WO2022037648A1 - 吡唑硼酸类化合物、包含其的药物组合物及它们的用途 - Google Patents

吡唑硼酸类化合物、包含其的药物组合物及它们的用途 Download PDF

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WO2022037648A1
WO2022037648A1 PCT/CN2021/113533 CN2021113533W WO2022037648A1 WO 2022037648 A1 WO2022037648 A1 WO 2022037648A1 CN 2021113533 W CN2021113533 W CN 2021113533W WO 2022037648 A1 WO2022037648 A1 WO 2022037648A1
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Prior art keywords
phenyl
acetamido
alkyl
pyrazol
boronic acid
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English (en)
French (fr)
Inventor
李润涛
王元强
韩利强
宋转转
葛泽梅
王欣
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Peking University
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Peking University
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Priority to EP21857740.1A priority Critical patent/EP4201941B1/en
Priority to US18/042,150 priority patent/US12473305B2/en
Priority to KR1020237009128A priority patent/KR20230074722A/ko
Priority to AU2021328979A priority patent/AU2021328979B2/en
Priority to JP2023512421A priority patent/JP7853957B2/ja
Publication of WO2022037648A1 publication Critical patent/WO2022037648A1/zh
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    • 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 Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the application belongs to the field of medicine, in particular, to the pyrazole boronic acid compounds shown in formula I, their pharmaceutically acceptable salts or their stereoisomers and pharmaceutical compositions containing them, and to their preparation of proteasomes Use in inhibitors.
  • the proteasome plays an important role in cell cycle regulation, cellular stress response and immune response. Therefore, the proteasome has become an ideal target for the treatment of various diseases, including tumors, malaria parasites, asthma, etc.
  • proteasome inhibitors on the market, such as bortezomib, MLN9708 (trade name Ninlaro; 31), carfilzomib and NPI0052 (trade name Marizomib).
  • the existing proteasome inhibitors have disadvantages such as poor biological selectivity, poor in vitro and in vivo stability, poor inhibitory effect on solid tumors, and large toxic and side effects, which limit their clinical application.
  • R 1 is selected from H, phenyl, C 1-4 alkyl, 5- or 6-membered heterocycle containing 1-3 heteroatoms selected from N or O or S, or
  • the phenyl group is optionally substituted by halogen, halogenated C 1-4 alkyl and/or C 1-4 alkyl
  • the Z 1 is one of C 1-10 chain hydrocarbon group or C 1-10 chain hydrocarbon group or Heterochain hydrocarbon groups in which a plurality of carbon atoms are substituted with heteroatoms selected from O, S or N
  • said R a and R b are each independently selected from H or C 1-4 alkyl, or R a and R b are attached thereto
  • the N atoms of N atoms together form a 5- to 10-membered saturated heterocycle
  • the 5- to 10-membered saturated heterocycle may contain 0-3 heteroatoms selected from N, O or S in addition to the N atom
  • the 5- to 10-membered saturated heterocycles are optionally substituted by C 1-4 al
  • R 2 and R 3 are each independently selected from OH, C 1-4 alkyl or O(O)C 1-4 alkyl, or R 2 and R 3 together with the B atom to which they are attached form a 4-15 membered ring
  • the Rc and Rd are each independently selected from O, S, NH, NRe, -CO, -NHCO, -NRfCO , -OS(O) 2 , -NHS(O ) 2 or -NRg- SO 2
  • the Z 2 is a C 1-10 chain hydrocarbon group, or a hetero chain hydrocarbon group in which one or more carbon atoms in the C 1-10 chain hydrocarbon group are substituted with a hetero atom selected from O, S or N, or 1 one or more R c and/or R d ;
  • R f and R g are each independently selected from halogen, C 1-10 alkyl, C 1-10 alkoxy or C 1-10 haloalkyl;
  • R 4 is selected from C 1-4 alkyl, phenyl, or a 5- or 6-membered heterocycle containing 1-3 heteroatoms selected from N or O or S, the phenyl optionally being substituted by halogen, cyano , C 1-4 alkyl, C 1-4 alkoxy, phenyl, C 1-4 alkyl sulfone and/or phenyl C 1-4 alkoxy substituted;
  • X is selected from NH, O, S, -OS(O) 2- or -NHS(O) 2- .
  • Another aspect of the present application relates to a pharmaceutical composition, which contains the above-mentioned compound represented by formula I, a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • Another aspect of the present application relates to the use of the above-mentioned compound represented by formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof or the above-mentioned pharmaceutical composition in the preparation of a proteasome inhibitor.
  • the proteasome inhibitor can be used to treat or alleviate proteasome-related diseases, such as tumors, Plasmodium infection, asthma or Alzheimer's disease, and the like.
  • another aspect of the present application relates to a method for treating or alleviating a disease associated with the proteasome, comprising administering to a subject in need a therapeutically effective amount of the compound shown in the above-mentioned formula I, a pharmaceutically acceptable salt thereof or Its stereoisomer, or the above-mentioned pharmaceutical composition.
