WO2023207889A1 - 一种硼酸类蛋白酶体抑制剂及其用途 - Google Patents

一种硼酸类蛋白酶体抑制剂及其用途 Download PDF

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WO2023207889A1
WO2023207889A1 PCT/CN2023/090235 CN2023090235W WO2023207889A1 WO 2023207889 A1 WO2023207889 A1 WO 2023207889A1 CN 2023090235 W CN2023090235 W CN 2023090235W WO 2023207889 A1 WO2023207889 A1 WO 2023207889A1
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李旭珂
朱振东
牛德强
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科辉智药生物科技（无锡）有限公司
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    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds
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    • A—HUMAN NECESSITIES
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    • A61P35/00—Antineoplastic agents
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    • A61P35/00—Antineoplastic agents
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • A—HUMAN NECESSITIES
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds

Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to a class of boric acid proteasome inhibitors, their uses and preparation methods.
  • proteasome-mediated degradation plays a key role in many cellular functional processes, such as class I major histocompatibility complex (MHC) antigen presentation, apoptosis, growth regulation, NF- ⁇ B activation, Antigen processing and pro-inflammatory signal transduction, etc.
  • MHC major histocompatibility complex
  • the proteasome is a multimeric protein composed of seven subunits. It exists in two forms in cells: the widely expressed constitutive proteasome and the immunoproteasome mainly expressed in the immune-inflammatory system.
  • the composition is different: the constitutive proteasome contains chymotrypsin-like active subunit ( ⁇ 5c), caspase-like active subunit ( ⁇ 1c) and trypsin-like active subunit ( ⁇ 2c).
  • ⁇ 5c chymotrypsin-like active subunit
  • ⁇ 1c caspase-like active subunit
  • ⁇ 2c trypsin-like active subunit
  • proteasome not only plays an important role in MHC class I antigen presentation, but is also involved in a variety of pathological conditions, including malignant tumors, inflammatory diseases, and autoimmune diseases.
  • the prior art has confirmed the relationship between the proteasome and the occurrence and progression of the above-mentioned diseases.
  • proteasome inhibition represents an important new strategy for cancer treatment.
  • King et al. described the important role of the ubiquitin-proteasome pathway in regulating cell cycle, tumor growth and metastasis (Science, 274:1652-1659 (1996)).
  • boronic acid proteasome inhibitors in the prior art exhibit good activity against both ⁇ 5c and ⁇ 5i subunits, their oral bioavailability is not satisfactory.
  • the marketed proteasome inhibitor bortezomib cannot be used orally due to low bioavailability.
  • the present invention discloses a new class of boric acid proteasome inhibitors, and some compounds have better oral bioavailability. Such compounds can be used to treat related diseases, especially malignant diseases and autoimmune diseases.
  • the invention provides a compound having the structure of formula I or a pharmaceutically acceptable salt thereof:
  • X is selected from: -C 1 ⁇ 4 alkyl-, -C 3 ⁇ 6 cycloalkyl-, -vinyl-, -ethynyl-, -NH-, -NH-NH- optionally substituted by the following substituents and -Heterocyclyl-, the substituent is selected from: deuterium, C 1 ⁇ 4 alkyl, C 1 ⁇ 10 alkoxy, C 3 ⁇ 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, Aryloxy, cyano, hydroxyl, mercapto, amino and halogen;
  • R1 and R3 are each independently selected from: hydrogen, or C 1 to 10 alkyl, C 3 to 6 cycloalkyl, aryl, heteroaryl, benzyl, heterocyclyl and bridge optionally substituted by the following substituents Cycloalkyl, the substituent is selected from: deuterium, C 1 to 4 alkyl, C 1 to 10 alkoxy, C 3 to 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy , cyano group, hydroxyl group, mercapto group, amino group and halogen;
  • R2 is selected from: C 1 to 10 alkyl, benzyl, biphenylmethyl and heterocyclyl optionally substituted by the following substituents, wherein the substituents are selected from: deuterium, C 1 to 4 alkyl, C 1 ⁇ 10 alkoxy group, C 3 ⁇ 6 cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, aryloxy group, cyano group, hydroxyl group, mercapto group, amino group and halogen.
  • the compound of Formula I has the following structure of Formula II:
  • R1, R2 and R3 have the definitions as stated in claim 1;
  • R 2a and R 2b are each independently selected from: hydrogen, deuterium, C 1 to 10 alkyl, benzyl, isopropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, heterocyclyl Methyl and halogen, or R 2a , R 2b and the carbon atoms connected to them together form a 3-6 membered carbon ring.
  • the compound of Formula I has the following structure of Formula III:
  • R1, R2 and R3 have the definitions as stated in claim 1;
  • R 3a is selected from: hydrogen, C 1 to 10 alkyl, benzyl, isopropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and heterocyclylmethyl.
  • the compound of Formula I has the following structure of Formula IV:
  • R1, R2 and R3 have the definitions as stated in claim 1;
  • R 4a , R 4b , R 4c and R 4d are each independently selected from: hydrogen, deuterium, C 1-10 alkyl, halogen, hydroxyl and amino, wherein the amino is optionally replaced by C 1-4 alkyl or C 3 to 6 cycloalkyl substitutions.
  • the compound of Formula I has the following structure of Formula V:
  • R1, R2 and R3 have the definitions as stated in claim 1;
  • R 5a and R 5b are each independently selected from: hydrogen, deuterium, C 1 to 4 alkyl, halogen and hydroxyl, and R 5a and R 5b are in cis or trans substitution form with each other.
  • the compound of Formula I has the following structure of Formula VI:
  • R1, R2 and R3 have the definitions as stated in claim 1;
  • Ring A is selected from: -C 3 ⁇ 6 cycloalkyl- and -heterocyclyl- optionally substituted by the following substituents, wherein the substituents are selected from C 1 ⁇ 4 alkyl, C 1 ⁇ 10 alkoxy , C 3 ⁇ 6 cycloalkyl, cyano, hydroxyl and halogen.
  • R1 and/or R3 may preferably be hydrogen and the following structures:
  • R2 may preferably have the following structure:
  • a pharmaceutical composition which includes the compound of formula I according to the present invention or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
  • the compound of Formula I has the structure of Formula II, Formula III, Formula IV, Formula V, or Formula VI described above.
  • the compound of Formula I is the specific compound described above.
  • the proteasome-related diseases include, for example, tumors and autoimmune diseases.
  • the tumors described in the present invention include solid tumors and hematological tumors, wherein the solid tumors are selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell Carcinoma, astrocytoma, neuroblastoma, meningioma, gastrointestinal stromal tumor, or nasopharyngeal carcinoma, including in situ tumors and metastases of the above tumors; hematological tumors selected from the group consisting of leukemia, multiple myeloma, Mantle cell lymphoma or histiocytic lymphoma; Hodgkin's lymphoma, non-Hodgkin's lymphoma.
  • autoimmune diseases of the present invention include, but are not limited to, inflammatory reactions, such as inflammatory skin diseases including psoriasis and dermatitis (e.g., atopic dermatitis); systemic scleroderma and sclerosis; and inflammatory bowel disease.
  • inflammatory skin diseases including psoriasis and dermatitis (e.g., atopic dermatitis); systemic scleroderma and sclerosis; and inflammatory bowel disease.
  • Reactions associated with disease such as Crohn's disease and ulcerative colitis); respiratory distress syndrome (including adult respiratory distress syndrome (ARDS)); dermatitis; meningitis; encephalitis; uveitis; colitis; renal insufficiency Glomerulonephritis; allergic conditions such as eczema and asthma and other conditions involving T cell infiltration and chronic inflammatory responses; atherosclerosis; insufficient leukocyte adhesion; rheumatoid arthritis; systemic lupus erythematosus (SLE); diabetes mellitus (e.g., type 1 diabetes or insulin-dependent diabetes); multiple sclerosis; Raynaud's syndrome; autoimmune thyroiditis; Graves'disease; allergic encephalomyelitis; Sjögren Sjogren's syndrome; juvenile-onset diabetes mellitus; and acute and delayed-onset diabetes mellitus mediated by cytokines and T lymphocytes commonly found in tuberculosis, sarcoidos
  • the disease is selected from tumors and autoimmune diseases.
  • the disease is multiple myeloma; in other embodiments, the disease is selected from the group consisting of systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD).
  • SLE systemic lupus erythematosus
  • IBD inflammatory bowel disease
  • the carbon atom connected to the boron atom in the compound of formula I must maintain the specific stereoconfiguration shown in formula I; and when other carbon atoms are chiral carbons, they can adopt the R configuration or the S configuration,
  • the compounds of the present invention accordingly include single stereoisomers or mixtures of isomers in varying proportions.
  • salts, solvates, hydrates, and boric acid polymers of a compound are alternative forms of the compound, and they can all be converted into the compound under certain conditions. Therefore, special attention should be paid to When a compound is referred to herein, it generally also includes its pharmaceutically acceptable salts and, by extension, its solvates, hydrates and boronic acid polymers.
  • Pharmaceutically acceptable salts of the present invention may be formed using, for example, the following inorganic or organic acids: "Pharmaceutically acceptable salts" refer to salts that, within the scope of reasonable medical judgment, are suitable for use in contact with humans and lower and other animal tissues without undue toxicity, irritation, allergic reactions, etc., which can be called a reasonable benefit/risk ratio.
  • the salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent, as summarized below. For example, the free base functionality can be reacted with a suitable acid.
  • suitable pharmaceutically acceptable salts thereof may include metal salts, such as alkali metal salts (such as sodium salts or potassium salts); and alkaline earth metal salts (such as calcium salts or magnesium salts) .
  • metal salts such as alkali metal salts (such as sodium salts or potassium salts); and alkaline earth metal salts (such as calcium salts or magnesium salts) .
  • pharmaceutically acceptable nontoxic acid addition salts are amino acids with inorganic acids (eg, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (eg, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or by using other methods in the art such as ion exchange.
  • salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, Camphor sulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerin Phosphate, gluconate, enanthate, hexanoate, hydroiodide, 2-hydroxy-ethyl Sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate , nitrate, oleate, oxalate, palmitate, pamate, pectate, persulfate
  • Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like.
  • Other pharmaceutically acceptable salts include, where appropriate, nontoxic ammonium salts, quaternary ammonium salts, and ammonium cations formed with counterions, e.g., halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower Alkyl sulfonates and aryl sulfonates.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an active ingredient, and its effective dose ranges from 0.1 to 1000 mg/kg body weight/day in mammals including humans (body weight about 70 kg), preferably 1 to 100 mg/kg body weight/day and administered in single or divided doses daily, or on/off scheduled times.
  • the dosage of the active ingredient may be adjusted according to a number of relevant factors such as the condition of the subject to be treated, the type and severity of the disease, the rate of administration and physician opinion. In some cases, amounts less than the above dosages may be appropriate. Amounts greater than the above dosages may be used if they do not cause deleterious side effects and may be administered in divided doses per day.
  • the present invention also provides a method for preventing and/or treating proteasome-related diseases, which includes administering a compound or pharmaceutical composition of the present invention to a mammal (including a human) in need thereof.
  • the proteasome-related disease is selected from the group consisting of tumors and autoimmune diseases.
  • the proteasome-associated disease is multiple myeloma; in other embodiments, the proteasome-associated disease is selected from the group consisting of systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD).
  • SLE systemic lupus erythematosus
  • IBD inflammatory bowel disease
  • the substituent when referring to "optionally substituted", may be deuterium, C 1 to 4 alkyl, C 1 to 10 alkoxy, C 3 to 6 cycloalkyl, heterocyclyl, aryl, hetero Aryl, aryloxy, cyano, hydroxyl, mercapto, amino and halogen; wherein the aryl group as a substituent can be deuterium, C 1 to 4 alkyl, C 1 to 10 alkoxy, C 3 to 6 Substituents such as cycloalkyl, cyano, hydroxyl, mercapto, amino and halogen are further substituted.
  • alkyl is used to represent a straight-chain or branched saturated hydrocarbon group.
  • C 1 to 3 alkyl refers to a saturated hydrocarbon group containing 1 to 3 carbon atoms
  • C 1 to 4 alkyl refers to a saturated hydrocarbon group containing 1 to 4 carbon atoms.
  • An alkyl group with 1 to 10 carbon atoms refers to a saturated hydrocarbon group with 1 to 10 carbon atoms.
  • alkoxy refers to alkyl-O-.
  • C 1-6 alkoxy is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy.
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), and tert-butoxy.
  • alkylthio or “thioalkoxy” means a sulfur-bridged alkyl group as defined above having the specified number of carbon atoms; for example, methyl-S- and ethyl-S-.
  • Preferred alkoxy groups herein are C 1 to 6 alkoxy groups.
  • cycloalkyl refers to non-aromatic carbocyclic groups, including cyclized alkyl groups. Cycloalkyl groups may include monocyclic, bicyclic or polycyclic ring systems. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. C 3 to 6 cycloalkyl groups refer to cycloalkyl groups containing 3 to 6 carbon atoms.
  • heterocycloalkyl refers to a non-aromatic heterocarbocyclyl group in which 1 or 2 or 3 ring-forming carbon atoms are replaced by heteroatoms such as O, N or S atoms. Heterocycloalkyl groups preferably have 3, 4, 5, 6 or 7 ring atoms.
  • the preferred heterocyclyl groups herein are C 3-8 heterocyclyl groups.
  • benzyl refers to benzyl.
  • Substituted benzyl means that at least one hydrogen atom on the benzyl ring of the benzyl group is replaced by a non-hydrogen moiety.
  • the substituent of benzyl can be halogen, -CN, -OH, - SH, -NH 2 , C 1-6 alkyl.
  • C 1-3 alkyl heterocyclyl refers to an aromatic heterocyclic group or a non-aromatic heterocyclic group substituted on a saturated hydrocarbon group containing 1 to 3 carbon atoms, including cyclized alkyl groups, where One or more ring-forming carbon atoms are replaced by heteroatoms such as O, N or S atoms.
  • Heterocycloalkyl groups preferably have 3, 4, 5, 6 or 7 ring atoms.
  • C 1-10 alkoxy refers to an -O-alkyl group.
  • the alkyl group includes straight chain, branched chain and cyclic alkyl groups, and the number of carbon atoms is 1 to 10.
  • alkoxy groups include methoxy, ethoxy, propoxy (eg, n-propoxy, isopropoxy and cyclopropoxy), tert-butoxy and the like.
  • Aryl refers to an aromatic carbocyclic group, including monocyclic, bicyclic, tricyclic or polycyclic aromatic hydrocarbons, such as phenyl, naphthyl, anthracenyl, phenanthrenyl, 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 wherein each ring in the system contains 3 to 7 ring members.
  • a ring member “Substituted aryl” means that at least one hydrogen atom on the benzene ring of the aryl is substituted by a non-hydrogen moiety.
  • the substituent of the aryl can be halogen, C 1 to 10 alkoxy, -CN, -OH, -SH , -NH 2 , C 1 ⁇ 6 alkyl.
  • Preferred aryl groups include phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl.
  • aralkyl or "arylalkyl” refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, Phenethyl et al.
  • the fused aryl group can be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring.
  • Example A dashed line drawn from a ring system shows that the bond can be attached to any suitable ring atom.
  • heteroaryl means a stable 5-12 membered aromatic monocyclic or aromatic bicyclic or aromatic polycyclic heterocyclic ring, which is completely unsaturated or partially unsaturated, and which contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. It includes 5-membered, 6-membered or 7-membered aromatic monocyclic rings or 8-membered, 9-membered, 10-membered, 11-membered or 12-membered aromatic bicyclic or aromatic polycyclic heterocyclic rings; preferably any heterocyclic ring defined above and Fused benzene rings. Nitrogen and sulfur heteroatoms may optionally be oxidized.
  • Nitrogen atoms are substituted or unsubstituted (ie, N or NR, where R is H or another substituent, if defined).
  • Heterocycles can be attached to their pendant groups at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclyl groups described herein may be substituted on 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, then these heteroatoms are not adjacent to each other.
  • aryl hetero groups include, but are not limited to, acridinyl, azetidinyl, azecinyl, benzimidazolyl, benzofuryl, benzothiofuranyl, benzothienyl, benzox Azolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dihydrofura[2,3-b]tetrahydrofuranyl, furyl, furanyl, imidazole Alkyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridyl, indolyl,
  • heteroaryl may also include a biaryl structure formed by the above-defined “aryl” and a monocyclic “heteroaryl”, such as but not limited to "-phenylbipyridyl-", “- "Phenylbipyrimidinyl”, “-pyridylbiphenyl”, “-pyridylbipyrimidinyl-", “-pyrimidinylbiphenyl-”.
  • Aryloxy refers to -O-aryl, and the concept of aryl is as described above. The most preferred example of aryloxy is phenoxy.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • bridged cycloalkyl refers to polycyclic compounds sharing two or more carbon atoms, including bicyclic bridged cyclic hydrocarbons and polycyclic bridged cyclic hydrocarbons.
  • the former is composed of two alicyclic rings sharing more than two carbon atoms; the latter is a bridged cyclic hydrocarbon composed of more than three rings.
  • Preferred bridged cycloalkyl groups herein are selected from adamantyl and adamantan-1-yl-methyl.
  • Step 2 (R)-2-methyl-N-((R)-2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- 2-yl)ethyl)propane-2-sulfinamide
  • reaction solution 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 separated and purified by column chromatography (eluent: 35% dichloromethane in petroleum ether) to obtain a colorless liquid compound (3.30 g, 60%).
  • Step 3 (R)-2-methyl-N-((R)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)- 2-(p-Tolyl)ethyl)propane-2-sulfinamide
  • reaction solution 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 separated and purified by column chromatography (eluent: 20% ethyl acetate in petroleum ether) to obtain a colorless liquid (1.35 g, 80%).
  • Step 4 (R)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-2-(p-tolyl)eth-1- Amine hydrochloride
  • Step 5 (R)-N-((R)-2-(benzofuran-3-yl)-1-(4,4,5,5-tetramethyl-1,3,2-dioxa Borane-2-yl)ethyl)-2-methylpropane-2-sulfinamide
  • reaction solution 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 separated and purified by column chromatography (eluent: 20% ethyl acetate in petroleum ether) to obtain a colorless liquid (1.3 g, 36%).
