 °C for 2 hours. After the reaction was complete, saturated sodium thiosulfate solution (30 mL) was added to quench the reaction mixture, and the mixture was stirred for 30 minutes. The organic phase was washed successively with saturated sodium bicarbonate solution (30 mL × 2) and saturated sodium chloride solution (30 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a colorless liquid (1.10 g, 82%).

[0088]

[0089] Step 2: (R,E)-2-methyl-N-(2-(p-tolyl)ethylidene)propane-2-sulfinamide

[0090]

[0091] 2-(p-Tolyl)acetaldehyde (1.10 g, 8.2 mmol) and (R)-2-methylpropane-2-sulfinamide (1.20 g, 9.8 mmol) were dissolved in dry tetrahydrofuran (20 mL), followed by the slow addition of tetraethyl titanate (3.4 mL, 16.4 mmol). The reaction mixture was stirred at 20 °C for 6 hours. After the reaction was complete, water (50 mL) was added to the reaction mixture, and stirring was continued for 30 minutes. The insoluble matter was filtered off, and the filtrate was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (eluent: 10% ethyl acetate in petroleum ether solution) to give a yellow liquid (1.10 g, 57%).

[0092]

[0093]

[0094] Step 3: (R)-2-methyl-N-((R)-1-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-2-(p-tolyl)ethyl)propane-2-sulfinamide

[0095]

[0096] (R,E)-2-methyl-N-(2-(p-tolyl)ethylene)propane-2-sulfinamide (1.10 g, 3.01 mmol) was dissolved in 1,4-dioxane (20 mL), followed by the addition of 4-methoxybenzylamine (32 mg, 0.23 mmol), tricyclohexylphosphine tetrafluoroborate (21 mg, 0.056 mmol), and an aqueous solution of copper sulfate (1.9 mL, 0.3 M, 0.056 mmol). After cooling the reaction mixture to 0 °C, pinacol diborate (1.76 g, 6.94 mmol) was added in portions. The reaction mixture was slowly heated to 20 °C under nitrogen protection and stirred for 8 hours. After the reaction was complete, the reaction mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (elution buffer: petroleum ether solution of 20% ethyl acetate) to give a colorless liquid (1.35 g, 80%).

[0097]

[0098]

[0099] Step 4: (R)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2-(p-tolyl)ethyl-1-amine hydrochloride

[0100]

[0101] (R)-2-methyl-N-((R)-1-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-2-(p-tolyl)ethyl)propane-2-sulfinamide (250 mg, 0.71 mmol) was dissolved in methanol (5 mL), followed by the addition of a dioxane solution of hydrogen chloride (0.9 mL, 4 M, 3.55 mmol). The reaction mixture was stirred at 20 °C for 10 minutes. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was slurried with tert-butyl methyl ether (2 mL) to give a yellow solid (210 mg, 99%).

[0102]

[0103]

[0104] Key intermediate fragment BB3: (R)-2-([1,1'-biphenyl]-4-yl)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl-1-amine hydrochloride

[0105]

[0106] The same procedure as fragment BB2 was followed, except that the corresponding 2-(p-tolyl)ethanol was replaced with 2-([1,1'-biphenyl]-4-yl)ethanol-1-ol to obtain the title compound.

[0107]

[0108]

[0109] Key intermediate fragment BB4: (S)-2-amino-N-((R)-3-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)butyl)-3-phenylpropionamide hydrochloride

[0110]

[0111]

[0112] Implementation steps:

[0113] Step 1: ((S)-1-(((R)-3-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)butyl)amino)-1-oxo-3-phenylprop-2-yl)tert-butyl carbamate

[0114]

[0115] At 0 °C, diisopropylethylamine (906 mg, 7.0 mmol) was added to a solution of BB4-a: (R)-1-amino-3-methylbutane-1-boronic acid pinacol ester hydrochloride (500 mg, 2.0 mmol), BB4-b: Boc-L-phenylalanine (638 mg, 2.4 mmol), and TBTU (O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate) (772 mg, 2.4 mmol) in dichloromethane (15 mL). The reaction mixture was slowly heated to 20 °C and stirred for 6 hours. After the reaction was complete, the reaction solution was diluted with water (10 mL), extracted with dichloromethane (10 mL × 2), and the organic phase was washed successively with saturated sodium bicarbonate solution (30 mL × 2) and saturated sodium chloride solution (30 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid (630 mg, 68%).

[0116]

[0117] Step 2: (S)-2-amino-N-((R)-3-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)butyl)-3-phenylpropionamide hydrochloride

[0118]

[0119] Fragment BB4-a: ((S)-1-(((R)-3-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)butyl)amino)-1-oxo-3-phenylprop-2-yl)carbamate tert-butyl ester (630 mg, 1.37 mmol) was dissolved in ethyl acetate (5 mL), followed by the addition of an ethyl acetate solution of hydrogen chloride (5.0 mL, 2 M, 10.0 mmol). The reaction mixture was stirred at 20 °C for 10 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure. The crude product was slurried with tert-butyl methyl ether (2 mL) to give a yellow solid (446 mg, 82%).

[0120]

[0121] Key intermediate fragment BB5: (S)-2-amino-3-phenyl-N-((R)-2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)ethyl)propionamide hydrochloride

[0122]

[0123] The procedure is the same as for fragment BB4, except that BB4-a is replaced with BB1 to obtain the title compound.

[0124]

[0125] Example 1 (Implementation Method 1): (R)-(1-(2-(benzylamino)-2-oxoacetamide)-2-phenylethyl)boronic acid

[0126]

[0127]

[0128] Implementation Method 1: Implementation Steps:

[0129] Step 1: N-Benzyloxalamide monoethyl ester

[0130]

[0131] Oxaloyl chloride monoethyl ester (7.30 g, 53.7 mmol) and triethylamine (10.85 g, 161.1 mmol) were added dropwise to a solution of dichloromethane (45 mL) containing benzylamine (5.00 g, 53.7 mmol) under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. After the reaction was complete, the reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (150 mL × 2). The combined organic layers were washed with saturated sodium chloride aqueous solution (160 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid (10.05 g, 90%).