  • another aspect of the present application relates to the above-mentioned compound of formula I, a pharmaceutically acceptable salt or a stereoisomer thereof, or the above-mentioned pharmaceutical composition for use in the treatment or alleviation of proteasome-related diseases.
  • Cmn means that the moiety modified by the term has mn carbon atoms in it (n is greater than m, and both are integers).
  • C 1-10 means that its modified part has 1-10 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms , 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • chain hydrocarbon group is used to refer to a chain-like group consisting of C and H, which includes straight or branched chain, saturated or unsaturated chain hydrocarbon groups, including but not limited to C 1-10 chain hydrocarbon group, C 1-9 chain hydrocarbon group, C 1-8 chain hydrocarbon group, C 1-7 chain hydrocarbon group, C 1-6 chain hydrocarbon group, C 1-5 chain hydrocarbon group, C 1-4 chain hydrocarbon group, C 1 -3 chain hydrocarbon group, C 1-2 chain hydrocarbon group and C 1 chain hydrocarbon group.
  • heteroalkane refers to 1 or more (eg, 2, 3, 4, 5, 6, 7, 8) of a chain , 9, 10, etc.), for example, 1-3 or 1-5 or 1-10 carbon atoms are substituted by heteroatoms selected from N, O or S. A chain-like group formed.
  • alkyl is used to refer to a saturated hydrocarbon group consisting only of carbon atoms and hydrogen atoms, including, but not limited to, C 1-10 alkyl, C 1-9 alkyl, C 1-8 alkyl, C 1-7 alkyl, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl and C 1 alkyl.
  • alkyl groups the following linear or branched saturated hydrocarbon groups may be mentioned: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl , n-pentyl and its other seven isomers, n-hexyl and its other sixteen isomers.
  • C1-7 alkyl includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and all isomers thereof.
  • heterocycle includes both alicyclic and aromatic heterocycles, and refers to a saturated or Unsaturated ring system, and may be substituted or unsubstituted.
  • saturated heterocycle refers to a heterocycle consisting of carbon atoms and 1-3 heteroatoms independently selected from N, O, or S, and may be substituted or unsubstituted replaced.
  • heterocycles include pyrrolyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, piperidinyl, piperazinyl, pyrimidinyl, pyrrolidinyl, morpholinyl, furanyl, tetrahydrofuran group, tetrahydropyranyl, oxiranyl, pyranyl, pyridyl or tetrahydropyridyl, but not limited thereto.
  • alkoxy is used to refer to a group in which an oxygen atom is attached to the above-mentioned alkyl group and through which the oxygen atom is single-bonded to the rest of the molecule, which encompasses a variety of possibilities Geometric and stereoisomeric groups.
  • alkoxy one can cite methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy and its other seven isomers, n-hexyloxy and its other sixteen isomers.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • haloalkyl is used to mean substituted with one or more, preferably 1-5 (eg 1, 2, 3, 4 or 5) halogen atoms Alkyl as defined above.
  • Haloalkyl includes monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, etc., such as chloromethyl, dichloromethyl, difluoromethyl, dibromomethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, etc.
  • the term “pharmaceutically acceptable” means suitable for use in contact with human and animal tissue without excessive toxicity, irritation, allergic reactions or other problems or complications within the scope of sound medical judgment symptoms, those compounds, materials, compositions and/or dosage forms commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to an acid or base addition salt of a compound of Formula 1 with a pharmaceutically acceptable free acid or free base.
  • Acid addition salts are obtained from acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methyl alcohol Sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, tartaric acid, fumaric acid, malic acid, oxalic acid, succinic acid, etc.
  • Base addition salts include sodium, potassium, calcium, ammonium, or magnesium salts, and the like.
  • wedge-shaped solid and dashed keys are used in this document Represents the absolute configuration of a stereocenter.
  • references to stereoisomers herein include both geometric isomers and enantiomers, all of which are within the scope of this application.
  • the term “optional” refers to the presence or absence, presence or absence of the object or event it modifies.
  • “optionally substituted” for a group means that the group may be substituted or unsubstituted.