  • Step 6 (R)-2-(benzofuran-3-yl)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)ethyl -1-amine hydrochloride
  • the title compound was obtained by following the same procedure as fragment BB2, except replacing the corresponding 2-(p-tolyl)ethan-1-ol with 2-([1,1'-biphenyl]-4-yl)ethan-1-ol.
  • BB5 (R)-1-amino-3-methylbutylboronic acid pinacol ester hydrochloride is a commercial fragment and can be purchased (purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.).
  • BB6 (R)-1-Amino-3-methylbutylboronic acid pinanediol ester trifluoroacetate is a commercial fragment and can be purchased (purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.).
  • Example 1 (Implementation Method 1): ((1R)-1-(2-methyl-3-oxo-3-(((6-phenylpyridin-2-yl)methyl)amino)propionylamino )-2-phenylethyl)boronic acid
  • Step 1 ((6-phenylpyridin-2-yl)methyl)carbamic acid tert-butyl ester
  • Step 3 ethyl 2-methyl-3-oxo-3-(((6-phenylpyridin-2-yl)methyl)amino)propionate
  • Step 4 2-Methyl-3-oxo-3-(((6-phenylpyridin-2-yl)methyl)amino)propionic acid
  • Step 5 2-Methyl-N 1 -((R)-2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )ethyl)-N 3 -((6-phenylpyridin-2-yl)methyl)malonamide
  • reaction mixture was stirred in an ice bath for 2 hours and then slowly warmed to room temperature overnight. After the reaction, the reaction solution was diluted with water (3mL) and extracted with dichloromethane (3mLx2). The combined organic layers were washed with saturated aqueous sodium chloride solution (3 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product as a yellow oil (90 mg).
  • Step 6 ((1R)-1-(2-methyl-3-oxo-3-(((6-phenylpyridin-2-yl)methyl)amino)propionylamino)-2-phenylethyl base) boric acid
  • reaction solution was washed with petroleum ether (2mLx2), the methanol layer was concentrated, and the crude product was separated and purified by thin layer preparative chromatography (chromatography solution: 9% methanol in dichloromethane) to obtain a white solid (12mg, 16%) .
  • Step 2 (R)-N 1 -benzyl-N 4 -(2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2- Ethyl) fumaramide
  • Step 3 (R,E)-(1-(4-(Benzylamino)-4-oxobut-2-enamido)-2-phenylethyl)boronic acid
  • Example 3 (implementation method three): ((1R)-1-(2-(cyclopropylmethyl)-3-((3-methoxybenzyl)amino)-3-oxopropionamide) -2-phenylethyl)boronic acid
  • Step 1 3-((3-methoxybenzyl)amino)-3-oxopropionic acid ethyl ester
  • Step 2 2-(cyclopropylmethyl)-3-((3-methoxybenzyl)amino)-3-oxopropionic acid ethyl ester
  • Step 4 2-(cyclopropylmethyl)-N 1 -(3-methoxybenzyl)-N 3 -((R)-2-phenyl-1-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)malonamide
  • reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mLx2). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product as a yellow oil (150 mg, 62%).
  • Step 5 ((1R)-1-(2-(cyclopropylmethyl)-3-((3-methoxybenzyl)amino)-3-oxopropionamido)-2-phenylethyl ) boric acid
  • reaction solution was concentrated under reduced pressure, then diluted with water (20 mL), and extracted with dichloromethane (20 mLx2). The combined organic layers were washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated and purified by reverse-phase preparative spectroscopy (mobile phase: 60% acetonitrile aqueous solution) to obtain a white solid (39 mg, 31%).
  • the implementation method is the same as method one, except that the starting material benzylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and dimethylmalonate monoethyl is used to replace methylmalonate monoethyl. ester to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material aniline is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and 1,1-cyclopropyldicarboxylic acid monomethyl ester is used to replace methylmalonic acid. Monoethyl ester gave the title compound.
  • the implementation method is the same as method 1, except that the starting material benzylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and 1,1-cyclopropyldicarboxylic acid monomethyl ester is used to replace methylpropanediamine. acid monoethyl ester to obtain the title compound.
  • Step 1 (R)-N 1 -(benzylcarbamoyl)-N 3 -2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Heterocyclopentan-2-yl)ethylurea
  • Step 2 (R)-(1-(3-(Benzylcarbamoyl)ureido)-2-phenylethyl)boronic acid
  • the implementation method is the same as method 2, except that the starting material aniline is used to replace the corresponding benzylamine to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material m-methoxybenzylamine is used to replace (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB3 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 2.
  • the starting material p-methylbenzylamine is used to replace the corresponding benzylamine, and the fragment BB2 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 2.
  • the starting material p-methylbenzylamine is used to replace the corresponding benzylamine, and the fragment BB5 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 2, except that the starting material 2,4-dichlorobenzylamine is used to replace the corresponding benzylamine to obtain the title compound.
  • the implementation method is the same as method 2.
  • the starting material (6-phenylpyridin-2-yl)methanamine hydrochloride is used to replace the corresponding benzylamine, and the fragment BB5 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 2, except that the starting material (6-phenylpyridin-2-yl)methanamine hydrochloride is used to replace the corresponding benzylamine to obtain the title compound.
  • the implementation method is the same as method 2, except that the starting material p-methylbenzylamine is used to replace the corresponding benzylamine to obtain the title compound.
  • the implementation method is the same as method 2, except that the starting material monoethyl succinate is used to replace the corresponding monoethyl fumarate to obtain the title compound.
  • the implementation method is the same as method 2, except that the starting material deuterated malonic acid is used to replace the corresponding monoethyl fumarate to obtain the title compound.
  • the implementation method is the same as method 2.
  • the starting material cyclohexylmethylamineamine is used to replace the corresponding benzylamine, and the fragment BB6 is used to replace the corresponding fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 2, except that the starting material (1R, 2R)-cyclopropane-1,2-dicarboxylic acid monoethyl ester is used to replace the corresponding fumaric acid monoethyl ester to obtain the title compound.
  • the implementation method is the same as method 2.
  • the starting material p-methoxybenzylamine is used to replace the corresponding benzylamine, and the fragment BB6 is used to replace the corresponding fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 2.
  • the starting material m-methoxybenzylamine is used to replace the corresponding benzylamine, and the fragment BB6 is used to replace the corresponding fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material monoethyl malonate is used to replace the corresponding 2-methylmalonate monoethyl ester, and [1,1'-biphenyl]-3-ylmethylamine is used to replace (6- Phenylpyridin-2-yl)methanamine hydrochloride, substituting fragment BB3 for fragment BB1, afforded the title compound.
  • the implementation method is the same as method 2.
  • the starting material (1R, 2R)-cyclopropane-1,2-dicarboxylic acid monoethyl ester is used to replace the corresponding fumaric acid monoethyl ester, and the fragment BB6 is used to replace the corresponding fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 2, except that fragment BB2 is used to replace the corresponding fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 2, except that fragment BB6 is used to replace the corresponding fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 2.
  • the starting material aniline is used to replace the corresponding benzylamine, and the fragment BB2 is used to replace the corresponding fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material monoethyl malonate is used to replace the corresponding 2-methylmalonate monoethyl ester, and [1,1'-biphenyl]-3-ylmethylamine is used to replace (6- Phenylpyridin-2-yl)methanamine hydrochloride, substituting fragment BB2 for fragment BB1, afforded the title compound.
  • the implementation method is the same as method 1.
  • the starting material benzylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB6 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1, except that the starting material benzylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride to obtain the title compound.
  • the implementation method is the same as method 2, except that the starting material cyclohexylmethylamine is used to replace the corresponding benzylamine to obtain the title compound.
  • 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.
  • the implementation method is the same as method 2, except that the starting material p-methoxybenzylamine is used to replace the corresponding benzylamine to obtain the title compound.
  • the implementation method is the same as method 2, except that the starting material tetrahydrofurfurylamine is used to replace the corresponding benzylamine to obtain the title compound.
  • the implementation method is the same as method 2.
  • the starting material tetrahydrofurfurylamine is used to replace the corresponding benzylamine, and the fragment BB5 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 2, except that the corresponding monoethyl fumarate is replaced with cononic acid in the starting material to obtain the title compound.
  • Example 36 ((1R)-2-([1,1'-biphenyl]-4-yl)-1-(3-((3-methoxybenzyl)amino)-2-methyl -3-Oxopropionamido)ethyl)boronic acid
  • the implementation method is the same as method 1.
  • the starting material m-methoxybenzylamine is used to replace (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB4 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 2, except that the starting material pyrazine-2-methylamine is used to replace the corresponding benzylamine to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material benzylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB2 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material aniline is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB5 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material aniline is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB2 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material cyclohexylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB5 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material cyclohexylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB2 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material m-methoxybenzylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB2 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material monoethyl malonate is used to replace the corresponding 2-methylmalonate monoethyl ester, and [1,1'-biphenyl]-3-ylmethylamine is used to replace (6- Phenylpyridin-2-yl)methanamine hydrochloride gave the title compound.
  • the implementation method is the same as method 1, except that fragment BB1 is replaced with fragment BB2 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material monoethyl malonate is used to replace the corresponding 2-methylmalonate monoethyl ester, and m-methoxybenzylamine is used to replace (6-phenylpyridin-2-yl)methyl.
  • the implementation method is the same as method 1, except that the starting material aniline is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride to obtain the title compound.
  • the implementation method is the same as method one, except that the starting material m-methoxybenzylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and monoethyl malonate is used to replace 2-methylpropanediamine. Acid monoethyl ester and replacing fragment BB1 with fragment BB5 gave the title compound.
  • the implementation method is the same as method one, except that the starting material m-methoxybenzylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and monoethyl malonate is used to replace 2-methylpropanediamine. acid monoethyl ester to obtain the title compound.
  • the implementation method is the same as method one, except that the starting material m-methoxybenzylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and monoethyl malonate is used to replace 2-methylpropanediamine. Acid monoethyl ester, substituting fragment BB2 for fragment BB1, gave the title compound.
  • the implementation method is the same as method 1.
  • the starting material tetrahydrofurfurylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB5 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material tetrahydrofurfurylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB2 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1, except that the starting material cyclohexylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride to obtain the title compound.
  • the implementation method is the same as method 1, except that the starting material m-methoxybenzylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material 3-ethoxy-2-fluoro-2-methyl-3-oxopropionic acid is used to replace the corresponding 2-methylmalonate monoethyl ester to obtain the title compound.
  • Example 56 ((1R)-1-(2-fluoro-2-methyl-3-oxo-3-(((6-phenylpyridin-2-yl)methyl)amino)propionylamino) -2-(p-Tolyl)ethyl)boronic acid
  • the implementation method is the same as method 1.
  • the starting material 3-ethoxy-2-fluoro-2-methyl-3-oxopropionic acid is used to replace the corresponding 2-methylmalonate monoethyl ester, and the fragment BB2 is used to replace the fragment BB1, the title compound was obtained.
  • the implementation method is the same as method 1.
  • the starting material (6-phenylpyridin-2-yl)methanamine hydrochloride is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride and the fragment BB3 is used. Fragment BB1 gave the title compound.
  • Example 58 ((1R)-2-([1,1'-biphenyl]-4-yl)-1-(2-methyl-3-oxo-3-((((6-phenyl) pyridin-2-yl)methyl)amino)propionamido)ethyl)boronic acid
  • the implementation method is the same as method 1, except that the starting material (6-phenylpyridin-2-yl)methanamine hydrochloride is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride and the fragment BB4 is used. Fragment BB1 gave the title compound.
  • the implementation method is the same as method 1.
  • the starting material 2,4-dichlorobenzylamine hydrochloride is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB2 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material 2,4-dichlorobenzylamine hydrochloride is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB3 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1, except that the starting material 2-(3-methoxyphenyl)ethyl-1-amine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride to obtain the title compound.
  • Example 62 ((1R)-1-(3-((3-methoxyphenylethyl)amino)-2-methyl-3-oxopropionamido)-2-(p-tolyl)ethyl base) boric acid
  • the implementation method is the same as method 1.
  • the starting material 2-(3-methoxyphenyl)ethyl-1-amine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride and the fragment BB2 is used. Fragment BB1 gave the title compound.
  • the implementation method is the same as method 1, except that the starting material 2-(3-methoxyphenyl)ethyl-1-amine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride and the fragment BB3 is used. Fragment BB1 gave the title compound.
  • Example 64 ((1R)-2-([1,1'-biphenyl]-4-yl)-1-(3-((3-methoxyphenethyl)amino)-2-methyl -3-Oxopropionamido)ethyl)boronic acid
  • the implementation method is the same as method 1, except that the starting material 2-(3-methoxyphenyl)ethyl-1-amine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride and the fragment BB4 is used. Fragment BB1 gave the title compound.
  • Example 65 ((1R)-1-(2-benzyl-3-((3-methoxybenzyl)amino)-3-oxopropionamido)-2-(p-tolyl)ethyl ) boric acid
  • the implementation method is the same as method 1.
  • the starting material 3-methoxybenzylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the corresponding 2-benzylmalonate monoethyl ester is used. of 2-methylmalonate monoethyl ester and replacing fragment BB1 with fragment BB2 to obtain the title compound.
  • the implementation method is the same as method one, using the starting material 3-methoxybenzylamine to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and using 2-benzylmalonate monoethyl ester to replace the corresponding 2-methylmalonate monoethyl ester, replacing fragment BB1 with fragment BB6 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material 4-methoxyaniline is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride to obtain the title compound.
  • Example 68 ((1R)-1-(3-((3-methoxyphenyl)amino)-2-methyl-3-oxopropionamido)-2-(p-tolyl)ethyl ) boric acid
  • the implementation method is the same as method 1.
  • the starting material 3-methoxyaniline is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB2 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material 4-methoxyaniline is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride to obtain the title compound.
  • Example 70 ((1R)-1-(3-((4-methoxyphenyl)amino)-2-methyl-3-oxopropionamido)-2-(p-tolyl)ethyl ) boric acid
  • the implementation method is the same as method 1.
  • the starting material 4-methoxyaniline is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB2 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material 3-methoxybenzylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the corresponding 2-benzylmalonate monoethyl ester is used.
  • 2-methylmalonate monoethyl ester replacing fragment BB1 with fragment BB3 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material 3-methoxybenzylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the corresponding 2-benzylmalonate monoethyl ester is used.
  • 2-methylmalonate monoethyl ester replacing fragment BB1 with fragment BB4 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material 3-trifluoromethoxybenzylamine hydrochloride is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB3 is used to replace the fragment BB1 to obtain Title compound.
  • the implementation method is the same as method 1.
  • the starting material 3-trifluoromethoxybenzylamine hydrochloride is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB4 is used to replace the fragment BB1 to obtain Title compound.
  • the implementation method is the same as method 1.
  • the starting material 3-methoxybenzylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride and 2-isopropylmalonate monoethyl ester.
  • the implementation method is the same as method 1.
  • the starting material 3-methoxybenzylamine is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride and 2-isopropylmalonate monoethyl ester.
  • Example 77 ((1R)-2-(benzofuran-3-yl)-1-(2-methyl-3-oxo-3-((3-(trifluoromethyl)benzyl)amino) )propionamido)ethyl)boric acid
  • the implementation method is the same as method 1.
  • the starting material 3-trifluoromethylbenzylamine hydrochloride is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB3 is used to replace the fragment BB1 to obtain the title compound.
  • Example 78 ((1R)-2-([1,1'-biphenyl]-4-yl)-1-(2-methyl-3-oxo-3-((3-(trifluoromethyl) Base)benzyl)amino)propionamido)ethyl)boronic acid
  • the implementation method is the same as method 1.
  • the starting material 3-trifluoromethylbenzylamine hydrochloride is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB4 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1, except that the starting material aniline is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and dimethylmalonate monoethyl ester is used to replace methylmalonate monoethyl ester. , to obtain the title compound.
  • Example 80 ((1R)-1-(2-(cyclopropylmethyl)-3-((3-methoxybenzyl)amino)-3-oxopropionamido)-2-(p Tolyl)ethyl)boric acid
  • the implementation method is the same as method 3, except that fragment BB1 is replaced with fragment BB2 to obtain the title compound.
  • Example 81 ((1R)-2-(benzofuran-3-yl)-1-(2-(cyclopropylmethyl)-3-((3-methoxybenzyl)amino)-3 -Oxopropionamido)ethyl)boronic acid
  • the implementation method is the same as method 3, except that fragment BB3 is used to replace fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 3, except that fragment BB1 is replaced with fragment BB6 to obtain the title compound.
  • the implementation method is the same as method 3.
  • the starting material bromomethylcyclohexane is used to replace the corresponding bromomethylcyclopropane, and the fragment BB2 is used to replace the fragment BB1 to obtain the title compound.
  • Example 84 ((1R)-2-(benzofuran-3-yl)-1-(2-(cyclohexylmethyl)-3-((3-methoxybenzyl)amino)-3- Oxypropionamido)ethyl)boronic acid
  • the implementation method is the same as method 3.
  • the starting material bromomethylcyclohexane is used to replace the corresponding bromomethylcyclopropane, and the fragment BB3 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 3.
  • the starting material bromomethylcyclohexane is used to replace the corresponding bromomethylcyclopropane, and the fragment BB6 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 1.
  • the starting material 3-trifluoromethoxybenzylamine hydrochloride is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB2 is used to replace the fragment BB1 to obtain Title compound.
  • the implementation method is the same as method 3.
  • the starting material 2-iodopropane is used to replace the corresponding bromomethylcyclopropane, and the fragment BB2 is used to replace the fragment BB1 to obtain the title compound.
  • the implementation method is the same as method 3.
  • the starting material 2,4-dichlorobenzylamine is used to replace the corresponding 3-methoxybenzylamine
  • the starting material 2-iodopropane is used to replace the corresponding bromomethylcyclopropane
  • the fragment BB2 is used Substitution of fragment BB1 afforded the title compound.