[0132]

[0133] Step 2: (R)-N 1 -Benzyl-N 2 -(2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)ethyl)oxalamide

[0134]

[0135] Diisopropylethylamine (119 mg, 920 μmol) was added to a solution of N-benzyloxamyl monoethyl ester (95 mg, 460 μmol) and fragment BB1:(R)-2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)ethyl-1-amine hydrochloride (130 mg, 460 μmol). The reaction mixture was stirred at 20 °C for 9 hours. After the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 2). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown solid (61 mg, 32%).

[0136] Step 3: (R)-(1-(2-(benzylamino)-2-oxoacetamide)-2-phenylethyl)boronic acid

[0137]

[0138] (R)-N 1 -Benzyl-N 2 1,41 mg (4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)ethyl)oxalamide (41 mg, 100 μmol) and isobutylboronic acid (31 mg, 306 μmol) were dissolved in methanol (3 mL), and then a dioxane solution of hydrogen chloride (0.13 mL, 4 M, 500 μmol) was added to the reaction solution. The reaction solution was stirred at 20 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL), and extracted with dichloromethane (20 mL × 2). The combined organic layers were washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative thin-layer chromatography (chromatographic solvent: 9% methanol in dichloromethane solution) to give a white solid (9 mg, 28%).

[0139]

[0140]

[0141] Example 2 (Implementation Method Two): ((1R)-1-(2-oxo-2-(((tetrahydrofuran-2-yl)methyl)amino)acetamido)-2-phenylethyl)boronic acid

[0142]

[0143]

[0144] Implementation Method Two: Implementation Steps:

[0145] Step 1: 2-oxo-2-(((tetrahydrofuran-2-yl)methyl)amino)ethyl acetate

[0146]

[0147] Tetrahydrofurfurylamide (5.00 g, 49.4 mmol) and triethylamine (15.00 g, 148.3 mmol) were added dropwise to a solution of oxaloyl chloride monoethyl ester (6.75 g, 49.4 mmol) in dichloromethane (50 mL) under ice bath conditions. The reaction mixture was stirred in an ice bath for 1 hour. After the reaction was complete, the reaction solution was diluted with water (100 mL) and extracted with dichloromethane (100 mL x 2). The combined organic layers were washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid (8.90 g, 90%).

[0148]

[0149] Step 2: 2-oxo-2-(((tetrahydrofuran-2-yl)methyl)amino)acetic acid

[0150]

[0151] Lithium hydroxide monohydrate (1.15 g, 27.28 mmol) was added to a solution of ethyl 2-oxo-2-(((tetrahydrofuran-2-yl)methyl)amino)acetate (5.00 g, 24.8 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at 20 °C for 3 h. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and the pH was adjusted to approximately 3–4 with dilute hydrochloric acid (3 N), followed by extraction with dichloromethane (100 mL x 2). The combined organic layers were washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid (3.86 g, 90%).

[0152]

[0153] Step 3: N 1 -((R)-2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)ethyl)-N 2 -((tetrahydrofuran-2-yl)methyl)oxalamide

[0154]

[0155] Diisopropylethylamine (125 mg, 970 μmol) was added to a solution of 2-oxo-2-(((tetrahydrofuran-2-yl)methyl)amino)acetic acid (67.2 mg, 380 μmol), fragment BB1:(R)-2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)ethyl-1-amine hydrochloride (80 mg, 320 μmol), and HATU (135 mg, 350 μmol) in dichloromethane (10 mL). The reaction mixture was stirred at 20 °C for 9 hours. After the reaction was complete, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 2). The combined organic layers were washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid (41.6 mg, 32%).

[0156] Step 4: ((1R)-1-(2-oxo-2-(((tetrahydrofuran-2-yl)methyl)amino)acetamido)-2-phenylethyl)boronic acid

[0157]

[0158] N 1 -((R)-2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)ethyl)-N 2 1,4-(tetrahydrofuran-2-yl)methyl)oxalamide (40 mg, 100 μmol) and isobutylboronic acid (31 mg, 306 μmol) were dissolved in methanol (2 mL), and then a dioxane solution of hydrogen chloride (0.1 mL, 4 M, 400 μmol) was added to the reaction solution. The reaction solution was stirred at 20 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with water (10 mL), and extracted with dichloromethane (10 mL x 2). The combined organic layers were washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative thin-layer chromatography (chromatographic solvent: 9% methanol in dichloromethane solution) to give a white solid (8.96 mg, 28%).

[0159]

[0160] Example 3 (Implementation Method 3): ((1R)-1-(2-((1-(3-methoxyphenyl)ethyl)amino)-2-oxoacetamide)-2-phenylethyl)boronic acid

[0161]

[0162]

[0163] Implementation Method 3: Implementation Steps:

[0164] Step 1: (R)-2-oxo-2-((2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)ethyl)amino)ethyl acetate

[0165]

[0166] Oxaloyl chloride monoethyl ester (217 mg, 1.60 mmol) and diisopropylethylamine (704 μL, 3.97 mmol) were added dropwise to a solution of dichloromethane (5 mL) containing fragment BB1:(R)-2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)ethyl-1-amine hydrochloride (450 mg, 1.59 mmol) under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 3 hours. After the reaction was complete, the reaction mixture was diluted with water (25 mL) and extracted with dichloromethane (25 mL × 2). The combined organic layers were washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid (500 mg, 91%).

[0167]

[0168] Step 2: (R)-(1-(2-ethoxy-2-oxoacetamido)-2-phenylethyl)boronic acid

[0169]

[0170] Ethyl (R)-2-oxo-2-((2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)ethyl)amino)ethyl acetate (500 mg, 1.44 mmol) and isobutylboronic acid (440 mg, 4.32 mmol) were dissolved in methanol (4 mL). A dioxane solution of hydrogen chloride (1.8 mL, 4 M, 7.20 mmol) was then added to the reaction mixture. The reaction mixture was stirred at 20 °C for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, diluted with water (20 mL), and extracted with dichloromethane (20 mL x 2). The combined organic layers were washed with a saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative chromatography (eluent: 30%–40% aqueous acetonitrile) to give a white solid (270 mg, 71%).

[0171]

[0172] Step 3: ((1R)-1-(2-((1-(3-methoxyphenyl)ethyl)amino)-2-oxoacetamide)-2-phenylethyl)boronic acid

[0173]

[0174] 1-(3-methoxyphenyl)ethyl-1-amine (29 mg, 192 μmol) was added to a solution of dichloromethane (1 mL) containing (R)-(1-(2-ethoxy-2-oxoacetamido)-2-phenylethyl)boronic acid (50 mg, 189 μmol). The reaction mixture was stirred at 20 °C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by reversed-phase preparative chromatography (mobile phase: 30%–60% aqueous acetonitrile) to give a white solid (20 mg, 29%).

[0175]

[0176]

[0177] Example 4: ((1R)-1-(2-oxo-2-((tetrahydrofuran-3-yl)amino)acetamide)-2-phenylethyl)boronic acid

[0178]

[0179] The method is the same as in Method 1, except that the starting material 3-aminotetrahydrofuran is used to replace the corresponding benzylamine to obtain the title compound.

[0180] LC-MS m / z: 289.0 [M-17] + .

[0181] Example 5: (R)-(1-(2-oxo-2-((pyrazin-2-ylmethyl)amino)acetamide)-2-phenylethyl)boronic acid

[0182]

[0183] The method is the same as in Method 1, except that the starting material 2-methylaminopyrazine is replaced with the corresponding benzylamine to obtain the title compound.

[0184]

[0185]

[0186] Example 6: (R)-(1-(2-((2,6-dichlorobenzyl)amino)-2-oxoacetamide)-2-(p-tolyl)ethyl)boronic acid

[0187]

[0188] The implementation method is the same as Method 2, except that the starting material 2,6-dichlorobenzylamine is used to replace the corresponding benzylamine, and fragment BB1 is used to replace fragment BB2 to obtain the title compound.

[0189]

[0190] Example 7: (R)-(1-(2-oxo-2-((2-oxo-2-(phenylamino)ethyl)amino)acetamide)-2-phenylethyl)boronic acid

[0191]

[0192] The procedure is the same as in Method 1, except that the starting material 2-amino-N-phenylacetamide is replaced with the corresponding benzylamine to obtain the title compound.

[0193]

[0194]

[0195] Example 8: (R)-(1-(2-((2-(benzylamino)-2-oxoethyl)amino)-2-oxoacetamide)-2-phenylethyl)boronic acid

[0196]

[0197] The procedure is the same as in Method 1, except that the starting material 2-amino-N-benzylacetamide is replaced with the corresponding benzylamine to obtain the title compound.

[0198]

[0199]

[0200] Example 9: ((R)-3-methyl-1-((S)-2-(2-oxo-2-(aniline)acetamido)-3-phenylpropamido)butyl)boronic acid

[0201]

[0202] The implementation method is the same as Method 1, except that the starting material aniline is replaced with the corresponding benzylamine and BB4 is replaced with the corresponding BB1 to obtain the title compound.

[0203]

[0204] Example 10: ((R)-1-((S)-2-(2-(benzylamino)-2-oxoacetamido)-3-phenylpropamido)-3-methylbutyl)boronic acid

[0205]

[0206] The implementation method is the same as Method 1, except that BB4 is used to replace the corresponding BB1 to obtain the title compound.

[0207]

[0208] Example 11: ((R)-1-((S)-2-(2-oxo-2-(aniline)acetamido)-3-phenylpropamido)-2-phenylethyl)boronic acid

[0209]

[0210] The implementation method is the same as Method 1, except that the starting material aniline is replaced with the corresponding benzylamine and BB1 is replaced with BB5 to obtain the title compound.

[0211]

[0212] Example 12: (R)-(2-([1,1'-biphenyl]-4-yl)-1-(2-((3-methoxybenzyl)amino)-2-oxoacetamido)ethyl)boronic acid

[0213]

[0214] The implementation method is the same as Method 2, except that the starting material m-methoxybenzylamine is used to replace the corresponding benzylamine, and fragment BB1 is used to replace fragment BB3 to obtain the title compound.

[0215]

[0216] Example 13: (R)-(1-(2-((3-methoxyphenylethyl)amino)-2-oxoacetamide)-2-phenylethyl)boronic acid

[0217]

[0218] The method is the same as in Method 2, except that the starting material 2-(3-methoxyphenyl)ethyl-1-amine is replaced with the corresponding benzylamine to obtain the title compound.

[0219]

[0220]

[0221] Example 14: ((R)-1-(2-(((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazaza-3-yl)amino)-2-oxoacetamide)-2-phenylethyl)boronic acid

[0222]

[0223] The method is the same as in Method 2, except that the starting material (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxaza-4(5H)-one is replaced with the corresponding tetrahydrofurfurylamine to obtain the title compound.

[0224]

[0225] Example 15: (R)-(1-(2-((3-methoxyphenethyl)amino)-2-oxoacetamide)-2-(p-tolyl)ethyl)boronic acid

[0226]

[0227] The implementation method is the same as Method 2, except that the starting material 2-(3-methoxyphenyl)ethyl-1-amine is replaced with the corresponding benzylamine, and fragment BB1 is replaced with fragment BB2 to obtain the title compound.

[0228]

[0229]

[0230] Example 16: (R)-(2-([1,1'-biphenyl]-4-yl)-1-(2-((3-methoxyphenethyl)amino)-2-oxoacetamide)ethyl)boronic acid

[0231]

[0232] The implementation method is the same as Method 2, except that the starting material 2-(3-methoxyphenyl)ethyl-1-amine is replaced with the corresponding benzylamine, and fragment BB1 is replaced with fragment BB3 to obtain the title compound.

[0233]

[0234]

[0235] Example 17: (R)-(1-(2-((2,6-dichlorophenylethyl)amino)-2-oxoacetamido)-2-phenylethyl)boronic acid

[0236]

[0237] The method is the same as in Method 2, except that the starting material 2-(2,6-dichlorophenyl)ethane-1-amine is replaced with the corresponding benzylamine to obtain the title compound.

[0238]

[0239] Example 18: (R)-(1-(2-oxo-2-(phenylamino)acetamido)-2-phenylethyl)boronic acid

[0240]

[0241] The implementation method is the same as Method 2, except that the starting material aniline is replaced with the corresponding benzylamine to obtain the title compound.