  • the implementation method is the same as method 3.
  • the starting material 2,4-dichlorobenzylamine is used to replace the corresponding 3-methoxybenzylamine
  • the starting material 2-iodopropane is used to replace the corresponding bromomethylcyclopropane
  • the fragment BB3 is used Substitution of fragment BB1 afforded the title compound.
  • the implementation method is the same as method 1.
  • the starting material 5-(aminomethyl)indole is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and 2-benzylmalonate monoethyl ester is used. Substitution of the corresponding 2-methylmalonate monoethyl ester and fragment BB2 for fragment BB1 gave the title compound.
  • the implementation method is the same as method 1.
  • the starting material 5-(aminomethyl)indole is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and 2-benzylmalonate monoethyl ester is used. Substituting the corresponding 2-methylmalonate monoethyl ester and fragment BB3 for fragment BB1 afforded the title compound.
  • the implementation method is the same as method 1.
  • the starting material 3-trifluoromethylbenzylamine hydrochloride is used to replace the corresponding (6-phenylpyridin-2-yl)methanamine hydrochloride, and the fragment BB2 is used to replace the fragment BB1 to obtain the title compound.
  • Example 93 ((R)-1-((S)-2-fluoro-2-methyl-3-oxo-3-((6-phenylpyridin-2-yl)methyl)amino) Propionamido)-2-(p-tolyl)ethyl)boronic acid and ((R)-1-((R)-2-fluoro-2-methyl-3-oxo-3-(((6- Phenylpyridin-2-yl)methyl)amino)propionamido)-2-(p-tolyl)ethyl)boronic acid
  • Example 94 ((R)-1-((R)-2-methyl-3-oxo-3-((3-(trifluoromethoxy)benzyl)amino)propionamido)-2 -(p-tolyl)ethyl)boronic acid and ((R)-1-((S)-2-methyl-3-oxo-3-((3-(trifluoromethoxy)benzyl)amino) )propionamido)-2-(p-tolyl)ethyl)boronic acid
  • Example 95 (implementation method four): ((1R)-1-(2-fluoro-3-oxo-3-((3-(trifluoromethoxy)benzyl)amino)propionamido)-2 -Phenylethyl)boronic acid
  • Step 2 2-Fluoro-N 1 -((R)-2-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl )ethyl)-N 3 -(3-(trifluoromethoxy)benzyl)malonamide
  • reaction solution was diluted with water (20 mL) and extracted with dichloromethane (20 mLx2). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a brown solid (120 mg, 71%).
  • Step 3 ((1R)-1-(2-fluoro-3-oxo-3-((3-(trifluoromethoxy)benzyl)amino)propionamido)-2-phenylethyl) Boric acid
  • reaction solution was washed with petroleum ether (2mLx2), the methanol layer was concentrated, and the crude product was separated and purified by thin layer preparative chromatography (chromatography solution: 9% methanol in dichloromethane solution) to obtain a white solid (55mg, 54%) .
  • Example 96 ((1R)-1-(2-fluoro-3-oxo-3-((3-(trifluoromethoxy)benzyl)amino)propionamido)-2-(p-tolyl )ethyl)boric acid
  • the implementation method is the same as method 4, except that fragment BB1 is replaced with fragment BB2 to obtain the title compound.
  • the implementation method is the same as method 4, except that fragment BB1 is replaced with fragment BB3 to obtain the title compound.
  • the implementation method is the same as method 4, except that 2,2-difluoromalonate diethyl ester is used to replace 2-fluoromalonate dimethyl ester, and fragment BB2 is used to replace fragment BB1 to obtain the title compound.
  • the implementation method was the same as Example 7, except that 1-(4-methoxybenzyl)urea was used to replace benzyl urea, and fragment BB2 was used to replace fragment BB1 to obtain the title compound.
  • Example 100 ((1R)-1-(2-fluoro-3-((3-methoxyphenylethyl)amino)-3-oxopropionamido)-2-(p-tolyl)ethyl ) boric acid
  • the implementation method is the same as method 4, except that 3-trifluoromethoxybenzylamine is replaced with 3-methoxyphenylethylamine, and fragment BB1 is replaced with fragment BB2 to obtain the title compound.
  • the implementation method is the same as method 4, except that 3-methoxyphenylethylamine is used to replace 3-trifluoromethoxybenzylamine, and fragment BB3 is used to replace fragment BB1 to obtain the title compound.
  • Example 102 ((1R)-1-(2-fluoro-3-((3-methoxybenzyl)amino)-3-oxopropionamido)-2-phenylethyl)boronic acid
  • the implementation method is the same as method 4, except that 3-trifluoromethoxybenzylamine is replaced with 3-methoxybenzylamine to obtain the title compound.
  • the implementation method is the same as method 4, except that 3-trifluoromethoxybenzylamine is replaced with 3-methoxybenzylamine, and fragment BB1 is replaced with fragment BB2 to obtain the title compound.
  • Example 104 ((1R)-2-(benzofuran-3-yl)-1-(2-fluoro-3-((3-methoxybenzyl)amino)-3-oxopropionamide )ethyl)boric acid
  • the implementation method is the same as method 4, except that 3-trifluoromethoxybenzylamine is replaced with 3-methoxybenzylamine, and fragment BB1 is replaced with fragment BB3 to obtain the title compound.
  • the present invention uses the fluorescent polypeptide substrate Ac-Ala-Asn-Trp-AMC (abbreviation Ac-ANW-AMC) to measure the activity of the ⁇ 5i subunit of the 20S proteasome.
  • the activity of the 20S proteasome ⁇ 5c subunit was measured using the Promega trypsin-like kit (Cat. No.: G8660) containing the fluorescent peptide substrate Suc-Leu-Leu-Val-Tyr-AMC (abbreviated Suc-LLVY-AMC).
  • the proteasome measured in the present invention came from Raji cells, the Ac-ANW-AMC fluorescent substrate was purchased from Roche Company, and other reagents were purchased from Sigma Company.
  • the experiment is divided into two parts: cell lysis system and enzyme reaction system.
  • the enzyme lysis system is 100 ⁇ L, including 7 ⁇ 10 5 cells of Raji cells, 100 ⁇ L of lysis solution; 50 ⁇ L of enzyme reaction system, 25 ⁇ L of proteasome, and 25 ⁇ L of substrate buffer.
  • the initial concentration of the drug (inhibitor) is 1 ⁇ M, diluted three times, and administered in 8 doses (that is, the dosage concentration can be 1 ⁇ M, 0.333 ⁇ M, 0.111 ⁇ M).
  • the specific experimental process is as follows:
  • the fluorescent peptide substrate Suc-LLVY-AMC was prepared according to the instructions of the Promega kit.
  • Inhibition rate (maximum signal value - compound signal value) / (maximum signal value - blank signal value) ⁇ 100%
  • the maximum signal was obtained from the cell lysate treated with DMSO only; the blank signal was obtained from the wells containing only the lysate.
  • the cells used in this experiment were MM.1S cell lines, and the detection reagent was CellTiter-Glo (from Promega Company).
  • the experimental system is 190 ⁇ L, which contains 100 ⁇ L of cell suspension, 50 ⁇ L of drug, and 40 ⁇ L of detection solution.
  • the specific experimental process is as follows: MM.1S cells in the logarithmic growth phase and in good cell condition are digested with trypsin into single cells, centrifuged to remove the supernatant, and then diluted to 1 ⁇ 10 5 cells/well after counting and spread in 96 wells. In the microplate, add 100 ⁇ L of cell suspension to each well, and set the well with only RPMI1640 complete medium as a blank control. Transfer the 96-well plate to a 37°C incubator containing 5% CO and incubate for 24 hours.
  • Drug handling is
  • Inhibition rate (maximum signal value - compound signal value) / (maximum signal value - blank signal value) ⁇ 100%
  • the maximum signal was obtained from cells treated with DMSO only; the blank signal was obtained from wells containing only culture medium.
  • LC-MS Shiadzu LC-MS 2020 and LC-2030Plus
  • SIM mode for standard solutions with concentrations of 1000ng/mL, 500ng/mL, 250ng/mL, 125ng/mL, 62.5ng/mL, and 31.25ng/mL.
  • concentrations 1000ng/mL, 500ng/mL, 250ng/mL, 125ng/mL, 62.5ng/mL, and 31.25ng/mL.
  • the calibration curve is used for quantitative analysis to obtain the drug concentration data of each processed blood sample.
  • Drug concentration in blood drug concentration in blood sample after treatment ⁇ 4/drug molecular weight; the average blood drug concentration is the average drug concentration in blood at each sampling time point.
  • the compound of the present invention has good oral blood concentration and can be well absorbed orally:
  • the compound of the present invention has good blood concentration and can be used as an oral drug. In this regard, it is significantly better than the control compound bortezomib.

Abstract

本发明提供了式I所示的硼酸类蛋白酶体抑制剂化合物以及其作为蛋白酶体抑制剂的应用。

Description

一种硼酸类蛋白酶体抑制剂及其用途
本申请要求于2022年4月29日提交到中国国家知识产权局的发明名称为“一种硼酸类蛋白酶体抑制剂及其用途”的中国专利申请202210468496.X的优先权，其内容通过引用以整体并入本文。
技术领域
本发明属于药物合成领域，具体涉及一类硼酸类蛋白酶体抑制剂，以及其用途和制备方法。
背景技术
在真核细胞中，蛋白质降解主要通过泛素化路径介导：其中将要被降解的蛋白质被多肽泛素连接，然后26S蛋白酶体通过三种主要蛋白水解活性的作用降解所述的泛素化的蛋白质。在细胞中，蛋白酶体介导的降解在许多细胞功能过程中起着关键作用，如I类主要组织相容性复合体(MHC)抗原提呈、细胞凋亡、生长调控、NF-κB活化、抗原加工和促炎信号转导等。
蛋白酶体是由七种亚基组成的多聚体蛋白，在细胞中呈两种存在形式：广泛表达的组成性蛋白酶体和主要在免疫炎症系统表达的免疫蛋白酶体，二者在其亚基的组成上有所不同：组成性蛋白酶体中包含胰凝乳蛋白酶样活性亚基(β5c)、胱天蛋白酶样活性亚基(β1c)和胰蛋白酶样活性亚基(β2c)，在免疫蛋白酶体中这三个亚基被INF-γ诱导转化为相应的免疫性亚基(分别为β5i/LMP7、β1i/LMP2、β2i/MECL1)。因此，真核细胞中可具有不同比例的两种蛋白酶体。
蛋白酶体不只在Ⅰ类MHC抗原提呈中起着重要作用，而且还涉及多种病理性病症，包括恶性肿瘤、炎症疾病和自身免疫病等。现有技术在这方面已证实了蛋白酶体与上述疾病的发生和进程之间的关系。特别地，蛋白酶体抑制体现了癌症治疗的一种重要新策略。例如，金(King)等人描述了泛素-蛋白酶体途径在调控细胞周期、肿瘤生长和转移方面的重要作用(Science,274:1652-1659(1996))。
现有技术中的硼酸类蛋白酶体抑制剂虽然针对β5c和β5i两种亚基展现了好的活性，但其口服生物利用度方面并不令人满意。例如，已上市的蛋白酶体抑制剂硼替佐米由于生物利用度低不能口服使用。
因此，现有技术中迫切需要一种具有更好的口服生物利用度的蛋白酶体抑制剂，本发明揭示了一类新型硼酸类蛋白酶体抑制剂，并且一些化合物具有更好的口服生物利用度。这类化合物可以用来实现对相关疾病的治疗，尤其是对恶性疾病和自身免疫性疾病的治疗。
发明内容
本发明人通过大量研究发现，以下的具有式I结构的化合物或其药学上可接受的盐具有优良的蛋白酶体抑制作用。
为此，在第一方面，本发明提供了一种具有式I结构的化合物或其药学上可接受的盐：
其中，
X选自：任选被以下取代基取代的-C1～4烷基-、-C3～6环烷基-、-乙烯基-、-乙炔基-、-NH-、-NH-NH-和-杂环基-，所述取代基选自：氘、C1～4烷基、C1～10烷氧基、C3～6环烷基、杂环基、芳基、杂芳基、芳氧基、氰基、羟基、巯基、氨基和卤素；
R1和R3各自独立地选自：氢，或者任选被以下取代基取代的C1～10烷基、C3～6环烷基、芳基、杂芳基、苄基、杂环基和桥环烷基，所述取代基选自：氘、C1～4烷基、C1～10烷氧基、C3～6环烷基、杂环基、芳基、杂芳基、芳氧基、氰基、羟基、疏基、氨基和卤素；
R2选自：任选被以下取代基取代的C1～10烷基、苄基、联苯甲基和杂环基，其中所述取代基选自：氘、C1～4烷基、C1～10烷氧基、C3～6环烷基、杂环基、芳基、杂芳基、芳氧基、氰基、羟基、疏基、氨基和卤素。
更具体地，在一些实施方案中，所述式I化合物具有以下式II结构：