[0242]

[0243]

[0244] Example 19: (R)-(1-(2-oxo-2-(phenylamino)acetamido)-2-(p-tolyl)ethyl)boronic acid

[0245]

[0246] The implementation method is the same as Method 2, except that the starting material aniline is replaced with the corresponding benzylamine, and fragment BB1 is replaced with fragment BB2 to obtain the title compound.

[0247]

[0248]

[0249] Example 20: (R)-(1-(2-oxo-2-(((6-phenylpyridin-2-yl)methyl)amino)acetamide)-2-phenylethyl)boronic acid

[0250]

[0251] The same method as Method 2 was used, except that the starting material (6-phenylpyridin-2-yl)methylamine hydrochloride was replaced with the corresponding benzylamine to obtain the title compound.

[0252]

[0253]

[0254] Example 21: (R)-(1-(2-oxo-2-(((6-phenylpyridin-2-yl)methyl)amino)acetamide)-2-(p-tolyl)ethyl)boronic acid

[0255]

[0256] The implementation method is the same as Method 2, except that the starting material (6-phenylpyridin-2-yl)methylamine hydrochloride is replaced with the corresponding benzylamine, and fragment BB1 is replaced with fragment BB2 to obtain the title compound.

[0257]

[0258]

[0259] Example 22: (R)-(1-(2-(benzylamino)-2-oxoacetamide)-2-(p-tolyl)ethyl)boronic acid

[0260]

[0261] The implementation method is the same as Method 2, except that the starting material m-methoxybenzylamine is used to replace the corresponding benzylamine, and fragment BB1 is used to replace fragment BB2 to obtain the title compound.

[0262]

[0263] Example 23: (R)-(1-(2-((2,4-dichlorobenzyl)amino)-2-oxoacetamide)-2-phenylethyl)boronic acid

[0264]

[0265] The method is the same as in Method 2, except that the starting material 2,4-dichlorobenzylamine is used to replace the corresponding benzylamine to obtain the title compound.

[0266]

[0267] Example 24: (R)-(1-(2-((2,4-dichlorobenzyl)amino)-2-oxoacetamide)-2-(p-tolyl)ethyl)boronic acid

[0268]

[0269] The implementation method is the same as Method 2, except that the starting material 2,4-dichlorobenzylamine is used to replace the corresponding benzylamine, and fragment BB1 is used to replace fragment BB2 to obtain the title compound.

[0270]

[0271] Example 25: ((R)-1-(2-oxo-2-((((R)-tetrahydrofuran-2-yl)methyl)amino)acetamide)-2-phenylethyl)boronic acid

[0272]

[0273] The implementation method is the same as Method 2, except that the starting material (R)-tetrahydrofurfurylamine is used to replace the corresponding benzylamine to obtain the title compound.

[0274]

[0275]

[0276] Example 26: ((R)-1-(2-oxo-2-((((S)-tetrahydrofuran-2-yl)methyl)amino)acetamide)-2-phenylethyl)boronic acid

[0277]

[0278] The implementation method is the same as Method 2, except that the starting material (S)-tetrahydrofurfurylamine is used to replace the corresponding benzylamine to obtain the title compound.

[0279]

[0280]

[0281] Example 27: (R)-(1-(2-((2,6-dichlorophenylethyl)amino)-2-oxoacetamido)-2-(p-tolyl)ethyl)boronic acid

[0282]

[0283] The implementation method is the same as Method 2, except that the starting material 2-(2,6-dichlorophenyl)ethane-1-amine is replaced with the corresponding benzylamine, and fragment BB1 is replaced with fragment BB2 to obtain the title compound.

[0284]

[0285] Example 28: (R)-(1-(2-((3-methoxybenzyl)amino)-2-oxoacetamide)-2-phenylethyl)boronic acid

[0286]

[0287] The implementation method is the same as Method 2, except that the starting material m-methoxybenzylamine is used to replace the corresponding benzylamine to obtain the title compound.

[0288]

[0289] Example 29: (R)-(1-(2-((3-methoxybenzyl)amino)-2-oxoacetamide)-2-(p-tolyl)ethyl)boronic acid

[0290]

[0291] The implementation method is the same as Method 2, except that the starting material m-methoxybenzylamine is used to replace the corresponding benzylamine, and fragment BB1 is used to replace fragment BB2 to obtain the title compound.

[0292]

[0293] Example 30: ((1R)-1-(2-oxo-2-(((tetrahydrofuran-3-yl)methyl)amino)acetamide)-2-phenylethyl)boronic acid

[0294]

[0295] The method is the same as in Method 3, except that the starting material (tetrahydrofuran-3-yl)methylamine is replaced with the corresponding 1-(3-methoxyphenyl)ethyl-1-amine to obtain the title compound.

[0296]

[0297] Example 31: (R)-(1-(2-(([1,1'-biphenyl]-3-ylmethyl)amino)-2-oxoacetamide)-2-phenylethyl)boronic acid

[0298]

[0299] The implementation method is the same as Method 3, except that the starting material [1,1'-biphenyl]-3-ylmethylamine is used to replace the corresponding 1-(3-methoxyphenyl)ethyl-1-amine to obtain the title compound.

[0300]

[0301]

[0302] Example 32: (R)-(2-([1,1'-biphenyl]-4-yl)-1-(2-((2,6-dichlorophenylethyl)amino)-2-oxoacetamido)ethyl)boronic acid

[0303]

[0304] The implementation method is the same as Method 2, except that the starting material 2-(2,6-dichlorophenyl)ethane-1-amine is replaced with the corresponding benzylamine, and fragment BB1 is replaced with fragment BB3 to obtain the title compound.

[0305]

[0306] Example 33: (R)-(1-(2-(isoindoline-2-yl)-2-oxoacetamide)-2-phenylethyl)boronic acid

[0307]

[0308] The same method as Method 3 was used, except that the starting material isodihydroindole hydrochloride was replaced with the corresponding 1-(3-methoxyphenyl)ethyl-1-amine to obtain the title compound.

[0309]

[0310]

[0311] Example 34: (R)-(1-(2-((4-fluorophenylethyl)amino)-2-oxoacetamide)-2-(p-tolyl)ethyl)boronic acid

[0312]

[0313] The implementation method is the same as in Method 3, except that the starting material 2-(4-fluorophenyl)ethyl-1-amine is replaced with the corresponding 1-(3-methoxyphenyl)ethyl-1-amine, and fragment BB1 is replaced with fragment BB2 to obtain the title compound.

[0314]

[0315] Example 35: (R)-(1-(2-(benzyl(methyl)amino)-2-oxoacetamide)-2-phenylethyl)boronic acid

[0316]

[0317] The implementation method is the same as in Method 3, except that the starting material N-methyl-1-phenylmethylamine is used to replace the corresponding 1-(3-methoxyphenyl)ethyl-1-amine to obtain the title compound.

[0318]

[0319] Example 36: ((1R)-1-(2-oxo-2-(((tetrahydrofuran-2-yl)methyl)amino)acetamide)-2-(p-tolyl)ethyl)boronic acid

[0320]

[0321] The implementation method is the same as Method 2, except that the starting material tetrahydrofurfurylamine is used to replace the corresponding benzylamine, and fragment BB1 is used to replace fragment BB2 to obtain the title compound.

[0322]

[0323] Example 37: (R)-(1-(2-((adamantane-1-ylmethyl)amino)-2-oxoacetamide)-2-phenylethyl)boronic acid

[0324]

[0325] The same method as Method 2 was used, except that the starting material adamantane-1-ylmethylamine was replaced with the corresponding benzylamine to obtain the title compound.

[0326]

[0327] Example 38: (R)-(1-(2-((adamantane-1-ylmethyl)amino)-2-oxoacetamide)-2-(p-tolyl)ethyl)boronic acid

[0328]

[0329] The implementation method is the same as Method 2, except that the starting material adamantane-1-ylmethylamine is replaced with the corresponding benzylamine, and fragment BB1 is replaced with fragment BB2 to obtain the title compound.

[0330]

[0331] Example 39: (R)-(1-(2-(([1,1'-biphenyl]-3-ylmethyl)amino)-2-oxoacetamide)-2-(p-tolyl)ethyl)boronic acid

[0332]

[0333] The implementation method is the same as Method 2, except that the starting material [1,1'-biphenyl]-3-ylmethylamine is used to replace the corresponding benzylamine, and fragment BB1 is replaced with fragment BB2 to obtain the title compound.

[0334]

[0335] Example 40: (R)-(1-(2-((2,6-dichlorobenzyl)amino)-2-oxoacetamide)-2-phenylethyl)boronic acid

[0336]

[0337] The method is the same as in Method 2, except that the starting material 2,6-dichlorobenzylamine is used to replace the corresponding benzylamine to obtain the title compound.

[0338]

[0339] Example 41: ((R)-3-methyl-1-((S)-2-(2-oxo-2-(piperidin-4-ylamino)acetamido)-3-phenylpropamido)butyl)boronic acid

[0340]

[0341] The procedure is the same as in Method 1, except that the starting material 1-Boc-4-aminopiperidine is replaced with the corresponding benzylamine, and BB4 is replaced with the corresponding BB1 to obtain the title compound.

[0342]

[0343]

[0344] Example 42: ((R)-1-((S)-2-(2-((1-(2-hydroxyacetyl)piperidin-4-yl)amino)-2-oxoacetylamino)-3-phenylpropionamido)-3-methylbutyl)boronic acid

[0345]

[0346] The procedure is the same as in Method 1, except that the starting material 1-(4-aminopiperidin-1-yl)-2-hydroxyethyl ketone hydrochloride is replaced with the corresponding benzylamine, and BB4 is replaced with the corresponding BB1 to obtain the title compound.

[0347]

[0348] Example 43: ((R)-3-methyl-1-((S)-2-(2-oxo-2-(piperazin-1-yl)acetamido)-3-phenylpropamido)butyl)boronic acid

[0349]

[0350] The implementation method is the same as Method 1, except that the starting material Boc-piperazine is replaced with the corresponding benzylamine and BB4 is replaced with the corresponding BB1 to obtain the title compound.

[0351]

[0352]

[0353] Example 44: ((R)-1-((S)-2-(2-(4-(2-hydroxyacetyl)piperazin-1-yl)-2-oxoacetamido)-3-phenylpropionamido)-3-methylbutyl)boronic acid

[0354]

[0355] The implementation method is the same as Method 1, except that the starting material 2-hydroxy-1-(piperazin-1-yl)ethyl ketone is replaced with the corresponding benzylamine, and BB4 is replaced with the corresponding BB1 to obtain the title compound.

[0356]

[0357] Biological testing

[0358] Assay for proteasome inhibitory activity

[0359] Cell preparation:

[0360] This application utilizes the fluorescent peptide substrate Ac-Ala-Asn-Trp-AMC (abbreviated Ac-ANW-AMC) to determine the activity of the 20S proteasome β5i subunit. The activity of the 20S proteasome β5c subunit is determined using a Promega trypsin kit (catalog number: G8660) containing the fluorescent peptide substrate Suc-Leu-Leu-Val-Tyr-AMC (abbreviated Suc-LLVY-AMC).

[0361] The proteasomes measured in this application were derived from Raji cells. Ac-ANW-AMC fluorescent substrate was purchased from Roche, and other reagents were purchased from Sigma. The experiment consisted of two parts: a cell lysis system and an enzyme reaction system. The enzyme lysis system was 100 µL, containing 7 × 10⁶ Raji cells. 5 Cells were prepared using 100 µL of lysis buffer; the enzyme reaction system consisted of 50 µL of enzyme, 25 µL of proteasome, and 25 µL of substrate buffer. The initial drug (inhibitor) concentration was 1 µM, diluted three-fold, and administered at eight different doses (i.e., the concentrations could be 1 µM, 0.333 µM, 0.111 µM, etc.). The specific experimental procedure is as follows:

[0362] Cell culture:

[0363] Raji cells (1×10⁻⁶) frozen in liquid nitrogen 6 Thaw the cells rapidly in a 37°C water bath, transfer the cell clusters to 15mL centrifuge tubes, add 9mL of fresh culture medium (Gibco RPMI 1640 with 10% fetal bovine serum and 1% antibiotics), centrifuge at 120g for 5 minutes, and seed into 25mL cell culture flasks. Passage the cells every 2-3 days.