其中R1、R2、R3具有如权利要求1中所述的定义；
R2a和R2b各自独立地选自：氢、氘、C1～10烷基、苄基、异丙基、环丙甲基、环丁甲基、环戊甲基、环己基甲基、杂环基甲基和卤素，或者R2a、R2b和与之相连的碳原子一起形成3-6元碳环。
在另一些实施方案中，所述式I化合物具有以下式III结构：
其中R1、R2、R3具有如权利要求1中所述的定义；
R3a选自：氢、C1～10烷基、苄基、异丙基、环丙甲基、环丁甲基、环戊甲基、环己基甲基和杂环基甲基。
在另一些实施方案中，所述式I化合物具有以下式IV结构：
其中R1、R2、R3具有如权利要求1中所述的定义；
R4a、R4b、R4c和R4d各自独立地选自：氢、氘、C1～10烷基、卤素、羟基和氨基，其中所述氨基任选地被C1～4烷基或C3～6环烷基取代。
在另一些实施方案中，所述式Ⅰ化合物具有以下式V结构：
其中R1、R2、R3具有如权利要求1中所述的定义；
R5a和R5b各自独立地选自：氢、氘、C1～4烷基、卤素和羟基，R5a和R5b彼此呈顺式或反式取代形式。
在另一些实施方案中，所述式I化合物具有以下式VI结构：
其中R1、R2、R3具有如权利要求1中所述的定义；
环A选自：任选被以下取代基取代的-C3～6环烷基-和-杂环基-，其中所述取代基选自C1～4烷基、C1～10烷氧基、C3～6环烷基、氰基、羟基和卤素。
在本发明中，对于上述式I化合物或者式II-VI化合物而言，
R1和/或R3可优选为氢和以下的结构：
在本发明中，对于上述式I化合物或者式II-VI化合物而言，
R2可优选为以下的结构：
本发明中优选以下化合物或其可药用盐：






本发明还更优选以下化合物或其可药用盐：



在本发明的另一个方面，提供了一种药物组合物，其包含本发明所述的式I化合物或者其可药用盐，以及任选的可药用载体。在一些实施方案中，所述式I化合物具有上述式II、式III、式IV、式V或式VI结构。在另一些实施方案中，所述式I化合物为上述具体的化合物。
在本发明的又一个方面，提供了本发明的上述化合物或其可药用盐或其药物组合物在制备用作蛋白酶体抑制剂的药物中的应用。
在本发明的又一个方面，提供了本发明的上述化合物或其可药用盐或其药物组合物在制备用于治疗或预防蛋白酶体相关疾病的药物中的应用。
所述蛋白酶体相关疾病，包括例如肿瘤和自身免疫性疾病。本发明所述肿瘤包括实体瘤和血液瘤，其中实体瘤选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、星状细胞瘤、神经母细胞瘤、脑脊髓膜瘤、胃肠间质瘤、或鼻咽癌，包含上述肿瘤的原位瘤和转移瘤；血液瘤选自白血病、多发性骨髓瘤、套细胞淋巴瘤或组织细胞性淋巴癌；何杰金氏(Hodgkin's)淋巴瘤、非何杰金氏(non-Hodgkin's)淋巴瘤。本发明所述自身免疫性疾病的实例包含但不限于炎性反应，如包含牛皮癣和皮炎(例如，特应性皮炎)的炎性皮肤疾病；全身性硬皮病和硬化症；与炎性肠疾病(如克罗恩病和溃疡性结肠炎)相关的反应；呼吸窘迫综合征(包含成人呼吸窘迫综合征(ARDS))；皮炎；脑膜炎；脑炎；葡萄膜炎；结肠炎；肾小球肾炎；如湿疹和哮喘等过敏性病状以及涉及T细胞浸润和慢性炎性反应的其它病状；动脉粥样硬化；白细胞粘附不足；类风湿性关节炎；全身性红斑狼疮(SLE)；糖尿病(例如，I型糖尿病或胰岛素依赖型糖尿病)；多发性硬化症；雷诺氏(Raynaud's)综合症；自身免疫性甲状腺炎；格雷夫氏(Graves')病；过敏性脑脊髓炎；舍格伦氏(Sjogren's)综合症；青少年发病型糖尿病；以及由通常在结核病、结节病、多发性肌炎、肉芽肿病和血管炎中发现的细胞因子和T淋巴细胞介导的与急性和迟发型超敏反应相关的免疫反应；恶性贫血(阿迪森氏病)；涉及白细胞渗出的疾病；中枢神经系统(CNS)炎性病症；多器官损伤综合征；溶血性贫血(包含但不限于冷球蛋白血症或库姆氏阳性贫血)；重症肌无力；抗原-抗体复合物介导的疾病；抗肾小球基底膜疾病； 免疫复合物性肾炎；IgA肾病；抗磷脂综合征；过敏性神经炎；兰伯特-伊顿肌无力综合征；天疱疮性大疱；天疱疮；自身免疫性多内分泌腺病；瑞特氏(Reiter's)综合征；僵人综合征；贝赛特氏(Behcet's)疾病；巨细胞动脉炎；IgM多发性神经病；免疫性血小板减少性紫癜(ITP)或自身免疫性血小板减少症；器官移植引起的排斥反应以及移植物抗宿主病。在特定情况下，自身免疫性疾病是全身性红斑狼疮或狼疮性肾炎。在一些情况下，自身免疫性疾病是全身性血管炎或特发性炎性肌病。
在一些实施方案中，所述疾病选自肿瘤和自身免疫性疾病。在一些实施方案中，所述疾病为多发性骨髓瘤；在另一些实施方案中，所述疾病选自系统性红斑狼疮(SLE)和炎症性肠病(IBD)。
在本文中，式I化合物中的硼原子所连接的碳原子须保持式I中所示的特定立体构型；而其他碳原子为手性碳时，其可以采取R构型或S构型，本发明的化合物相应地包括单一的立体异构体或者不同比例的异构体的混合物。
本领域技术人员公知，一种化合物的盐、溶剂合物、水合物、硼酸多聚体是化合物的替代性存在形式，它们都可以在一定条件下转化为所述化合物，因此，特别注意的是在本文中当提到一种化合物时，一般地还包括它的可药用盐，进而还包括其溶剂合物、水合物和硼酸多聚体。
本发明所述的可药用盐可使用例如以下的无机酸或有机酸而形成：“可药用盐”是指这样的盐，在合理的医学判断范围内，其适用于接触人和较低等动物的组织，而没有不适当的毒性、刺激性、过敏反应等，称得上合理的受益/风险比。可以在本发明化合物的最终分离和纯化期间原位制备所述盐，或单独通过将游离碱或游离酸与合适的试剂反应制备所述盐，如下概述。例如，游离碱官能团可以与合适的酸反应。此外，当本发明的化合物带有酸性部分时，其合适的可药用盐可包括金属盐，例如碱金属盐(如钠盐或钾盐)；和碱土金属盐(如钙盐或镁盐)。可药用的无毒酸加成盐的示例是氨基与无机酸(例如，盐酸、氢溴酸、磷酸、硫酸和高氯酸)或有机酸(例如，醋酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐，或通过使用现有技术中的其他方法如离子交换形成的盐。其他可药用盐包括己二酸盐、海藻酸钠、抗坏血酸盐、天门冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙 磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。代表性碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐等。其他可药用盐包括(适当时)无毒铵盐、季铵盐和用反离子形成的铵阳离子，例如，卤化物、氢氧化物、羧酸盐、硫酸盐、磷酸盐、硝酸盐、低级烷基磺酸盐和芳基磺酸盐。
本发明的化合物或其可药用盐可作为活性成分通过口服或肠胃外施用，其有效量的范围为在哺乳动物包括人(体重约70kg)的情况下0.1至1000mg/kg体重/天、优选1至100mg/kg体重/天，并且每天以单次或分次剂量，或者遵循/不遵循预定时间施用。活性成分的剂量可根据多个相关因素(例如待治疗对象的情况、疾病类型和严重性、施用速率和医生意见)进行调整。在某些情况下，小于以上剂量的量可能是合适的。如果不引起有害的副作用则可使用大于以上剂量的量并且该量可以每天以分次剂量施用。
除此之外，本发明还提供了一种预防和/或治疗蛋白酶体相关疾病的方法，其包括向有此需要的哺乳动物(包括人)施用本发明的化合物或药物组合物。在一些实施方案中，所述蛋白酶体相关疾病选自肿瘤和自身免疫性疾病。在一些实施方案中，所述蛋白酶体相关疾病为多发性骨髓瘤；在另一些实施方案中，所述蛋白酶体相关疾病选自系统性红斑狼疮(SLE)和炎症性肠病(IBD)。
本文中“任选被以下取代基取代”是指X、R1、R2和R3等所述基团可以被取代基取代，也可以不被取代基取代，即并不仅限于被所列举的取代基取代的情况，也包括不被所列举的取代基取代的情况。这种表达方式与“R为取代或未取代的C1～10烷基、C3～6环烷基或杂环烷基、苯基、萘基或吲哚基，其中取代基为C1～4烷基、C1～4烷氧基、氰基、羟基、疏基、氨基或卤素”的表达方式相同，但是取代或未取代的限定并非仅狭义地指C1～10烷基，而是适用于所有所述的基团。在本文中，提及“任选取代”时，取代基可以是氘、C1～4烷基、C1～10烷氧基、C3～6环烷基、杂环基、芳基、杂芳基、芳氧基、氰基、羟基、巯基、氨基和卤素；其中所述作为取代基的芳基可以被氘、C1～4烷基、C1～10烷氧基、C3～6环烷基、氰基、羟基、巯基、氨基和卤素等取代基进一步取代。
术语“烷基”用于表示直链或支链的饱和烃基，例如，C1～3烷基是指含有1～3个碳原子的饱和烃基，C1～4烷基是指含有1～4个碳原子的饱和烃基，C1～10的烷基是指含有1～10个碳原子的饱和烃基。
术语“烷氧基”是指烷基-O-。“C1～6烷氧基”意欲包括C1、C2、C3、C4、C5、C6烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)和叔丁氧基。类似地，“烷基硫基”或“硫代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的烷基；例如甲基-S-和乙基-S-。本文中优选的烷氧基是C1～6烷氧基。
术语“环烷基”指非芳族碳环基，包括环化的烷基。环烷基可以包括单环、二环或多环系统。环烷基的例子包括环丙基、环丁基、环戊基、环己基、环庚基等，C3～6环烷基是指含有3～6个碳原子的环烷基。
术语“杂环烷基”或“杂环基”是指非芳族杂碳环基，其中1个或2个或3个成环碳原子被杂原子例如O、N或S原子取代。杂环烷基优选具有3，4，5，6或7个成环原子。本文中优选的杂环基是C3-8杂环基。
术语“苄基”是指苯甲基，取代的苄基是指在苄基的苯环上至少一个氢原子被非氢部分取代，苄基的取代基可以是卤素、-CN、-OH、-SH、-NH2、C1-6烷基。
术语“C1～3烷基杂环基”是指在含有1～3个碳原子的饱和烃基上取代芳族杂环基团或者非芳族杂环基团，包括环化的烷基，其中一个或多个成环碳原子被杂原子例如O，N或S原子取代。杂环烷基优选具有3，4，5，6或7个成环原子。
“C1～10烷氧基”是指-O-烷基基团，烷基包括直链、支链和环状烷基，其碳原子数为1～10个。烷氧基的例子包括甲氧基，乙氧基，丙氧基(如，正丙氧基、异丙氧基和环丙氧基)，叔丁氧基等。
“芳基”是指芳族碳环基，包括单环、二环、三环或多环芳烃，例如苯基，萘基，蒽基，菲基等。芳基优选具有5至12个环成员的单环、二环或三环的环系统，其中所述系统中的至少一个环为芳族的且其中所述系统中的每个环含有3至7个环成员。“取代的芳基”是指在芳基的苯环上至少一个氢原子被非氢部分取代，芳基的取代基可以是卤素、C1～10烷氧基、-CN、-OH、-SH、-NH2、C1～6烷基。优选的芳基包括苯基、联苯基、茚满基、1-萘基、2-萘基和四氢萘基。术语“芳烷基”或“芳基烷基”是指连接至芳基环的烷基残基。非限制性实例包括苄基、 苯乙基等。稠合的芳基可在环烷基环或芳族环的合适位置上连接至另一基团。例从环系统中画出的虚线表明键可连接至任意合适的环原子。
术语“杂芳基”意指稳定的5-12元的芳香单环或芳香二环或芳香多环杂环，其为完全不饱和的、部分不饱和的，且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子。其包括5元、6元或7元的芳香单环或8元、9元、10元、11元、12元的芳香二环或芳香多环杂环；优选上文所定义的任意杂环与苯环稠合。氮和硫杂原子可任选地被氧化。氮原子为取代的或未取代的(即N或NR，其中R为H或如果被定义，则为另一取代基)。杂环可在得到稳定结构的任何杂原子或碳原子处连接至其侧基。如果所得化合物是稳定的，则本文所述的杂环基可在碳或氮原子上被取代。杂环中的氮可任选地被季铵化。优选地，当杂环中S和O原子的总数超过1时，则这些杂原子彼此不相邻。芳杂基的实施例包括但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、萘嵌间二氮杂苯基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基、喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢-喹啉基、 2,3-二氢-苯并呋喃基、1,2,3,4-四氢-喹喔啉基和1,2,3,4-四氢-喹唑啉基。术语“杂芳基”还可以包括由上述所定义的“芳基”与单环“杂芳基”所形成的联芳基结构，例如但不限于“-苯基联吡啶基-”、“-苯基联嘧啶基”、“-吡啶基联苯基”、“-吡啶基联嘧啶基-”、“-嘧啶基联苯基-”。
“芳氧基”是指-O-芳基，而芳基的概念如上所述，芳氧基最优选的例子是苯氧基。
“卤素”包括氟、氯、溴和碘。
本文使用的术语“桥环烷基”指的是共用两个或两个以上碳原子的多环化合物，包括二环桥环烃及多环桥环烃。前者由两个脂环共用两个以上碳原子所构成；后者是由三个以上的环组成的桥环烃。本文中优选的桥环烷基选自金刚烷基和金刚烷-1-基-甲基。
具体实施方式
第一部分：化合物的合成
合成实施例：
关键中间体片段BB1：(R)-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)乙-1-胺盐酸盐：
实施步骤：
步骤1：(R,E)-2-甲基-N-(2-苯基亚乙基)丙烷-2-亚磺酰胺
将苯乙醛(4.40g,20.0mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(2.43g,20.0mmol)溶于干燥的四氢呋喃(40mL)中，然后缓慢滴加钛酸四乙酯(7.7mL,40.0mmol)。反应液在室温下搅拌反应26小时。反应结束后向反应液中加入水(60mL)继续搅拌30分钟，将不溶物过滤后滤液用乙酸乙酯(60ml×2)萃取，有机相合并后用饱和氯化钠溶液(40mL)洗涤，无水硫酸钠干燥，过滤后浓缩。剩余物经柱层析分离纯化(洗脱液：10％乙酸乙酯的石油醚溶液)得到无色液体(3.50g,78％)。
LC-MS m/z:224.0[M+1]+.
1HNMR(400MHz,CDCl3):δ8.13(t,J＝5.2Hz,1H),7.35–7.22(m,5H),3.88–3.78(m,2H),1.19(s,9H).
步骤2：(R)-2-甲基-N-((R)-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)乙基)丙烷-2-亚磺酰胺
将(R,E)-2-甲基-N-(2-苯基亚乙基)丙烷-2-亚磺酰胺(3.50g,15.7mmol)溶于1,4-二氧六环(35mL)中，然后加入4-甲氧基苄胺(107mg,0.78mmol)，三环己基膦四氟硼酸盐(69mg,0.19mmol)和硫酸铜水溶液(6.3mL,0.03M,0.19mmol)，将反应液降至0℃后分批加入联硼酸频那醇酯(5.97g,23.5mmol)。反应液在氮气保护下缓慢升至室温并搅拌反应15小时。反应结束后将反应液倒入水(40mL)中，用乙酸乙酯(30ml×2)萃取，有机相合并后用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤后浓缩。剩余物经柱层析分离纯化(洗脱液：35％二氯甲烷的石油醚溶液)得到无色液体化合物(3.30g,60％)。
1HNMR(400MHz,DMSO-d6):δ7.28–7.16(m,5H),4.79(d,J＝5.6Hz,1H),3.09–3.03(m,1H),2.97–2.92(m,1H),2.82–2.77(m,1H),1.11(s,6H),1.08(s,9H),1.03(s,6H).
步骤3：(R)-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)乙-1-胺盐酸盐
将(R)-2-甲基-N-((R)-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)乙基)丙烷-2-亚磺酰胺(250mg,0.72mmol)溶于甲醇(5mL)中，然后加入氯化氢的二氧六环溶液(0.9mL,4M,3.55mmol)。反应液在室温下搅拌30分钟，反应结束后将反应液减压浓缩，粗产物经叔丁基甲醚(2mL)打浆得到黄色固体(210mg,99％)。
LC-MS m/z:248.1[M+1]+.
1HNMR(400MHz,DMSO-d6):δ8.00(brs,3H).7.34–7.30(m,2H),7.26–7.23(m,3H),3.03–2.96(m,2H),2.90–2.83(m,1H),1.18(s,6H),1.14(s,6H).
关键中间体片段BB2：(R)-1-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2-(对甲苯基)乙-1-胺盐酸盐:
实施步骤：
步骤1：2-(对甲苯基)乙醛
将2-(对甲苯基)乙-1-醇(1.36g,10.0mmol)溶于二氯甲烷(25mL)中，然后在0℃下分3批加入戴斯-马丁试剂(4.67g,11.0mmol)。反应结束后向反应液中加入饱和硫代硫酸钠溶液(30mL)淬灭并搅拌30分钟。有机相依次用饱和碳酸氢钠溶液(30ml×2)、饱和氯化钠溶液(30mL)洗涤，然后用无水硫酸钠干燥，过滤后减压浓缩得到无色液体(1.10g,82％)。
1HNMR(400MHz,CDCl3):δ9.73(t,J＝2.4Hz,1H),7.19–7.17(m,2H),7.11–7.09(m,2H),3.64(d,J＝2.4Hz,2H),2.35(s,3H).
步骤2：(R,E)-2-甲基-N-(2-(对甲苯基)亚乙基)丙烷-2-亚磺酰胺
将2-(对甲苯基)乙醛(1.10g,8.2mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(1.20g,9.8mmol)溶于干燥的四氢呋喃(20mL)中，然后缓慢滴加钛酸四乙酯(3.4mL,16.4mmol)。反应液在室温下搅拌反应6小时。反应结束后向反应液中加入水(50mL)继续搅拌30分钟，将不溶物过滤后滤液用乙酸乙酯(50ml×2)萃取，有机相合并后用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤后浓缩。剩余物经柱层析分离纯化(洗脱液：10％乙酸乙酯的石油醚溶液)得到黄色液体(1.10g,57％)。
LC-MS m/z:238.3[M+1]+.
1HNMR(400MHz,CDCl3):δ8.11(t,J＝5.2Hz,1H),7.15–7.10(m,4H),3.83–3.74(m,2H),2.33(s,3H),1.19(s,9H),
步骤3：(R)-2-甲基-N-((R)-1-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-2-(对甲苯基)乙基)丙烷-2-亚磺酰胺
将(R,E)-2-甲基-N-(2-(对甲苯基)亚乙基)丙烷-2-亚磺酰胺(1.10g,3.01mmol)溶于1,4-二氧六环(20mL)中，然后加入4-甲氧基苄胺(32mg,0.23mmol)，三环己基膦四氟硼酸盐(21mg,0.056mmol)和硫酸铜水溶液(1.9mL,0.3M,0.056mmol)，将反应液降至0℃后分批加入联硼酸频那醇酯(1.76g,6.94mmol)。反应液在氮气保护下缓慢升至室温并搅拌反应6小时。反应结束后将反应液倒入水(50mL)中，用乙酸乙酯(50ml×2)萃取，有机相合并后用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤后浓缩。剩余物经柱层析分离纯化(洗脱液：20％乙酸乙酯的石油醚溶液)得到无色液体(1.35g,80％)。
LC-MS m/z:366.1[M+1]+.
1HNMR(400MHz,CDCl3):δ7.15(d,J＝8.0Hz,2H),7.08(d,J＝8.0Hz,2H),3.34–3.29(m,1H),3.24–3.22(m,1H),3.00–2.91(m,2H),2.30(s,3H),1.24(s,9H),1.20(s,6H),1.18(s,6H).
步骤4:(R)-1-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2-(对甲苯基)乙-1-胺盐酸盐
将(R)-2-甲基-N-((R)-1-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-2-(对甲苯基)乙基)丙烷-2-亚磺酰胺(250mg,0.71mmol)溶于甲醇(5mL)中，然后加入氯化氢的二氧六环溶液(0.9mL,4M,3.55mmol)。反应液在室温下搅拌30分钟，反应结束后将反应液减压浓缩，粗产物经叔丁基甲醚(2mL)打浆得到黄色固体(210mg,99％)。
LC-MS m/z:239.3[M-17]+.
1HNMR(400MHz,DMSO-d6):δ7.89(brs,3H),7.13(s,4H),2.98–2.90(m,2H),2.86–2.80(m,1H),2.27(s,3H),1.18(d,J＝13.2Hz,12H).
关键中间体片段BB3：(R)-2-(苯并呋喃-3-基)-1-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)乙-1-胺盐酸盐:
实施步骤：
步骤1：2-(苯并呋喃-3-基)乙酸乙酯
将苯并呋喃-3(2H)-酮(4g,29.8mmol)溶于甲苯(200mL)中，然后加入甲氧羰基亚甲基三苯基正磷(15.6g,44.7mmol)，反应液在氮气保护下搅拌反应48小时。反应结束后将反应液降至室温，将反应液减压浓缩，粗产物经柱层析分离纯化(洗脱液：2％—4％乙酸乙酯的石油醚溶液)得到黄色液体(3.5g,57％)。
LC-MS m/z:204.8[M+1]+.
1HNMR(400MHz,CDCl3):δ7.63(s,1H),7.58–7.56(m,1H),7.47(d,J＝8.0Hz,1H),7.32–7.28(m,1H),7.27-7.23(m,1H),4.22–4.16(m,2H),3.70(d,J＝1.2Hz,2H),1.27(t,J＝7.2Hz,3H).
步骤2：2-(苯并呋喃-3-基)乙-1-醇
将2-(苯并呋喃-3-基)乙酸乙酯(3.5g,17.1mmol)溶于四氢呋喃(20mL)中，然后在冰水浴、氮气保护下缓慢滴加到氢化铝锂(1.3g,34.2mmol)的四氢呋喃混悬液(50mL)中。反应液在室温下搅拌反应4小时。反应结束后向反应液中依次加入水(1.3mL)，氢氧化钠水溶液(1.3mL,15％)和水(3.9mL)，继续搅拌30分钟。过滤除去固体后滤液用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤后浓缩。剩余物经柱层析分离纯化(洗脱液：30％乙酸乙酯的石油醚溶液)得到黄色液体(2.3g,83％)。
LC-MS m/z:162.8[M+1]+.
1HNMR(400MHz,CDCl3):δ7.58–7.56(m,1H),7.52(brs,1H),7.49–7.47(m,1H),7.32–7.23(m,2H),3.96–3.91(m,2H),2.97–2.94(m,2H),1.55(t,J＝4.8Hz,1H).
步骤3：2-(苯并呋喃-3-基)乙醛
将2-(苯并呋喃-3-基)乙-1-醇(2.3g,14.2mmol)溶于二氯甲烷(110mL)中，然后在0℃下分3批加入戴斯-马丁试剂(7.2g,17mmol)。反应液在室温下搅拌反应16小时。反应结束后向反应液中加入饱和硫代硫酸钠溶液(30mL)淬灭并搅拌30分钟。有机相用饱和碳酸氢钠溶液(30mL×2)、饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，减压浓缩得到无色液体(2.23g,98％)。
1HNMR(400MHz,CDCl3):δ9.82(t,J＝2.0Hz,1H),7.65(brs,1H),7.52–7.48(m,2H),7.36–7.31(m,1H),7.29–7.25(m,1H),3.78–3.77(m,2H).
步骤4：(R,E)-N-(苯并呋喃-3-基)亚乙基)-2-甲基丙烷-2-亚磺酰胺
将2-(苯并呋喃-3-基)乙醛(2.23g,13.9mmol)、(R)-2-甲基丙烷-2-亚磺酰胺(2.03g,16.7mmol)和4-甲基苯磺酸吡啶(175mg,0.7mmol)溶于干燥的二氯甲烷(60mL)中，然后加入无水硫酸镁(8.4g,69.7mmol)。反应液在氮气保护下室温下搅拌反应24小时。反应结束将反应液过滤后浓缩。剩余物经柱层析分离纯化(洗脱液：10％乙酸乙酯的石油醚溶液)得到黄色液体(2.3g,62％)。
LC-MS m/z:263.9[M+1]+.
1HNMR(400MHz,CDCl3):δ8.19(t,J＝4.8Hz,1H),7.59(brs,1H),7.54–7.48(m,2H),7.34–7.30(m,1H),7.27–7.23(m,1H),3.91–3.90(m,2H),1.18(s,9H).
步骤5：(R)-N-((R)-2-(苯并呋喃-3-基)-1-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺
将(R,E)-N-(苯并呋喃-3-基)亚乙基)-2-甲基丙烷-2-亚磺酰胺(2.4g,9.1mmol)溶于甲苯(30mL)中，然后加入苄胺(49mg,0.45mmol)，三环己基膦四氟硼酸盐(41mg,0.11mmol)和硫酸铜水溶液(0.03N,3.7mL)，将反应液降至0℃后分批加入联硼酸频那醇酯(3.46g,13.7mmol)。反应液在氮气保护下缓慢升至室温并搅拌反应6小时。反应结束后将反应液倒入水(50mL)中，用乙酸乙酯(50mL×2)萃取，有机相合并后用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤后浓缩。剩余物经柱层析分离纯化(洗脱液：20％乙酸乙酯的石油醚溶液)得到无色液体(1.3g,36％)。
LC-MS m/z:391.9[M+1]+.
1HNMR(400MHz,DMSO-d6):δ7.77(s,1H),7.66–7.64(m,1H),7.53(d,J＝7.6Hz,1H),7.32–7.24(m,2H),5.02(d,J＝5.6Hz,1H),3.24–3.18(m,1H),3.02–2.91(m,2H),1.16(s,6H),1.11(s,9H),1.02(s,6H).
步骤6:(R)-2-(苯并呋喃-3-基)-1-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)乙-1-胺盐酸盐
将(R)-N-((R)-2-(苯并呋喃-3-基)-1-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺(1.3g,3.32mmol)溶于甲醇(5mL)中，然后加入氯化氢的二氧六环溶液(4N,1mL)。反应液在室温下搅拌1小时，反应结束后将反应液减压浓缩，粗产物经叔丁基甲基醚(15mL)打浆后得到黄色固体(403mg,37％)。
LC-MS m/z:288.0[M+1]+.
1HNMR(400MHz,DMSO-d6):δ8.07(brs,3H),7.85(s,1H),7.73(d,J＝7.6Hz,1H),7.56(d,J＝8.0Hz,1H),7.35–7.26(m,2H),3.11–2.98(m,3H),1.17(s,6H),1.15(s,6H).
关键中间体片段BB4：(R)-2-([1,1'-联苯]-4-基)-1-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)乙-1-胺盐酸盐
实施步骤同片段BB2，用2-([1,1'-联苯]-4-基)乙-1-醇替换相应的2-(对甲苯基)乙-1-醇，获得标题化合物。
LC-MS m/z:324.2[M+1]+.
1HNMR(400MHz,DMSO-d6)δ7.97(s,3H),7.69–7.58(m,4H),7.51–7.43(m,2H),7.41–7.29(m,3H),3.10–2.85(m,3H),1.19(d,J＝13.0Hz,12H).
关键中间体片段BB5：(R)-1-氨基-3-甲基丁基硼酸频哪醇酯盐酸盐
BB5:(R)-1-氨基-3-甲基丁基硼酸频哪醇酯盐酸盐为商业化片段，可购买获得(购自上海毕得医药科技股份有限公司)。
关键中间体片段BB6：(R)-1-氨基-3-甲基丁基硼酸蒎烷二醇酯三氟乙酸盐
BB6:(R)-1-氨基-3-甲基丁基硼酸蒎烷二醇酯三氟乙酸盐为商业化片段，可购买获得(购自上海毕得医药科技股份有限公司)。
实施例1(实施方法一)：((1R)-1-(2-甲基-3-氧代-3-(((6-苯基吡啶-2-基)甲基)氨基)丙酰氨基)-2-苯乙基)硼酸

实施方法一：实施步骤：
步骤1：((6-苯基吡啶-2-基)甲基)氨基甲酸叔丁酯
在氮气保护下向((6-氯吡啶-2-基)甲基)氨基甲酸叔丁酯(800mg,3.30mmol)，苯硼酸(600mg,4.92mmol)和碳酸钠(870mg,8.20mmol)的1,4-二氧六环(8mL)和水(1mL)溶液中加入双二茂铁二氯化钯(241mg,0.33mmol)，反应体系氮气置换3次，加热至80℃反应18小时。反应结束后向反应液加水(60mL)和乙酸乙酯(60mL)萃取，合并有机相，无水硫酸钠干燥，过滤后减压浓缩，所得粗品经制备薄层层析分离纯化(洗脱液：50％乙酸乙酯的石油醚溶液)得到褐色固体(800mg,85％)。
LC-MS m/z:285.0[M+1]+.
步骤2：(6-苯基吡啶-2-基)甲胺盐酸盐
向((6-苯基吡啶-2-基)甲基)氨基甲酸叔丁酯(800mg,2.81mmol)的甲醇(8mL)溶液中加入和氯化氢的二氧六环溶液(6mL,4.0M)。反应液在室温下搅拌反应4小时。反应结束后将反应液减压浓缩，得到黄色固体(600mg)。粗产物未经进一步纯化直接用于下一步反应中。
LC-MS m/z:185.1[M+1]+.
步骤3：2-甲基-3-氧代-3-(((6-苯基吡啶-2-基)甲基)氨基)丙酸乙酯
向(6-苯基吡啶-2-基)甲胺盐酸盐(300mg,2.05mmol)，2-甲基丙二酸单乙酯(415mg,2.26mmol)和HATU(860mg,2.26mmol)的二氯甲烷(5mL)溶液中滴加二异丙基乙胺(795mg,6.16mmol)。反应混合物在冰浴下搅拌反应1小时后缓慢升至室温搅拌过夜。反应结束后将反应液用水(10mL)稀释，二氯甲烷(5mLx2)萃取。合并的有机层用饱和氯化钠水溶液(10mL)洗涤，无水硫酸钠干燥，过滤后浓缩，得到粗品产物黄色油状物(800mg)。
步骤4：2-甲基-3-氧代-3-(((6-苯基吡啶-2-基)甲基)氨基)丙酸
向2-甲基-3-氧代-3-(((6-苯基吡啶-2-基)甲基)氨基)丙酸乙酯(600mg,1.92mmol)的乙醇(10mL)溶液中加入氢氧化锂一水合物(242mg,5.77mmol)。反应混合物在室温下搅拌反应3小时。反应结束后减压浓缩，加水(10mL)溶解，并用稀盐酸(1N)调节pH至5～6左右用二氯甲烷(5mLx2)萃取，合并有机相后用饱和氯化钠水溶液(10mL)洗涤，无水硫酸钠干燥，过滤后浓缩，得到白色固体(300mg，55％)。
步骤5：2-甲基-N1-((R)-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)乙基)-N3-((6-苯基吡啶-2-基)甲基)丙二酰胺
向2-甲基-3-氧代-3-(((6-苯基吡啶-2-基)甲基)氨基)丙酸(50mg,0.18mmol)和片段BB1：(R)-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)乙-1-胺盐酸盐(55mg,0.19mmol)和HATU(2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)(80mg,0.21mmol)的二氯甲烷(1mL)溶液中加入二异丙基乙胺(57mg,0.44mmol)。反应混合物在冰浴下搅拌反应2小时后缓慢升至室温过夜。反应结束后将反应液用水(3mL)稀释，二氯甲烷(3mLx2)萃取。合并的有机层用饱和氯化钠水溶液(3mL)洗涤，无水硫酸钠干燥，过滤后浓缩得到粗品产物为黄色油状物(90mg)。
LC-MS m/z:514.0[M+1]+.
步骤6：((1R)-1-(2-甲基-3-氧代-3-(((6-苯基吡啶-2-基)甲基)氨基)丙酰氨基)-2-苯乙基)硼酸
将2-甲基-N1-((R)-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)乙基)-N3-((6-苯基吡啶-2-基)甲基)丙二酰胺(90mg,0.18mmol)和异丁基硼酸(53.6mg,0.53mmol)溶于甲醇(1mL)中，然后向反应液中加入氯化氢的甲醇溶液(0.13mL,4M,0.35mmol)。反应液在室温下搅拌反应3小时。反应结束后将反应液用石油醚(2mLx2)洗涤，甲醇层浓缩，粗产物经薄层制备色谱分离纯化(层析液：9％甲醇的二氯甲烷溶液)得到白色固体(12mg,16％)。
LC-MS m/z:413.8[M-17]+.
实施例2(实施方法二)：(R,E)-(1-(4-(苄基氨基)-4-氧代丁-2-烯酰胺基)-2-苯乙基)硼酸
实施方法二：实施步骤：
步骤1：N-苄基富马酸单酰胺
向含有富马酸单乙酯(2.12g,14.7mmol)，苄胺(1.50g,14.0mmol)和二异丙基乙胺(5.43g,42.0mmol)的二氯甲烷(45mL)溶液中加入HATU(5.59g,14.7mmol)。反应混合物在室温下搅拌反应9小时。反应结束后将反应液用水(100mL)稀释，二氯甲烷(80mLx2)萃取。合并的有机层用饱和氯化钠水溶液(60mL)洗涤，无水硫酸钠干燥，过滤后浓缩。剩余物经柱层析分离纯化(洗脱液：25％乙酸乙酯的石油醚溶液)得到白色固体(3.05g，94％)。然后将此白色固体(3.05g,13.1mmol)用乙醇(30mL)溶解后加入氢氧化锂一水合物(1.65g,39.3mmol)，反应液在室温下搅拌反应11小时。反应结束后将反应液减压浓缩，剩余物用水(30mL)溶解，然后冰浴下加入氯化氢的二氧六环溶液(12mL,4M,48.0mmol)，继续搅 拌10分钟，有白色固体生成。将生成的白色固体过滤后用水(50mL)洗涤，减压干燥后得白色固体(2.71g，94％)。
LC-MS m/z:206.1[M+1]+.
步骤2：(R)-N1-苄基-N4-(2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)乙基)富马酰胺
向含有N-苄基富马酸单酰胺(90mg,440μmol)，硼酸片段BB1：(R)-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)乙-1-胺盐酸盐(126mg,440μmol)和二异丙基乙胺(113mg,880μmol)的二氯甲烷(10mL)溶液中加入HATU(200mg,530μmol)。反应混合物在冰浴下搅拌反应9小时。反应结束后将反应液用水(20mL)稀释，二氯甲烷(20mLx2)萃取。合并的有机层用饱和氯化钠水溶液(20mL)洗涤，无水硫酸钠干燥，过滤后浓缩得到棕色固体(110mg，57％)。
步骤3：(R,E)-(1-(4-(苄基氨基)-4-氧代丁-2-烯酰胺基)-2-苯乙基)硼酸
将(R)-N1-苄基-N4-(2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)乙基)富马酰胺(110mg,250μmol)和异丁基硼酸(77mg,750μmol)溶于甲醇(3mL)中，然后向反应液中加入氯化氢的二氧六环溶液(0.31mL,4M,1.24mmol)。反应液在室温下搅拌反应3小时。反应结束后将反应液减压浓缩，然后用水(20mL)稀释，二氯甲烷(20mLx2)萃取。合并的有机层用饱和氯化钠水溶液(20mL)洗涤，无水硫酸钠干燥，过滤后浓缩，粗产物经薄层制备色谱分离纯化(层析液：9％甲醇的二氯甲烷溶液)得到白色固体(40mg，45％)。
LC-MS m/z:335.0[M-17]+.
1HNMR(400MHz,DMSO-d6)δ9.32(s,1H),8.95(t,J＝6.0Hz,1H),7.34–7.11(m,10H),6.97(q,J＝15.3Hz,2H),4.37(d,J＝5.9Hz,2H),2.96–2.87(m,1H),2.81(dd,J＝14.3,5.1Hz,1H),2.59–2.52(m,1H).
实施例3(实施方法三)：((1R)-1-(2-(环丙基甲基)-3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)-2-苯乙基)硼酸
实施方法三：实施步骤：
步骤1：3-((3-甲氧基苄基)氨基)-3-氧代丙酸乙酯
冰浴条件下向含有丙二酸单乙酯钾盐(3.00g,17.6mmol)的二氯甲烷(30mL)溶液中滴加草酰氯单乙酯(2.70g,53.7mmol)和一滴N,N-二甲基甲酰胺，反应混合物在室温下搅拌反应1小时。将反应液过滤后滤液减压浓缩，然后用二氯甲烷(30mL)稀释，在冰浴下滴加3-甲氧基苄氨(2.42g,17.6mmol)和三乙胺(3.7mL,26.5mmol)。反应混合物在冰浴下搅拌反应1小时。反应结束后将反应液用水(200mL)稀释，二氯甲烷(150mLx2)萃取。合并的有机层用饱和氯化钠水溶液(160mL)洗涤，无水硫酸钠干燥，过滤后浓缩，粗产物经柱层析分离纯化(洗脱液：25％乙酸乙酯的石油醚溶液)，得到无色液体(2.73g，62％)。
LC-MS m/z:252.1[M+1]+.
步骤2：2-(环丙基甲基)-3-((3-甲氧基苄基)氨基)-3-氧代丙酸乙酯
向含有3-((3-甲氧基苄基)氨基)-3-氧代丙酸乙酯(700mg,2.79mmol)，溴甲基环丙烷(409mg,3.01mmol)的乙腈(10mL)溶液中加入碳酸铯(1.82g,5.57mmol)。反应混合物在室温下搅拌反应16小时。反应结束后将反应液用水(20mL)稀释，二氯甲烷(20mLx2)萃取。合并的有机层用饱和氯化钠水溶液(20mL)洗涤，无水硫酸钠干燥，过滤后浓缩得到的粗产物经柱层析分离纯化(洗脱液：25％乙酸乙酯的石油醚溶液)，得到无色液体(530mg，62％)。
LC-MS m/z:306.1[M+1]+.
步骤3：2-(环丙基甲基)-3-((3-甲氧基苄基)氨基)-3-氧代丙酸
向2-(环丙基甲基)-3-((3-甲氧基苄基)氨基)-3-氧代丙酸乙酯(530mg,1.74mmol)的乙醇(10mL)溶液中加入氢氧化锂一水合物(240mg,5.75mmol)。反应混合物在室温下搅拌反应3小时。反应结束后减压浓缩，加水(10mL)溶解，并用稀盐酸(1N)调节pH至4～5左右用二氯甲烷(5mLx2)萃取，合并有机相后用饱和 氯化钠水溶液(10mL)洗涤，无水硫酸钠干燥，过滤后浓缩，得到白色固体(450mg，93％)。
步骤4：2-(环丙基甲基)-N1-(3-甲氧基苄基)-N3-((R)-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)乙基)丙二酰胺
向2-(环丙基甲基)-3-((3-甲氧基苄基)氨基)-3-氧代丙酸(100mg,0.38mmol)和片段BB1：(R)-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)乙-1-胺盐酸盐(94mg,0.38mmol)和HATU(159mg,0.42mmol)的二氯甲烷(5mL)溶液中加入二异丙基乙胺(147mg,1.14mmol)。反应混合物在冰浴下搅拌反应2小时后缓慢升至室温过夜。反应结束后将反应液用水(10mL)稀释，二氯甲烷(10mLx2)萃取。合并的有机层用饱和氯化钠水溶液(10mL)洗涤，无水硫酸钠干燥，过滤后浓缩得到粗品产物为黄色油状物(150mg，62％)。
LC-MS m/z:507.2[M+1]+.
步骤5：((1R)-1-(2-(环丙基甲基)-3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)-2-苯乙基)硼酸
将2-(环丙基甲基)-N1-(3-甲氧基苄基)-N3-((R)-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)乙基)丙二酰胺(150mg,256μmol)和异丁基硼酸(78mg,768μmol)溶于甲醇(3mL)中，然后向反应液中加入氯化氢的二氧六环溶液(0.26mL,4M,1.0mmol)。反应液在室温下搅拌反应3小时。反应结束后将反应液减压浓缩，然后用水(20mL)稀释，二氯甲烷(20mLx2)萃取。合并的有机层用饱和氯化钠水溶液(20mL)洗涤，无水硫酸钠干燥，过滤后浓缩，粗产物经反相制备谱分离纯化(流动相：60％乙腈的水溶液)得到白色固体(39mg,31％)。
LC-MS m/z:407.2[M-17]+.