[0364] Drug preparation:

[0365] Weigh the drug and dissolve it in DMSO to a concentration of 10 mM. Dilute the drug sequentially with fresh culture medium to 200 µM, 66.67 µM, 22.22 µM, 7.41 µM, 2.47 µM, 0.82 µM, 0.27 µM and 0.091 µM.

[0366] Raji cells in good growth condition were divided into 7×10 5 / mL was seeded into 48-well cell culture plates.

[0367] Cell-based drug delivery:

[0368] Raji cells in good growth condition were counted, and then 7 × 10⁻⁶ cells were collected. 5 / mL was seeded into 48-well cell culture plates. Following the above drug dilution concentrations, 5µL was added sequentially to the already seeded cell culture plates. The minimum drug concentration was 0µM. Bortezomib (Velcade) and ONX-0914 were used as positive control drugs. Incubation was performed at 37°C for 4 hours.

[0369] Proteasome isolation:

[0370] After drug treatment, cells were sequentially transferred to 1.5 mL centrifuge tubes and centrifuged at 10,000 rpm for 2 minutes, discarding the supernatant. Cells were resuspended in 1 mL PBS and centrifuged at 10,000 rpm for 2 minutes, discarding the supernatant. Cells were then resuspended in 100 µL of cell lysis buffer (50 mM Tris (pH 7.5), 150 mM NaCl, 5 mM MgCl2, 5 mM ATP, 1 mM DTT, 0.01% NP-40, 1 mM Digitonin, Cocktail) and incubated on ice for 30 minutes; centrifuged at 13,000 rpm for 10 minutes.

[0371] Substrate preparation:

[0372] 2 mg of the fluorescent peptide substrate AC-ANW-AMC was dissolved in 424.7 µL of DMSO to obtain an 8 mM stock solution, which was stored at -20 °C. Before use, it was diluted 100-fold to achieve a final concentration of 8 µM in the reaction system. The fluorescent peptide substrate Suc-LLVY-AMC was prepared according to the Promega kit instructions.

[0373] Preparation of the reaction system:

[0374] Add 20 µL of the prepared proteasome solution to each well of a 96-well white fluorescent microplate. Then add 25 µL of AC-ANW-AM substrate buffer (50 mM Tris (pH 7.5), 150 mM NaCl, 5 mM MgCl2, 5 mM ATP, 80 µM Ac-ANW-AMC, and 1 mM DTT) and 25 µL of Suc-LLVY-AMC substrate buffer, respectively. Incubate at 37 °C in the dark for 10 minutes. Read the fluorescence values ​​using a 345 nm / 445 nm fluorescent microplate reader.

[0375] Data processing:

[0376] Export the data and calculate the inhibition percentage using the following formula:

[0377] Inhibition rate = (Maximum signal value - Compound signal value) / (Maximum signal value - Blank signal value) × 100%

[0378] The maximum signal was obtained from cell lysate treated only with DMSO; the blank signal was obtained from wells containing only lysate.

[0379] Assay for tumor cell line inhibitory activity:

[0380] Cell preparation:

[0381] The cells used in this experiment were MM.1S cells, and the detection reagent was CellTiter-Glo (from Promega). The experimental volume was 190 µL, containing 100 µL of cell suspension, 50 µL of drug, and 40 µL of detection solution. The specific experimental procedure is as follows:

[0382] MM.1S cells in the logarithmic growth phase and in good cell condition were digested into single cells using trypsin, centrifuged to remove the supernatant, counted, and then diluted to 1×10⁻⁶ cells. 5 Cells were seeded per well in a 96-well microplate, with 100 µL of cell suspension added to each well. Wells containing only RPMI 1640 complete culture medium were included as a blank control. The 96-well plates were then transferred to a 37°C incubator containing 5% CO2 and incubated for 24 hours.

[0383] Drug treatment:

[0384] Accurately weigh the drug and dissolve it in DMSO to a final volume of 10. -2 M. Use a pipette to add 10 µL to 190 µL of DMSO to obtain 5 × 10⁻⁶ ppm. -4 M. Take a new 96-well microplate and start from 5 × 10⁻⁶. -5 Add 6 µL of the M concentration drug to 194 µL of RPMI 1640 complete culture medium, and perform a 3-fold serial dilution. Transfer 50 µL of the diluted drug to a 96-well microplate containing cells to achieve a final drug concentration of 5 × 10⁻⁶. -7 M, 1.67×10 -7 M, 5.55×10 -8 M, 1.85×10 -8 M, 6.17×10 -9 M, 2.06×10 -9 M, 6.86×10 -10 M, 2.29×10 -10 M, the last concentration is 0M, no drug added, and DMSO of the same concentration is added. Bortezomib, a commercially available drug, is used as a positive control. The 96-well microplates with added drugs are placed back into a 37°C incubator for 72 hours.

[0385] Cell detection:

[0386] When the predetermined detection time is reached, place the 96-well microplate at 20°C. Add 40 μL of CellTiter-Glo assay reagent to each well and cover the microplate with a dark cap or aluminum foil. Mix the contents on a 150 rpm oscillator for 10 minutes to ensure complete cell lysis. Detect the luminescence value using a BioTek Synergy H1 Hybrid Multi-Mode Reader.

[0387] Data processing:

[0388] Export the data and calculate the inhibition percentage using the following formula:

[0389] Inhibition rate = (maximum signal value - compound signal value) / (maximum signal value - blank signal value) × 100%;

[0390] The strongest signal was obtained from cells treated with DMSO only; the blank signal was obtained from wells containing only culture medium.

[0391] The activities of the compounds provided in this application are shown in Table 1 below.