实施例4：(R)-(1-(3-(苄基氨基)-2,2-二甲基-3-氧代丙酰胺基)-2-苯乙基)硼酸
实施方法同方法一，用起始原料苄胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用二甲基丙二酸单乙酯替换甲基丙二酸单乙酯，获得标题化合物。
LC-MS m/z:351.0[M-17]+.
1HNMR(400MHz,DMSO-d6)δ8.50(d,J＝2.8Hz,1H),8.18(t,J＝5.9Hz,1H),7.29–7.24(m,2H),7.21–7.09(m,8H),4.24(d,J＝5.8Hz,2H),2.81(dd,J＝13.2,6.4Hz,1H),2.71(d,J＝3.0Hz,1H),2.59(dd,J＝13.2,6.3Hz,1H),1.31(d,J＝8.4Hz,6H).
实施例5：(R)-(2-苯基-1-(1-(苯基氨基甲酰基)环丙烷-1-甲酰胺基)乙基)硼酸
实施方法同方法一，用起始原料苯胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用1,1-环丙基二甲酸单甲酯替换甲基丙二酸单乙酯，获得标题化合物。
LC-MS m/z:335.0[M-17]+.
实施例6：(R)-(1-(1-(苄基氨基甲酰基)环丙烷-1-甲酰胺基)-2-苯乙基)硼酸
实施方法同方法一，用起始原料苄胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用1,1-环丙基二甲酸单甲酯替换甲基丙二酸单乙酯，获得标题化合物。
LC-MS m/z:349.0[M-17]+.
1HNMR(500MHz,DMSO-d6)δ9.06(s,1H),8.41(t,J＝5.7Hz,1H),7.27(dd,J＝13.7,6.5Hz,2H),7.22–7.13(m,8H),4.28–4.21(m,2H),2.75(d,J＝10.0Hz,2H),2.62–2.54(m,1H),1.46–1.27(m,4H).
实施例7：(R)-(1-(3-(苄基氨基甲酰基)脲基)-2-苯乙基)硼酸
实施方法：
实施步骤：
步骤1：(R)-N1-(苄基氨基甲酰基)-N3-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)乙基脲
冰浴条件下向含有片段BB1:(R)-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)乙-1-胺盐酸盐(80mg,282μmol)和三光气(98mg,330μmol)的二氯甲烷(10mL)溶液中滴加二异丙基乙胺(7.30g,53.7mmol)。反应混合物在冰浴下搅拌反应半小时，然后将反应液减压浓缩，剩余物用二氯甲烷(10mL)溶解，并加入苄基 脲(47mg,310μmol)，反应液在室温下搅拌2小时。反应结束后将反应液用水(15mL)稀释，二氯甲烷(10mLx2)萃取。合并的有机层用饱和氯化钠水溶液(20mL)洗涤，无水硫酸钠干燥，过滤后浓缩，得到黄色油状物(80mg，67％)。
LC-MS m/z:424.1[M+1]+.
步骤2：(R)-(1-(3-(苄基氨基甲酰基)脲基)-2-苯乙基)硼酸
将(R)-N1-(苄基氨基甲酰基)-N3-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)乙基脲(85mg,189μmol)和异丁基硼酸(57mg,560μmol)溶于甲醇(3mL)中，然后向反应液中加入氯化氢的二氧六环溶液(0.23mL,4M,933μmol)。反应液在室温下搅拌反应2小时。反应结束后将反应液减压浓缩，然后用正己烷(10mL)和甲醇(10mL)稀释。将甲醇相浓缩，粗产物经薄层制备色谱分离纯化(层析液：9％甲醇的二氯甲烷溶液)得到白色固体(3mg,5％)。
LC-MS m/z:324.0[M-17]+.
实施例8：(R,E)-(1-(4-氧代-4-(苯基氨基))丁-2-烯酰胺基)-2-苯乙基)硼酸
实施方法同方法二，用起始原料苯胺替换相应的苄胺，获得标题化合物。
LC-MS m/z:321.0[M-17]+.
1HNMR(500MHz,DMSO-d6)δ10.54(s,1H),9.43(s,1H),7.68(d,J＝7.2Hz,2H),7.24(tdd,J＝36.5,14.3,7.3Hz,10H),7.11–6.96(m,2H),2.99(s,1H),2.86(dd,J＝14.3,4.7Hz,1H),2.60(dd,J＝14.2,9.6Hz,1H).
实施例9：((1R)-2-(苯并呋喃-3-基)-1-(3-((3-甲氧基苄基)氨基)-2-甲基-3-氧代丙酰胺基)乙基)硼酸
实施方法同方法一，用起始原料间甲氧基苄胺替换(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:407.1[M-17]+.
实施例10：(R,E)-(1-(4-((4-甲基苄基)氨基))-4-氧代丁-2-烯酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法二，用起始原料对甲基苄胺替换相应的苄胺，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:363.1[M-17]+.
1HNMR(400MHz,DMSO-d6)δ9.27(s,1H),8.89(t,J＝5.4Hz,1H),7.12(s,5H),7.04(dd,J＝15.6,8.2Hz,5H),6.95(d,J＝13.1Hz,2H),4.31(d,J＝5.4Hz,2H),2.87(s,1H),2.74(d,J＝14.3Hz,2H),2.27(s,3H),2.22(s,3H).
实施例11：(R,E)-(3-甲基-1-(4-((4-甲基苄基)氨基))-4-氧代丁-2-烯酰胺基)丁基)硼酸
实施方法同方法二，用起始原料对甲基苄胺替换相应的苄胺，用片段BB5替换片段BB1，获得标题化合物。
LC-MS m/z:315.1[M-17]+.
1HNMR(400MHz,DMSO-d6)δ9.30(s,1H),8.88(s,1H),7.13(s,4H),6.93(d,J＝13.6Hz,2H),4.32(s,2H),2.70(s,1H),2.27(s,3H),1.59(s,1H),1.24(s,2H),0.83(s,6H).
实施例12：(R,E)-(1-(4-((2,5-二氯苄基)氨基))-4-氧代丁-2-烯酰胺基)-2-苯乙基)硼酸
实施方法同方法二，用起始原料2,4-二氯苄胺替换相应的苄胺，获得标题化合物。
LC-MS m/z:402.9[M-17]+.
实施例13：(R,E)-(3-甲基-1-(4-氧代-4-(((6-苯基吡啶-2-基)甲基)氨基)丁-2-烯酰胺基)丁基)硼酸
实施方法同方法二，用起始原料(6-苯基吡啶-2-基)甲胺盐酸盐替换相应的苄胺，用片段BB5替换片段BB1，获得标题化合物。
LC-MS m/z:378.0[M-17]+.
实施例14：(R,E)-(1-(4-氧代-4-(((6-苯基吡啶-2-基)甲基)氨基)丁-2-烯酰胺基)-2-苯乙基)硼酸
实施方法同方法二，用起始原料(6-苯基吡啶-2-基)甲胺盐酸盐替换相应的苄胺，获得标题化合物。
LC-MS m/z:412.1[M-17]+.
1HNMR(400MHz,DMSO-d6)δ9.33(s,1H),9.08(s,1H),8.06(d,J＝7.2Hz,2H),7.80(d,J＝3.9Hz,2H),7.52–7.31(m,3H),7.21(s,1H),7.03(d,J＝18.0Hz,1H),6.92(d,J＝15.1Hz,1H),4.52(d,J＝5.4Hz,2H),2.70(s,1H),1.59(s,1H),1.29(d,J＝18.9Hz,2H),0.81(s,6H).
实施例15：(R,E)-(1-(4-((4-甲基苄基)氨基))-4-氧代丁-2-烯酰胺基)-2-苯乙基)硼酸
实施方法同方法二，用起始原料对甲基苄胺替换相应的苄胺，获得标题化合物。
LC-MS m/z:349.0[M-17]+.
实施例16：(R)-(1-(4-(苄基氨基)-4-氧代丁酰氨基)-2-苯乙基)硼酸
实施方法同方法二，用起始原料对丁二酸单乙酯替换相应的富马酸单乙酯，获得标题化合物。
LC-MS m/z:337.0[M-17]+.
1HNMR(500MHz,DMSO-d6)δ8.60(d,J＝3.4Hz,1H),8.37(t,J＝5.9Hz,1H),7.33–7.08(m,10H),4.24(t,J＝6.6Hz,2H),2.83–2.69(m,2H),2.52(d,J＝9.8Hz,1H),2.49–2.32(m,4H).
实施例17：(R,E)-(1-(4-(苄基氨基)-4-氧代丁-2-烯酰胺基-2,3-D2)-2-苯乙基)硼酸
实施方法同方法二，用起始原料氘代丙二酸替换相应的富马酸单乙酯，获得标题化合物。
LC-MS m/z:337.1[M-17]+.
实施例18：(R,E)-(1-(4-((环己基甲基)氨基)-4-氧代丁-2-烯酰胺基)-3-甲基丁基)硼酸
实施方法同方法二，用起始原料环己基甲胺胺替换相应的苄胺，用片段BB6替换相应的片段BB1，获得标题化合物。
LC-MS m/z:307.1[M-17]+.
实施例19：((R)-1-((1R,2R)-2-(苄基氨基甲酰基)环丙烷)-1-甲酰胺基)-2-苯乙基)硼酸
实施方法同方法二，用起始原料(1R,2R)-环丙烷-1,2-二羧酸单乙酯替换相应的富马酸单乙酯，获得标题化合物。
LC-MS m/z:349.1[M-17]+.
实施例20：(R,E)-(1-(4-((4-甲氧基苄基)氨基)-4-氧代丁-2-烯酰胺基)-3-甲基丁基)硼酸
实施方法同方法二，用起始原料对甲氧基苄胺替换相应的苄胺，用片段BB6替换相应的片段BB1，获得标题化合物。
LC-MS m/z:331.1[M-17]+.
实施例21：(R,E)-(1-(4-((3-甲氧基苄基)氨基)-4-氧代丁-2-烯酰胺基)-3-甲基丁基)硼酸
实施方法同方法二，用起始原料间甲氧基苄胺替换相应的苄胺，用片段BB6替换相应的片段BB1，获得标题化合物。
LC-MS m/z:331.1[M-17]+.
实施例22：(R)-(1-(3-(([1,1'-联苯基]-3-基甲基)氨基)-3-氧代丙酰胺基)-2-(苯并呋喃-3-基)乙基)硼酸
实施方法同方法一，用起始原料丙二酸单乙酯替换相应的2-甲基丙二酸单乙酯，用[1,1'-联苯]-3-基甲胺替换(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:439.1[M-17]+.
实施例23：((R)-1-((1R,2R)-2-(苄基氨基甲酰基)环丙烷-1-甲酰胺基)-3-甲基丁基)硼酸
实施方法同方法二，用起始原料(1R,2R)-环丙烷-1,2-二羧酸单乙酯替换相应的富马酸单乙酯，用片段BB6替换相应的片段BB1，获得标题化合物。
LC-MS m/z:315.1[M-17]+.
实施例24：(R,E)-(1-(4-(苄基氨基)-4-氧代丁-2-烯酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法二，用片段BB2替换相应的片段BB1，获得标题化合物。
LC-MS m/z:349.1[M-17]+.
实施例25：(R,E)-(1-(4-(苄基氨基)-4-氧代丁-2-烯酰胺基)-3-甲基丁基)硼酸
实施方法同方法二，用片段BB6替换相应的片段BB1，获得标题化合物。
LC-MS m/z:301.1[M-17]+.
实施例26：(R,E)-(1-(4-氧代-4-(苯基氨基)丁-2-烯酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法二，用起始原料苯胺替换相应的苄胺，用片段BB2替换相应的片段BB1，获得标题化合物。
LC-MS m/z:335.1[M-17]+.
实施例27：(R)-(1-(3-(([1,1'-联苯基]-3-基甲基)氨基)-3-氧代丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用起始原料丙二酸单乙酯替换相应的2-甲基丙二酸单乙酯，用[1,1'-联苯]-3-基甲胺替换(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:413.1[M-17]+.
实施例28：((1R)-1-(3-(苄基氨基)-2-甲基-3-氧代丙酰胺基)-3-甲基丁基)硼酸
实施方法同方法一，用起始原料苄胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB6替换片段BB1，获得标题化合物。
LC-MS m/z:303.1[M-17]+.
实施例29：((1R)-1-(3-(苄基氨基)-2-甲基-3-氧代丙酰胺基)-2-苯乙基)硼酸
实施方法同方法一，用起始原料苄胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，获得标题化合物。
LC-MS m/z:337.1[M-17]+.
实施例30：(R,E)-(1-(4-((环己基甲基)氨基)-4-氧代丁-2-烯酰胺基)-2-苯乙基)硼酸
实施方法同方法二，用起始原料环己基甲胺替换相应的苄胺，获得标题化合物。
LC-MS m/z:341.1[M-17]+.
实施例31：(R,E)-(1-(4-((3-甲氧基苄基)氨基)-4-氧代丁-2-烯酰胺基)-2-苯乙基)硼酸
实施方法同方法二，用起始原料间甲氧基苄胺替换相应的苄胺，获得标题化合物。
LC-MS m/z:365.1[M-17]+.
实施例32：(R,E)-(1-(4-((4-甲氧基苄基)氨基)-4-氧代丁-2-烯酰胺基)-2-苯乙基)硼酸
实施方法同方法二，用起始原料对甲氧基苄胺替换相应的苄胺，获得标题化合物。
LC-MS m/z:365.1[M-17]+.
实施例33：((1R)-1-((E)-4-氧代-4-(((四氢呋喃-2-基)甲基)氨基)丁-2-烯酰胺基)-2-苯乙基)硼酸
实施方法同方法二，用起始原料四氢糠胺替换相应的苄胺，获得标题化合物。
LC-MS m/z:329.1[M-17]+.
实施例34：((1R)-3-甲基-1-((E)-4-氧代-4-(((四氢呋喃-2-基)甲基)氨基)丁-2-烯酰胺基)丁基)硼酸
实施方法同方法二，用起始原料四氢糠胺替换相应的苄胺，用片段BB5替换片段BB1，获得标题化合物。
LC-MS m/z:295.1[M-17]+.
实施例35：(R,E)-(1-(4-(苄基氨基)-2-甲基)-4-氧代丁-2-烯酰胺基)-2-苯乙基)硼酸
实施方法同方法二，用起始原料中康酸替换相应的富马酸单乙酯，获得标题化合物。
LC-MS m/z:349.1[M-17]+.
实施例36：((1R)-2-([1,1'-联苯基]-4-基)-1-(3-((3-甲氧基苄基)氨基)-2-甲基-3-氧代丙酰胺基)乙基)硼酸
实施方法同方法一，用起始原料间甲氧基苄胺替换(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB4替换片段BB1，获得标题化合物。
LC-MS m/z:443.2[M-17]+.
实施例37：(R,E)-(1-(4-氧代-4-((吡嗪-2-基甲基)氨基)丁-2-烯酰胺基)-2-苯乙基)硼酸
实施方法同方法二，用起始原料吡嗪-2-甲胺替换相应的苄胺，获得标题化合物。
LC-MS m/z:337.1[M-17]+.
实施例38：((1R)-1-(3-(苄基氨基)-2-甲基-3-氧代丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用起始原料苄胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:351.1[M-17]+.
实施例39：((1R)-3-甲基-1-(2-甲基-3-氧代-3-(苯基氨基)丙酰胺基)丁基)硼酸
实施方法同方法一，用起始原料苯胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB5替换片段BB1，获得标题化合物。
LC-MS m/z:289.1[M-17]+.
实施例40：((1R)-1-(2-甲基-3-氧代-3-(苯氨基)丙酰胺)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用起始原料苯胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:337.1[M-17]+.
实施例41：((1R)-1-(3-(环己基氨基)-2-甲基-3-氧代丙酰胺基)-3-甲基丁基)硼酸
实施方法同方法一，用起始原料环己基胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB5替换片段BB1，获得标题化合物。
LC-MS m/z:295.1[M-17]+.
实施例42：((1R)-1-(3-(环己基氨基)-2-甲基-3-氧代丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用起始原料环己基胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:343.1[M-17]+.
1HNMR(400MHz,DMSO-d6)δ8.10–7.86(m,1H),7.28(t,J＝5.6Hz,4H),3.51(ddd,J＝7.8,5.2,2.7Hz,1H),3.31(q,J＝7.1Hz,1H),3.05(dt,J＝13.7,5.5Hz,1H),2.93(td,J＝13.2,8.0Hz,1H),2.79–2.75(m,3H),2.08–1.70(m,5H),1.50(d,J＝9.6Hz,3H),1.43–1.26(m,5H).
实施例43：((1R)-1-(3-((3-甲氧基苄基)氨基)-2-甲基-3-氧代丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用起始原料间甲氧基苄胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:381.1[M-17]+.
1HNMR(400MHz,DMSO-d6+D2O)δ7.21(t,J＝8.1Hz,1H),6.99(d,J＝4.4Hz,4H),6.78(d,J＝6.5Hz,3H),4.21(t,J＝6.1Hz,2H),3.70(s,3H),3.22(d,J＝7.2Hz,1H),3.16(q,J＝7.0Hz,1H),2.76(d,J＝8.3Hz,1H),2.67(t,J＝8.4Hz,1H),2.22(s,3H),1.16(d,J＝8.5Hz,3H).
实施例44：(R)-(1-(3-(([1,1'-联苯基]-3-基甲基)氨基)-3-氧代丙酰胺基)-2-苯乙基)硼酸
实施方法同方法一，用起始原料丙二酸单乙酯替换相应的2-甲基丙二酸单乙酯，用[1,1'-联苯]-3-基甲胺替换(6-苯基吡啶-2-基)甲胺盐酸盐，获得标题化合物。
LC-MS m/z:399.1[M-17]+.
实施例45：((1R)-1-(2-甲基-3-氧代-3-(((6-苯基吡啶-2-基)甲基)氨基)丙酰胺)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:428.1[M-17]+.