[0392]

[0393]

[0394] Anti-inflammatory (inhibition of IL-6 secretion) activity assay:

[0395] Cell preparation:

[0396] THP-1 cells are a cell line derived from human monocytic leukemia and are widely used to study the biological functions of monocytes and macrophages. Using PMA (phorbol-12-myristate-13-acetate) and LPS (lipopolysaccharide)-induced polarization methods, THP-1 cells can differentiate into a macrophage-like state and further polarize into different functional subtypes. The specific experimental procedure is as follows:

[0397] THP-1 cells were seeded in culture plates at a density of 500,000 cells per milliliter. PMA was added to the culture medium to a final concentration of 100 nM. The cells were incubated at 37°C in a 5% CO2 incubator for 48 hours. After induction, THP-1 cells adhered and exhibited a macrophage-like morphology. Undifferentiated suspension cells could be removed by washing with PBS.

[0398] THP-1 cells in the logarithmic growth phase and in good cell condition after PMA-induced differentiation were digested into single cells using trypsin, centrifuged to remove the supernatant, counted, and diluted to 1×10⁻⁶ cells. 5Cells were seeded per well in a 96-well microplate, with 200 µL of cell suspension added to each well. Wells containing only RPMI 1640 complete culture medium were set up as blank controls.

[0399] Drug treatment:

[0400] Accurately weigh the drug and dissolve it in DMSO to a final volume of 10. -2 M. Use a pipette to add 10 µL to 190 µL of DMSO to obtain 5 × 10⁻⁶ ppm. -4 M. Take a new 96-well microplate and start from 5 × 10⁻⁶. -5 Take 6 µL of the M concentration drug and add it to 194 µL of RPMI 1640 complete culture medium for dilution. Transfer the quantified diluted drug to a 96-well microplate containing cells to achieve a final drug concentration of 2 × 10⁻⁶. -7 M and 2×10 -8 M, the last concentration is 0M, no drug added, and DMSO of the same concentration is added. ONX-0914 is used as a positive control. The 96-well microplate with added drug is placed back into the 37°C incubator for 2 hours. Then, 100 ng / mL LPS is added to the culture medium and the plate is incubated for another 24 hours.

[0401] Cytokine detection:

[0402] When the predetermined detection time is reached, place the 96-well microplate to be tested at 20°C and record the concentration of IL-6 in each well using ELISA.

[0403] Data processing:

[0404] Export the data and calculate the inhibition percentage using the following formula:

[0405] Inhibition rate % = (1 - (reading value in the drug-treated group - reading value in the blank group) / (reading value in the DMSO group - reading value in the blank group)) × 100%

[0406] The readings for the drug-treated group were obtained from each well containing the drug; the readings for the DMSO group were obtained from cells treated with DMSO only; and the readings for the blank group were obtained from wells containing only culture medium.

[0407] Table 2 below provides the inhibitory activity of some of the compounds in the examples on IL-6 secretion from THP-1 (PAM) cells.

[0408]

[0409] The results above show that the compound of this application has good proteasome inhibitory activity and has anti-tumor and anti-inflammatory effects.

[0410] In vivo experiments

[0411] Oral drug concentration test in mice:

[0412] Implementation method:

[0413] The C57BL / 6JNifdc mice used in this experiment were provided by Zhejiang Vital River Laboratory Animal Technology Co., Ltd. The compound was dissolved in DMSO (dimethyl sulfoxide) / Solutol HS 15 (polyethylene glycol-15-hydroxystearate) / Saline (physiological saline) (v / v / v = 10 / 10 / 80) as a stock solution (3 mg / mL). The stock solution was orally administered to six C57BL / 6JNifdc mice at a dose of 30 mg / kg. Blood was collected from the orbital venous plexus at 0.5 h, 1 h, 1.5 h, and 2 h after oral administration.

[0414] Plasma treatment:

[0415] Approximately 200 µL of blood sample was collected into an EDTAK2 blood collection tube, and then immediately centrifuged at 10,000 rpm for 5 minutes. 66 µL of supernatant plasma was collected, and 198 µL of acetonitrile (from Amex) was added. The tube was vortexed for 5 minutes, and then immediately centrifuged at 13,000 rpm for 8 minutes. 200 µL of supernatant was collected to detect the blood drug concentration.

[0416] Preparation of standard samples:

[0417] Accurately weigh the drug and dissolve it in acetonitrile to a concentration of 100 µg / mL. Using a pipette, pipette 50 µL of the solution to 4.95 mL of acetonitrile / water (v / v = 3 / 1) to obtain a 1000 ng / mL stock solution. Take 650 µL of the stock solution and serially dilute it two-fold with acetonitrile / water (v / v = 3 / 1) solutions to obtain standard samples with concentrations of 500 ng / mL, 250 ng / mL, 125 ng / mL, 62.5 ng / mL, and 31.25 ng / mL, respectively.

[0418] Sample concentration monitoring:

[0419] Standard solutions with concentrations of 1000 ng / mL, 500 ng / mL, 250 ng / mL, 125 ng / mL, 62.5 ng / mL, and 31.25 ng / mL were detected using LC-MS (Shimadzu LC-MS 2020 and LC-2030 Plus) in SIM mode to obtain calibration curves. Processed blood samples were also analyzed using this method, and quantitative analysis was performed using the calibration curves to obtain drug concentration data for each processed blood sample.

[0420] Data processing:

[0421] Export the data and calculate the average blood drug concentration at each sampling time point:

[0422] Drug concentration in blood = Drug concentration in treated blood sample × 4 / Drug molecular weight; Average blood drug concentration is the average drug concentration in blood at each sampling time point.

[0423] The compounds of this application have good oral blood drug concentrations (as shown in Table 3) and can be well absorbed orally.

[0424]

[0425] As can be seen from the above results, the compound of this application has good in vivo blood drug concentration and can be used as an oral drug, which is significantly better than the control compound bortezomib in this respect.

[0426] The applicant declares that this application illustrates the boric acid compounds and their applications through the above embodiments, but this application is not limited to the above embodiments, that is, it does not mean that this application must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to this application, equivalent substitutions of the raw materials of the product, addition of auxiliary components, and selection of specific methods, etc., all fall within the protection scope and disclosure scope of this application.

[0427] The preferred embodiments of this application have been described in detail above. However, this application is not limited to the specific details of the above embodiments. Within the scope of the technical concept of this application, various simple modifications can be made to the technical solution of this application, and these simple modifications all fall within the protection scope of this application.

[0428] It should also be noted that the various specific technical features described in the above embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, this application will not describe the various possible combinations separately.