实施例46：(R)-(2-(苯并呋喃-3-基)-1-(3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)乙基)硼酸
实施方法同方法一，用起始原料丙二酸单乙酯替换相应的2-甲基丙二酸单乙酯，用间甲氧基苄胺替换(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:393.1[M-17]+.
实施例47：((1R)-1-(2-甲基-3-氧代-3-(苯氨基)丙酰氨基)-2-苯乙基)硼酸
实施方法同方法一，用起始原料苯胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，获得标题化合物。
LC-MS m/z:323.1[M-17]+.
1HNMR(400MHz,DMSO-d6+D2O)9.87(d,J＝9.3Hz,1H),7.70–7.39(m,3H),7.31(td,J＝7.8,5.9Hz,2H),7.20–6.94(m,5H),3.31(s,2H),2.83(ddd,J＝16.0,13.7,5.2Hz,1H),2.78–2.65(m,1H),1.39–1.12(m,3H).
实施例48：(R)-(1-(3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)-3-甲基丁基)硼酸
实施方法同方法一，用起始原料间甲氧基苄胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用丙二酸单乙酯替换2-甲基丙二酸单乙酯，用片段BB5替换片段BB1，获得标题化合物。
LC-MS m/z:319.2[M-17]+.
实施例49：(R)-(1-(3-((3-甲氧基苄基)氨基)-3-氧代丙酰氨基)-2-苯乙基)硼酸
实施方法同方法一，用起始原料间甲氧基苄胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用丙二酸单乙酯替换2-甲基丙二酸单乙酯，获得标题化合物。
LC-MS m/z:353.2[M-17]+.
实施例50：(R)-(1-(3-((3-甲氧基苄基)氨基)-3-氧代丙酰氨基)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用起始原料间甲氧基苄胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用丙二酸单乙酯替换2-甲基丙二酸单乙酯，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:367.2[M-17]+.
1HNMR(400MHz,DMSO-d6)δ7.69(d,J＝3.4Hz,1H),7.22(t,J＝7.8Hz,1H),7.02(d,J＝1.8Hz,4H),6.88–6.75(m,3H),4.24(d,J＝4.2Hz,2H),3.72(s,3H),3.23(dd,J＝8.2,5.1Hz,1H),3.16(d,J＝6.4Hz,1H),3.06(d,J＝4.0Hz,1H),2.78(dd,J＝13.7,5.4Hz,1H),2.65(dd,J＝13.8,8.2Hz,1H),2.22(s,3H).
实施例51：((1R)-3-甲基-1-(2-甲基-3-氧代-3-(((四氢呋喃-2-基)甲基)氨基)丙酰胺基)丁基)硼酸
实施方法同方法一，用起始原料四氢糠胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB5替换片段BB1，获得标题化合物。
LC-MS m/z:297.2[M-17]+.
实施例52：((1R)-1-(2-甲基-3-氧代-3-(((四氢呋喃-2-基)甲基)氨基)丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用起始原料四氢糠胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:345.2[M-17]+.
实施例53：((1R)-1-(3-(环己基氨基)-2-甲基-3-氧代丙酰胺基)-2-苯乙基)硼酸
实施方法同方法一，用起始原料环己基胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，获得标题化合物。
LC-MS m/z:329.2[M-17]+.
实施例54：((1R)-1-(3-((3-甲氧基苄基)氨基)-2-甲基-3-氧代丙酰胺基)-2-苯乙基)硼酸
实施方法同方法一，用起始原料间甲氧基苄胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，获得标题化合物。
LC-MS m/z:367.2[M-17]+.
实施例55：((1R)-1-(2-氟-2-甲基-3-氧代-3-(((6-苯基吡啶-2-基)甲基)氨基)丙酰氨基)-2-苯乙基)硼酸
实施方法同方法一，用起始原料3-乙氧基-2-氟-2-甲基-3-氧代丙酸替换相应的2-甲基丙二酸单乙酯，获得标题化合物。
LC-MS m/z:432.1[M-17]+.
其中，3-乙氧基-2-氟-2-甲基-3-氧代丙酸实施方法如下：
实施步骤：
步骤1：2-氟-2-甲基丙二酸二乙酯
在氮气保护下向2-甲基丙二酸二乙酯(1.0g,5.74mmol)和N-氟代双苯磺酰胺(3.63g,11.5mmol)的二氯甲烷(10mL)中加入钛酸四乙酯(800mg,3.5mmol)，反应在氮气保护下室温搅拌18小时。反应结束后将反应液加水(60mL)和二氯甲烷(30ml×3)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，所得粗品经制备薄层层析分离纯化(洗脱液：10％乙酸乙酯的石油醚溶液)得到淡黄色油状物(541mg,49％)。
1H NMR(400MHz,CDCl3)δ4.29(q,J＝7.1Hz,4H),1.78(d,J＝22.0Hz,3H),1.30(t,J＝7.1Hz,6H).
步骤2：3-乙氧基-2-氟-2-甲基-3-氧代丙酸
向化合物2-氟-2-甲基丙二酸二乙酯(540mg，2.8mmol)的乙醇(10mL)溶液中加入和一水合氢氧化锂(124mg,2.95mmol)在室温下搅拌反应2小时。反应结束后将反应液减压浓缩，用水(40mL)稀释，并用稀盐酸(3N)调节pH至3～4左右，然后用二氯甲烷(20mLx2)萃取。合并的有机层用饱和氯化钠水溶液(30mL)洗涤，无水硫酸钠干燥，过滤后浓缩，得到无色液体化合物(169mg,37％)。
LC-MS m/z:163.1[M-1]-.
实施例56：((1R)-1-(2-氟-2-甲基-3-氧代-3-(((6-苯基吡啶-2-基)甲基)氨基)丙酰氨基)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用起始原料3-乙氧基-2-氟-2-甲基-3-氧代丙酸替换相应的2-甲基丙二酸单乙酯，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:446.1[M-17]+.
实施例57：((1R)-2-(苯并呋喃-3-基)-1-(2-甲基-3-氧代-3-(((6-苯基吡啶-2-基)甲基)氨基)丙酰胺基)乙基)硼酸
实施方法同方法一，用起始原料(6-苯基吡啶-2-基)甲胺盐酸盐替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:454.2[M-17]+.
实施例58：((1R)-2-([1,1'-联苯基]-4-基)-1-(2-甲基-3-氧代-3-((((6-苯基吡啶-2-基)甲基)氨基)丙酰胺基)乙基)硼酸
实施方法同方法一，用起始原料(6-苯基吡啶-2-基)甲胺盐酸盐替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB4替换片段BB1，获得标题化合物。
LC-MS m/z:490.2[M-17]+.
实施例59：((1R)-1-(3-((2,4-二氯苄基)氨基)-2-甲基-3-氧代丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用起始原料2,4-二氯苄胺盐酸盐替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:419.1[M-17]+.
实施例60：((1R)-2-(苯并呋喃-3-基)-1-(3-((2,4-二氯苄基)氨基)-2-甲基-3-氧代丙酰胺基)乙基)硼酸
实施方法同方法一，用起始原料2,4-二氯苄胺盐酸盐替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:445.0[M-17]+.
实施例61：((1R)-1-(3-((3-甲氧基苯乙基)氨基)-2-甲基-3-氧代丙酰胺基)-2-苯乙基)硼酸
实施方法同方法一，用起始原料2-(3-甲氧基苯基)乙-1-胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，获得标题化合物。
LC-MS m/z:381.1[M-17]+.
实施例62：((1R)-1-(3-((3-甲氧基苯乙基)氨基)-2-甲基-3-氧代丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用起始原料2-(3-甲氧基苯基)乙-1-胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:395.2[M-17]+.
实施例63：((1R)-2-(苯并呋喃-3-基)-1-(3-((3-甲氧基苯乙基)氨基)-2-甲基-3-氧代丙酰胺基)乙基)硼酸
实施方法同方法一，用起始原料2-(3-甲氧基苯基)乙-1-胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:421.1[M-17]+.
实施例64：((1R)-2-([1,1'-联苯]-4-基)-1-(3-((3-甲氧基苯乙基)氨基)-2-甲基-3-氧代丙酰胺基)乙基)硼酸
实施方法同方法一，用起始原料2-(3-甲氧基苯基)乙-1-胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB4替换片段BB1，获得标题化合物。
LC-MS m/z:457.2[M-17]+.
实施例65：((1R)-1-(2-苄基-3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用起始原料3-甲氧基苄胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用2-苄基丙二酸单乙酯替换相应的2-甲基丙二酸单乙酯，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:457.2[M-17]+
实施例66：((1R)-1-(2-苄基-3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)-3-甲基丁基)硼酸
实施方法同方法一，用起始原料3-甲氧基苄胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用2-苄基丙二酸单乙酯替换相应的2-甲基丙二酸单乙酯，用片段BB6替换片段BB1，获得标题化合物。
LC-MS m/z:409.2[M-17]+.
实施例67：((1R)-1-(3-((3-甲氧基苯基)氨基)-2-甲基-3-氧代丙酰胺基)-2-苯乙基)硼酸
实施方法同方法一，用起始原料4-甲氧基苯胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，获得标题化合物。
LC-MS m/z:353.1[M-17]+.
实施例68：((1R)-1-(3-((3-甲氧基苯基)氨基)-2-甲基-3-氧代丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用起始原料3-甲氧基苯胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:367.1[M-17]+.
实施例69：((1R)-1-(3-((4-甲氧基苯基)氨基)-2-甲基-3-氧代丙酰胺基)-2-苯乙基)硼酸
实施方法同方法一，用起始原料4-甲氧基苯胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，获得标题化合物。
LC-MS m/z:353.1[M-17]+.
实施例70：((1R)-1-(3-((4-甲氧基苯基)氨基)-2-甲基-3-氧代丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用起始原料4-甲氧基苯胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:367.1[M-17]+.
实施例71：((1R)-2-(苯并呋喃-3-基)-1-(2-苄基-3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)乙基)硼酸
实施方法同方法一，用起始原料3-甲氧基苄胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用2-苄基丙二酸单乙酯替换相应的2-甲基丙二酸单乙酯，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:483.2[M-17]+.
实施例72：((1R)-2-([1,1'-联苯]-4-基)-1-(2-苄基-3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)乙基)硼酸
实施方法同方法一，用起始原料3-甲氧基苄胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用2-苄基丙二酸单乙酯替换相应的2-甲基丙二酸单乙酯，用片段BB4替换片段BB1，获得标题化合物。
LC-MS m/z:519.2[M-17]+.
实施例73：((1R)-2-(苯并呋喃-3-基)-1-(2-甲基-3-氧代-3-((3-(三氟甲氧基)苄基)氨基)丙酰胺基)乙基)硼酸
实施方法同方法一，用起始原料3-三氟甲氧基苄胺盐酸盐替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:461.1[M-17]+.
实施例74：((1R)-2-([1,1'-联苯]-4-基)-1-(2-甲基-3-氧代-3-((3-(三氟甲氧基)苄基)氨基)丙酰胺基)乙基)硼酸
实施方法同方法一，用起始原料3-三氟甲氧基苄胺盐酸盐替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB4替换片段BB1，获得标题化合物。
LC-MS m/z:497.1[M-17]+.
实施例75：((1R)-2-(苯并呋喃-3-基)-1-(2-((3-甲氧基苄基)氨基甲酰基)-3-甲基丁酰胺基)乙基)硼酸
实施方法同方法一，用起始原料3-甲氧基苄胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用2-异丙基丙二酸单乙酯替换相应的2-甲基丙二酸单乙酯，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:435.2[M-17]+.
实施例76：((1R)-2-([1,1'-联苯]-4-基)-1-(2-((3-甲氧基苄基)氨基甲酰基)-3-甲基丁酰胺基)乙基)硼酸
实施方法同方法一，用起始原料3-甲氧基苄胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用2-异丙基丙二酸单乙酯替换相应的2-甲基丙二酸单乙酯，用片段BB4替换片段BB1，获得标题化合物。
LC-MS m/z:471.2[M-17]+.
实施例77：((1R)-2-(苯并呋喃-3-基)-1-(2-甲基-3-氧代-3-((3-(三氟甲基)苄基)氨基)丙酰胺基)乙基)硼酸
实施方法同方法一，用起始原料3-三氟甲基苄胺盐酸盐替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:445.1[M-17]+.
实施例78：((1R)-2-([1,1'-联苯]-4-基)-1-(2-甲基-3-氧代-3-((3-(三氟甲基)苄基)氨基)丙酰胺基)乙基)硼酸
实施方法同方法一，用起始原料3-三氟甲基苄胺盐酸盐替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB4替换片段BB1，获得标题化合物。
LC-MS m/z:481.1[M-17]+.
实施例79：(R)-(1-(2,2-二甲基-3-氧代-3-(苯基氨基)丙酰胺基)-2-苯基乙基)硼酸
实施方法同方法一，用起始原料苯胺替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用二甲基丙二酸单乙酯替换甲基丙二酸单乙酯，获得标题化合物。
LC-MS m/z:337.0[M-17]+.
1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),8.52(s,1H),7.57(d,J＝7.8Hz,2H),7.27(t,J＝7.9Hz,2H),7.15–7.03(m,6H),2.80(dd,J＝12.9,6.3Hz,1H),2.73(d,J＝2.9Hz,1H),2.62(dd,J＝12.9,6.2Hz,1H),1.38(d,J＝8.7Hz,6H).
实施例80：((1R)-1-(2-(环丙基甲基)-3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法三，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:421.2[M-17]+.
实施例81：((1R)-2-(苯并呋喃-3-基)-1-(2-(环丙基甲基)-3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)乙基)硼酸
实施方法同方法三，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:447.2[M-17]+.
实施例82：((1R)-1-(2-(环丙基甲基)-3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)-3-甲基丁基)硼酸
实施方法同方法三，用片段BB6替换片段BB1，获得标题化合物。
LC-MS m/z:373.2[M-17]+.
实施例83：((1R)-1-(2-(环己基甲基)-3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法三，用起始原料溴甲基环己烷替换相应的溴甲基环丙烷，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:463.2[M-17]+.
实施例84：((1R)-2-(苯并呋喃-3-基)-1-(2-(环己基甲基)-3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)乙基)硼酸
实施方法同方法三，用起始原料溴甲基环己烷替换相应的溴甲基环丙烷，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:489.1[M-17]+.
实施例85：((1R)-1-(2-(环己基甲基)-3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)-3-甲基丁基)硼酸
实施方法同方法三，用起始原料溴甲基环己烷替换相应的溴甲基环丙烷，用片段BB6替换片段BB1，获得标题化合物。
LC-MS m/z:415.2[M-17]+.
实施例86：((1R)-1-(2-甲基-3-氧代-3-((3-(三氟甲氧基)苄基)氨基)丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用起始原料3-三氟甲氧基苄胺盐酸盐替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:435.1[M-17]+.
实施例87：((1R)-1-(2-((3-甲氧基苄基)氨基甲酰基)-3-甲基丁酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法三，用起始原料2-碘代丙烷替换相应的溴甲基环丙烷，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:409.2[M-17]+.
实施例88：((1R)-1-(2-((2,4-二氯苄基)氨基甲酰基)-3-甲基丁酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法三，用起始原料2，4-二氯苄胺替换相应的3-甲氧基苄胺，用起始原料2-碘代丙烷替换相应的溴甲基环丙烷，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:447.1[M-17]+.
实施例89：((1R)-2-(苯并呋喃-3-基)-1-(2-((2,4-二氯苄基)氨基甲酰基)-3-甲基丁酰胺基)乙基)硼酸
实施方法同方法三，用起始原料2，4-二氯苄胺替换相应的3-甲氧基苄胺，用起始原料2-碘代丙烷替换相应的溴甲基环丙烷，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:473.1[M-17]+.
实施例90：((1R)-1-(3-(((1H-吲哚-5-基)甲基)氨基)-2-苄基-3-氧代丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用起始原料5-(氨甲基)吲哚替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用2-苄基丙二酸单乙酯替换相应的2-甲基丙二酸单乙酯，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:466.2[M-17]+
实施例91：((1R)-1-(3-(((1H-吲哚-5-基)甲基)氨基)-2-苄基-3-氧代丙酰胺基)-2-(苯并呋喃-3-基)乙基)硼酸
实施方法同方法一，用起始原料5-(氨甲基)吲哚替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用2-苄基丙二酸单乙酯替换相应的2-甲基丙二酸单乙酯，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:492.1[M-17]+
实施例92：((1R)-1-(2-甲基-3-氧代-3-((3-(三氟甲基)苄基)氨基)丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法一，用起始原料3-三氟甲基苄胺盐酸盐替换相应的(6-苯基吡啶-2-基)甲胺盐酸盐，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:419.1[M-17]+.
实施例93：((R)-1-((S)-2-氟-2-甲基-3-氧代-3-(((6-苯基吡啶-2-基)甲基)氨基)丙酰胺基)-2-(对甲苯基)乙基)硼酸和((R)-1-((R)-2-氟-2-甲基-3-氧代-3-(((6-苯基吡啶-2-基)甲基)氨基)丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法：用实施例56所制备的消旋的起始原料((1R)-1-(2-氟-2-甲基-3-氧代-3-(((6-苯基吡啶-2-基)甲基)氨基)丙酰胺基)-2-(对甲苯基)乙基)硼酸(10mg)经手性HPLC分离(分析柱：CHIRALPAK AD-H；流动相和梯度：0-20min,3％异丙醇的正己烷溶液；20min-20.1min,3％-5％异丙醇的正己烷溶液；20.1min-80min,5％异丙醇的正己烷溶液；80min-81min,5％-3％异丙醇的正己烷溶液；81min-85min,3％异丙醇的正己烷溶液；流速2mL/min)得到标题2个组分：异构体93A(3.5mg,35％)，在上述条件下保留时间为56.59min,LC-MS m/z:446.2[M-17]+；异构体93B(3.9mg,39％)，在上述条件下保留时间为69.85min,LC-MS m/z:446.2[M-17]+.
实施例94：((R)-1-((R)-2-甲基-3-氧代-3-((3-(三氟甲氧基)苄基)氨基)丙酰胺基)-2-(对甲苯基)乙基)硼酸和((R)-1-((S)-2-甲基-3-氧代-3-((3-(三氟甲氧基)苄基)氨基)丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法：用实施例86所制备的消旋的起始原料((1R)-1-(2-甲基-3-氧代-3-((3-(三氟甲氧基)苄基)氨基)丙酰胺基)-2-(对甲苯基)乙基)硼酸(50mg)经手性HPLC分离(分析柱：CHIRALPAK AD-H；流动相和梯度：0-50min,4％异丙醇的正己烷溶液,流速1.3mL/min)得到标题2个组分：异构体94A(8.5mg,17％)，在上述条件下保留时间为9.59min,LC-MS m/z:435.1[M-17]+；异构体94B(13mg,26％)，在上述条件下保留时间为13.5min,LC-MS m/z:435.1[M-17]+.
实施例95(实施方法四)：((1R)-1-(2-氟-3-氧代-3-((3-(三氟甲氧基)苄基)氨基)丙酰胺基)-2-苯基乙基)硼酸
实施方法四：实施步骤：
步骤1：2-氟-3-氧代-3-((3-(三氟甲氧基)苄基)氨基)丙酸甲酯
向含有2-氟丙二酸二甲酯(785mg,5.23mmol)的甲醇(15mL)溶液中加入3-三氟甲氧基苄胺(1.00g,5.23mmol)。反应混合物在室温下搅拌反应16小时。反应结束后将反应液减压浓缩，得到的粗产物经柱层析分离纯化(洗脱液：15％乙酸乙酯的石油醚溶液)，得到无色液体(680mg，42％)。
LC-MS m/z:310.0[M+1]+.
步骤2：2-氟-N1-((R)-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)乙基)-N3-(3-(三氟甲氧基)苄基)丙二酰胺
向含有2-氟-3-氧代-3-((3-(三氟甲氧基)苄基)氨基)丙酸甲酯(100mg,0.32mmol)和片段BB1：(R)-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)乙-1-胺盐酸盐(91mg,0.33mmol)的二氯甲烷(15mL)溶液中加入二异丙基乙胺(125mg,0.97mmol)。反应混合物在室温下搅拌反应12小时。反应结束后将反应液用水(20mL)稀释，二氯甲烷(20mLx2)萃取。合并的有机层用饱和氯化钠水溶液(20mL)洗涤，无水硫酸钠干燥，过滤后浓缩得到棕色固体(120mg，71％)。
LC-MS m/z:525.1[M+1]+.
步骤3：((1R)-1-(2-氟-3-氧代-3-((3-(三氟甲氧基)苄基)氨基)丙酰胺基)-2-苯基乙基)硼酸
将2-氟-N1-((R)-2-苯基-1-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)乙基)-N3-(3-(三氟甲氧基)苄基)丙二酰胺(120mg,0.23mmol)和异丁基硼酸(70mg,0.69mmol)溶于甲醇(3mL)中，然后向反应液中加入氯化氢的甲醇溶液(0.29mL,4M,1.14mmol)。反应液在室温下搅拌反应3小时。反应结束后将反应液用石油醚(2mLx2)洗涤，甲醇层浓缩，粗产物经薄层制备色谱分离纯化(层析液：9％甲醇的二氯甲烷溶液)得到白色固体(55mg,54％)。
LC-MS m/z:425.1[M-17]+.
实施例96：((1R)-1-(2-氟-3-氧代-3-((3-(三氟甲氧基)苄基)氨基)丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法四，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:439.1[M-17]+.
实施例97：((1R)-2-(苯并呋喃-3-基)-1-(2-氟-3-氧代-3-((3-(三氟甲氧基)苄基)氨基)丙酰胺基)乙基)硼酸
实施方法同方法四，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:465.0[M-17]+.
实施例98：(R)-(1-(2,2-二氟-3-氧代-3-((3-(三氟甲氧基)苄基)氨基)丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法四，用2,2-二氟丙二酸二乙酯替换2-氟丙二酸二甲酯，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:457.1[M-17]+.
实施例99：((1R)-2-(苯并呋喃-3-基)-1-(2-氟-3-氧代-3-((3-(三氟甲氧基)苄基)氨基)丙酰胺基)乙基)硼酸
实施方法同实施例7，用1-(4-甲氧基苄基)脲替换苄基脲，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:368.1[M-17]+.
实施例100：((1R)-1-(2-氟-3-((3-甲氧基苯乙基)氨基)-3-氧代丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法四，用3-甲氧基苯乙胺替换3-三氟甲氧基苄胺，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:399.2[M-17]+.
实施例101：((1R)-2-(苯并呋喃-3-基)-1-(2-氟-3-((3-甲氧基苯乙基)氨基)-3-氧代丙酰胺基)乙基)硼酸
实施方法同方法四，用3-甲氧基苯乙胺替换3-三氟甲氧基苄胺，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:425.1[M-17]+.
实施例102：((1R)-1-(2-氟-3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)-2-苯基乙基)硼酸
实施方法同方法四，用3-甲氧基苄胺替换3-三氟甲氧基苄胺，获得标题化合物。
LC-MS m/z:371.1[M-17]+.
实施例103：((1R)-1-(2-氟-3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)-2-(对甲苯基)乙基)硼酸
实施方法同方法四，用3-甲氧基苄胺替换3-三氟甲氧基苄胺，用片段BB2替换片段BB1，获得标题化合物。
LC-MS m/z:385.1[M-17]+.
实施例104：((1R)-2-(苯并呋喃-3-基)-1-(2-氟-3-((3-甲氧基苄基)氨基)-3-氧代丙酰胺基)乙基)硼酸
实施方法同方法四，用3-甲氧基苄胺替换3-三氟甲氧基苄胺，用片段BB3替换片段BB1，获得标题化合物。
LC-MS m/z:411.1[M-17]+.
第二部分：蛋白酶体抑制活性测定
细胞制备：
本发明利用荧光多肽底物Ac-Ala-Asn-Trp-AMC(简写Ac-ANW-AMC)来测定20S蛋白酶体β5i亚基的活性。利用包含荧光多肽底物Suc-Leu-Leu-Val-Tyr-AMC(简写Suc-LLVY-AMC)的Promega类胰蛋白酶试剂盒(货号：G8660)来测定20S蛋白酶体β5c亚基的活性。
本发明中所测定的蛋白酶体来自于Raji细胞，Ac-ANW-AMC荧光底物购自Roche公司，其它试剂购自Sigma公司。实验分为细胞裂解体系和酶反应体系两部分。酶裂解体系为100μL，其中Raji细胞7×105个细胞，裂解液100μL；酶反应体系50μL,蛋白酶体25μL，底物缓冲液25μL。药物(抑制剂)起始浓度为1μM，三倍稀释，8剂量(即给药浓度可依次为1μM、0.333μM、0.111μM……)给药。具体实验过程如下：
细胞培养：
将冻存于液氮中的Raji细胞(1×106个细胞)在37℃水浴中快速解冻，将细胞团转移至15mL离心管中，加入9mL新鲜培养基(Gibco RPMI1640添加10％胎牛血清及1％双抗)，120g离心5分钟，接种到25mL细胞培养瓶中，每隔2-3天传代一次。
药物配制：
称取药物，加入DMSO溶解为10mM。用新鲜培养基将药物依次稀释为200μM、66.67μM、22.22μM、7.41μM、2.47μM、0.82μM、0.27μM和0.091μM。 将生长状态良好的Raji细胞按7×105/mL接种到48孔细胞培养板中。
细胞给药：
取生长状态良好的Raji细胞进行计数，然后按7×105/mL接种到48孔细胞培养板中，按上述药物稀释浓度，依次取5μL加入到已经接种细胞的培养板中，最低药物浓度为0μM，使用药物硼替佐米(万珂)和ONX-0914作为阳性对照药物。37℃孵育4小时。
蛋白酶体分离：
将药物处理后的细胞依次转入1.5mL离心管中，10000转/分钟，2分钟离心，去上清；加入1mL PBS重悬细胞团，10000转/分钟，2分钟离心，去上清。加入100μL细胞裂解液(50mM Tris,pH 7.5、150mM NaCl、5mM MgCl2、5mM ATP、1mM DTT、0.01％NP-40、1mM Digitonin、Cocktail)重悬细胞，冰浴30分钟；13000转/分钟，10分钟离心。
底物制备：
将2mg荧光多肽底物AC-ANW-AMC溶解于424.7μL DMSO中，得到8mM储存液，-20℃保存，使用时稀释100倍，反应体系中的最终浓度为8μM。荧光多肽底物Suc-LLVY-AMC的制备依据Promega试剂盒说明书。
反应体系制备：
分别取20μL上述制备的蛋白酶体溶液加入到96孔白色荧光酶标板中，然后分别加入25μL AC-ANW-AM底物缓冲液(50mM Tris,pH 7.5、150mM NaCl、5mM MgCl2、5mM ATP、80uM Ac-ANW-AMC和1mM DTT)和25μL Suc-LLVY-AMC底物缓冲液，37℃下避光反应10分钟。利用345nm/445nm荧光酶标仪读取荧光值。
数据处理：
导出数据，按照如下公式计算抑制百分比：
抑制率＝(最大信号值-化合物信号值)/(最大信号值-空白信号值)×100％
其中最大信号是从仅经DMSO处理的细胞裂解液中获得；空白信号是从仅含裂解液的孔中获得。
细胞株抑制活性测定：
细胞制备：
本实验所用的细胞为MM.1S细胞株，检测试剂为CellTiter-Glo(来自Promega公司)。实验体系为190μL，其中含有细胞悬液100μL，药物50μL，检测液40μL。具体实验过程如下：将处在对数生长期、细胞状态良好的MM.1S细胞用胰蛋白酶消化成单个细胞，离心去除上清液，计数后稀释成1×105个/孔铺在96孔酶标板中，每孔加入100μL细胞悬液，设置只有RPMI1640完全培养基的孔作为空白对照。将96孔板转移至含5％CO2的37℃培养箱中培养24小时。药物处理：
准确称量药物，加入DMSO溶解至10-2M。用移液器吸取10μL加至190μL DMSO得到5×10-4M。取一块新的96孔酶标板，从5×10-5M浓度药物中吸取6μL加入至194μL RPMI1640完全培养基中，3倍梯度稀释。转移50μL已稀释的药物至含有细胞的96孔酶标板中，使得最终的药物浓度为5×10-7M、1.67×10-7M、5.55×10-8M、1.85×10-8M、6.17×10-9M、2.06×10-9M、6.86×10-10M、2.29×10-10M，最后一个浓度为0M，不加药物，加入相同浓度的DMSO。使用已上市的药物硼替佐米作为阳性对照。将加了药物的96孔酶标板放回37℃培养箱中培养72小时。
细胞检测：
当达到预定的检测时间时，将要检测的96孔酶标板至于室温，向每孔中加入40μL的CellTiter-Glo检测试剂，用深色盖子或铝箔片盖住酶标板。在轨道振荡器上混合内容物10分钟，以确保细胞完全裂解，振动速度为150转/分钟。在多功能微孔板检测仪(BioTek Synergy H1 Hybrid Multi-Mode Reade)上检测发光值。
数据处理：
将数据导出，按照如下公式计算抑制百分比：
抑制率＝(最大信号值-化合物信号值)/(最大信号值-空白信号值)×100％
其中最大信号是从仅经DMSO处理的细胞中获得；空白信号是从仅含培养基的孔中获得。
本发明提供的实施例化合物的活性如下表：


+:IC50>500nM；++:200nM<IC50≤500nM；+++:50nM<IC50≤200nM；++++:
IC50≤50nM；ND:未检测
第三部分：小鼠口服血药浓度测试：
实施方式：
本实验所用的C57BL/6JNifdc小鼠由浙江维通利华实验动物技术有限公司提供。将化合物溶解于DMSO/Solutol/Saline(v/v/v＝10/10/80)中作为储备溶液(3mg/mL)。将储备溶液以30mg/kg的剂量口服给予6只C57BL/6JNifdc小鼠。在口服给药后分别在0.5小时、1小时、1.5小时、2小时，从眼眶静脉丛采集血液。
血浆处理：
将约200μL血液样品收集到EDTAK2采血管中，然后立即以10000转/分钟离心5分钟，取上清血浆66μL，加入198μL乙腈(来自安耐吉公司)后涡旋5分钟，然后立即以13000转/分钟离心8分钟，取上清液200μL检测血药浓度。
标准样品配制：
准确称量药物，加入乙腈溶解至100μg/mL。用移液器吸取50μL加至4.95mL乙腈/水(v/v＝3/1)的溶液得到1000ng/mL母液。取650μL母液，依次用乙腈/水(v/v＝3/1)的溶液2倍梯度稀释母液，分别得到浓度为500ng/mL、250ng/mL、125ng/mL、62.5ng/mL、31.25ng/mL的标准样品。
样品浓度监测：
将浓度为1000ng/mL、500ng/mL、250ng/mL、125ng/mL、62.5ng/mL、31.25ng/mL的标准溶液用LC-MS(岛津公司LC-MS 2020与LC-2030Plus)SIM模式检测，获得校准曲线。将处理好的血液样品也用此方法检测后，用校准曲线进行定量分析，得到每个处理后的血液样品药物浓度数据。
数据处理：
将数据导出，计算各个采样时间点的平均血药浓度：
血液中药物浓度＝处理后的血液样品药物浓度×4/药物分子量；平均血药浓度为每个采样时间点血液中药物浓度的平均值。
本发明的化合物具有良好的口服血药浓度，可以很好的被口服吸收：
由上述结果可见，本发明的化合物具有良好的血药浓度，可以用作口服药物，在此方面显著优于对照化合物硼替佐米。
出于清楚和理解的目的,已经通过说明和示例的方式详细描述了前述公开。对于本领域技术人员而言显而易见的是,可以在所附申请专利范围的范围内实施改变和修改。因此,应该理解的是,以上描述旨在是说明性的而非限制性的。所以,本公开的范围不应参照以上描述来确定,而应该参照所附申请专利范围以及这些申请专利范围有权要求的等效物的全部范围来确定。

Claims (15)

  1. 式I化合物：
    或者其可药用盐，
    其中，
    X选自：任选被以下取代基取代的-C1～3烷基-、-C3～6环烷基-、-乙烯基-、-乙炔基-、-NH-、-NH-NH-和-杂环基-，所述取代基选自：氘、C1～4烷基、C1～10烷氧基、C3～6环烷基、杂环基、芳基、杂芳基、芳氧基、氰基、羟基、巯基、氨基和卤素；
    R1和R3各自独立地选自：氢，或者任选被以下取代基取代的C1～10烷基、C3～6环烷基、芳基、杂芳基、苄基、杂环基和桥环基，所述取代基选自：氘、C1～4烷基、C1～10烷氧基、C3～6环烷基、杂环基、芳基、杂芳基、芳氧基、氰基、羟基、疏基、氨基和卤素；
    R2选自：任选被以下取代基取代的C1～10烷基、苄基、联苯甲基和杂环基，其中所述取代基选自：氘、C1～4烷基、C1～10烷氧基、C3～6环烷基、杂环基、芳基、杂芳基、芳氧基、氰基、羟基、疏基、氨基和卤素。
  2. 根据权利要求1所述的式I化合物或者其可药用盐，其中式I化合物具有以下式II结构：
    其中R1、R2、R3具有如权利要求1中所述的定义；
    R2a和R2b各自独立地选自：氢、氘、C1～10烷基、苄基、异丙基、环丙甲基、环丁甲基、环戊甲基、环己基甲基、杂环基甲基和卤素，或者R2a、R2b和与之相连的碳原子一起形成3-6元碳环。
  3. 根据权利要求1所述的式I化合物或者其可药用盐，其中式I化合物具有以下式III结构：
    其中R1、R2、R3具有如权利要求1中所述的定义；
    R3a选自：氢、C1～10烷基、苄基、异丙基、环丙甲基、环丁甲基、环戊甲基、环己基甲基和杂环基甲基。
  4. 根据权利要求1所述的式I化合物或者其可药用盐，其中式I化合物具有以下式IV结构：
    其中R1、R2、R3具有如权利要求1中所述的定义；
    R4a、R4b、R4c和R4d各自独立地选自：氢、氘、C1～10烷基、卤素、羟基和氨基，其中所述氨基任选地被C1～4烷基或C3～6环烷基取代。
  5. 根据权利要求1所述的式I化合物或者其可药用盐，其中式I化合物具有以下式V结构：
    其中R1、R2、R3具有如权利要求1中所述的定义；
    R5a和R5b各自独立地选自：氢、氘、C1～4烷基、卤素和羟基，R5a和R5b彼此呈顺式或反式取代形式。
  6. 根据权利要求1所述的式I化合物或者其可药用盐，其中式I化合物具有以下式VI结构：
    其中R1、R2、R3具有如权利要求1中所述的定义；
    环A选自：任选被以下取代基取代的-C3～6环烷基-和-杂环基-，其中所述取代基选自C1～4烷基、C1～10烷氧基、C3～6环烷基、氰基、羟基和卤素。
  7. 根据权利要求1-6中任一项所述的化合物或者其可药用盐，其中R1和R3选自氢和以下结构：
  8. 根据权利要求1-7中任一项所述的化合物或者其可药用盐，其中R2选自以下结构：
  9. 根据权利要求1-8中任一项所述的化合物或者其可药用盐，其中所述化合物选自：






  10. 一种药物组合物，其包含权利要求1至9中任一项所述的化合物或者其可药用盐，以及任选的可药用载体。
  11. 如权利要求1至9中任一项所述的化合物或者其可药用盐在制备用作蛋白酶体抑制剂的药物中的应用。
  12. 如权利要求1至9中任一项所述的化合物或者其可药用盐在制备用于治疗或预防蛋白酶体相关疾病的药物中的应用。
  13. 根据权利要求12的应用，其中所述疾病选自肿瘤和自身免疫性疾病。
  14. 根据权利要求12的应用，其中所述疾病为多发性骨髓瘤。
  15. 根据权利要求12的应用，其中所述疾病选自系统性红斑狼疮(SLE)和炎症性肠病(IBD)。
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