Claims

1. A boric acid compound or its tautomers, stereoisomers, polymers, solvates, or pharmaceutically acceptable salts, wherein, The structure of the boric acid compound is shown in Formula I: ； R1 is selected from hydrogen, substituted or unsubstituted C. 1~10 Alkyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 6-10 aryl, substituted or unsubstituted 5-12 heteroaryl, substituted or unsubstituted 3-12 heterocyclic, substituted or unsubstituted bridged ring group, wherein the substituent is selected from (=O), -OCF3, -OCHF2, C 1~6 Alkyl, C 1~10 Alkoxy, C 3~6 Cycloalkyl, 3-12 heterocyclic, 6-10 aryl, 5-12 heteroaryl, 6-10 aryloxy, cyano, hydroxyl, sulfhydryl, amino or halogen; R2 is selected from hydrogen or C. 1~6 alkyl; R1 and R2 exist independently or are connected to each other, forming a substituted or unsubstituted 4- to 12-membered heterocycle together with L1 and the nitrogen atom. The substituents are selected from (=O), halogen, hydroxyl, cyano, amino, mercapto, or -(CO)-(CH2). 1~3 -OH, wherein the 4-12 membered heterocycles are not fused or are fused with benzene rings or 5-6 membered heteroaromatic rings; R3 is selected from hydrogen or C. 1~6 Alkyl, C 1~10 Alkoxy, C 3~6 Cycloalkyl, 3-12-membered heterocyclic, 6-membered aryl, 5-6-membered heteroaryl, 6-10-membered aryloxy, cyano, hydroxyl, sulfhydryl, amino or halogen; L1 is selected from -CH(R4)-, -N(R4)COCH2-, or -OCH2CH2-; L2 is -CONH-CH(R5)-; R4 and R5 are independently selected from hydrogen, substituted or unsubstituted C4. 1~10 Alkyl, substituted or unsubstituted benzyl, wherein the substituent is selected from cyano, hydroxyl, sulfhydryl, amino or halogen; m and n are independently selected from 0, 1 or 2; when m is 0, L1 does not exist, and the two atoms connected to the two ends of L1 are directly connected; when n is 0, L2 does not exist, and the two atoms connected to the two ends of L2 are directly connected.

2. The boric acid compound or its tautomers, stereoisomers, polymers, solvates, or pharmaceutically acceptable salts according to claim 1, wherein, Where n is 1, the structure of the boric acid compound is shown in Formula II: ； R5 is selected from hydrogen, substituted or unsubstituted C. 1~10 Alkyl, substituted or unsubstituted benzyl, wherein the substituent is selected from cyano, hydroxyl, sulfhydryl, amino or halogen; R1, R2, R3, L1, m have the same scope as in claim 1.

3. The boric acid compound or its tautomers, stereoisomers, polymers, solvates, or pharmaceutically acceptable salts according to claim 2, wherein, R5 is selected from any one of hydrogen, isobutyl or benzyl.

4. The boric acid compound or its tautomers, stereoisomers, polymers, solvates, or pharmaceutically acceptable salts according to claim 1, wherein, Where n is 0, the structure of the boric acid compound is shown in Formula III: ； R1, R2, R3, L1, and m have the same scope as in claim 1.

5. The boric acid compound or its tautomers, stereoisomers, polymers, solvates, or pharmaceutically acceptable salts according to claim 1, wherein, R2 is hydrogen.

6. The boric acid compound or its tautomers, stereoisomers, polymers, solvates, or pharmaceutically acceptable salts according to claim 1, wherein, R1 is selected from hydrogen, substituted or unsubstituted C. 1~6 Alkyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 6-10 aryl, substituted or unsubstituted 5-12 heteroaryl, substituted or unsubstituted 3-12 heterocyclic, substituted or unsubstituted bridged ring group, wherein the substituent is selected from (=O), -OCF3, -OCHF2, C 1~6 Alkyl, C 1~10 Alkoxy, C 3~6 Cycloalkyl, 6-10 aryl, hydroxyl, amino or halogen.

7. The boric acid compound or its tautomers, stereoisomers, polymers, solvates, or pharmaceutically acceptable salts according to claim 1, wherein, R1 is selected from any of the following structures:

8. The boric acid compound or its tautomers, stereoisomers, polymers, solvates, or pharmaceutically acceptable salts according to claim 1, wherein, R1 and R2 are interconnected and together with L1 and the nitrogen atom form any one of the following structures:

9. The boric acid compound or its tautomers, stereoisomers, polymers, solvates, or pharmaceutically acceptable salts according to any one of claims 1-8, wherein, R2 is selected from hydrogen, L1 is selected from -CH(R4)-, -N(R4)COCH2- or -OCH2CH2-, and R4 has the same defined range as in claim 1; Preferably, L1 is selected from -CH2-, -CH(CH3)-, and -NHCOCH2-.

10. The boric acid compound or its tautomers, stereoisomers, polymers, solvates, or pharmaceutically acceptable salts according to any one of claims 1-9, wherein, The boric acid compound is selected from any one of the following structures: ； ； 11. A pharmaceutical composition comprising any one of the borate compounds or pharmaceutically acceptable salts thereof according to claims 1-10.

12. An antibody-drug conjugate, wherein, The small molecule drug portion of the antibody-drug conjugate includes any one of the borate compounds or pharmaceutically acceptable salts thereof according to any one of claims 1-10.

13. The use of a borate compound or its pharmaceutically acceptable salt according to any one of claims 1-10 in the preparation of a proteasome inhibitor.

14. The use of a borate compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10 in the preparation of a medicament for treating or preventing proteasome-related diseases.

15. The application according to claim 14, wherein, The diseases mentioned include tumors and autoimmune diseases; Preferably, the diseases include multiple myeloma, acute myeloid leukemia, myeloid cell 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, stomach cancer, thyroid cancer, prostate cancer, bladder cancer, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, scleroderma, adhesive capsulitis, atherosclerosis, Behcet's disease, Crohn's disease, inflammatory bowel disease, ulcerative colitis, autoimmune hepatitis, Sjögren's syndrome, asthma, amyotrophic lateral sclerosis, psoriasis, immunoglobulin A nephropathy, allergic purpura, or Alzheimer's disease.

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