  • the application relates to a compound shown in formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:
  • R 1 is selected from H, phenyl, C 1-4 alkyl, 5- or 6-membered heterocycle containing 1-3 heteroatoms selected from N or O or S, or
  • the phenyl group is optionally substituted by halogen, halogenated C 1-4 alkyl and/or C 1-4 alkyl
  • the Z 1 is one of C 1-10 chain hydrocarbon group or C 1-10 chain hydrocarbon group or Heterochain hydrocarbon groups in which a plurality of carbon atoms are substituted with heteroatoms selected from O, S or N
  • said R a and R b are each independently selected from H or C 1-4 alkyl, or R a and R b are attached thereto
  • the N atoms together form a 5- to 10-membered saturated heterocycle, the 5- to 10-membered saturated heterocycle also contains 0-3 heteroatoms selected from N, O or S in addition to the N atom, and the 5 A membered to 10-membered saturated heterocycle is optionally substituted with C 1-4 alkyl,
  • R 2 and R 3 are each independently selected from OH, C 1-4 alkyl or O(O)C 1-4 alkyl, or R 2 and R 3 together with the B atom to which they are attached form a 4-15 membered ring
  • the Rc and Rd are each independently selected from O, S, NH, NRe, -CO, -NHCO, -NRfCO , -OS(O) 2 , -NHS(O ) 2 or -NRg- SO 2
  • the Z 2 is a C 1-10 chain hydrocarbon group, or a hetero chain hydrocarbon group in which one or more carbon atoms in the C 1-10 chain hydrocarbon group are substituted with a hetero atom selected from O, S or N, or 1 one or more R c and/or R d ;
  • R f and R g are each independently selected from halogen, C 1-10 alkyl, C 1-10 alkoxy or C 1-10 haloalkyl;
  • R 4 is selected from C 1-4 alkyl, phenyl, or a 5- or 6-membered heterocycle containing 1-3 heteroatoms selected from N or O or S, the phenyl optionally being substituted by halogen, cyano , C 1-4 alkyl, C 1-4 alkoxy, phenyl, C 1-4 alkyl sulfone and/or phenyl C 1-4 alkoxy substituted;
  • X is selected from NH, O, S, -OS(O) 2- or -NHS(O) 2- .
  • R 1 is selected from H, phenyl, halophenyl, halo-C 1-4 alkyl phenyl, C 1-4 alkyl phenyl, containing 1-3 selected from N or O or a 5- or 6-membered unsaturated heterocycle of a heteroatom of S, or
  • the Z 1 is a C 1-10 alkyl group, and the R a and R b are each independently selected from C 1-4 alkyl groups, or R a and R b together with the N atom to which they are attached form a 5- to 7-membered saturated Heterocycle, the 5- to 7-membered saturated heterocycle is optionally substituted with C 1-4 alkyl or phenyl.
  • R 1 is selected from H, phenyl, halophenyl, halo C 1-4 alkylphenyl, C 1-4 alkyl phenyl, Said Z 1 is a C 1-6 alkyl group, said R a and R b are each independently selected from C 1-4 alkyl group, or R a and R b together with the N atom to which they are attached form a 5- or 6-membered saturated Heterocycle, the 5- or 6-membered saturated heterocycle is optionally substituted with C 1-4 alkyl or phenyl.
  • R 1 is selected from H, halogenated C 1-4 alkylphenyl, fluorophenyl, chlorophenyl, bromophenyl, C 1-4 alkylphenyl, n is an integer selected from 1-6, m and m' are the same or different and each independently is an integer selected from 0-3, the Optionally substituted with C 1-4 alkyl or phenyl.
  • R 2 and R 3 are each independently selected from OH, C 1-3 alkyl or O(O)C 1-3 alkyl, or R 2 , R 3 together with the B atom to which they are attached form 6 -10 yuan ring
  • the R c and R d are each independently selected from O, S, -CO or -OS(O) 2
  • the Z 2 is a C 1-5 chain hydrocarbon group, or 1-3 in the C 1-5 chain hydrocarbon group Heterochain hydrocarbon groups in which carbon atoms are substituted with heteroatoms selected from O, S or N.
  • R 2 and R 3 are each independently selected from OH, C 1-3 alkyl or O(O)C 1-3 alkyl, or R 2 , R 3 are formed together with the B atom to which they are attached
  • R 4 is selected from the group consisting of C 1-4 alkyl, phenyl, halophenyl, halo C 1-4 alkyl phenyl, C 1-4 alkyl phenyl, cyanophenyl, C 1-4 alkoxyphenyl, biphenyl, C 1-4 alkylsulfonyl phenyl, phenyl C 1-4 alkoxy phenyl, or containing 1-3 selected from N or O or S 5- or 6-membered unsaturated heterocycle of the heteroatom.
  • R 4 is selected from C 1-4 alkyl, phenyl, fluorophenyl, chlorophenyl, bromophenyl, fluoro C 1-4 alkylphenyl, chloro C 1 -4 alkylphenyl, bromo C1-4 alkylphenyl, C1-4 alkylphenyl, cyanophenyl, C1-4 alkoxyphenyl, biphenyl, C1-4 Alkylsulfonylphenyl, phenylC1-4alkoxyphenyl , or 5- or 6-membered unsaturated heterocycle containing 1-2 heteroatoms selected from N or O or S.
  • R 4 is selected from C 1-4 alkyl, phenyl, fluorophenyl, chlorophenyl, bromophenyl, fluoro C 1-4 alkylphenyl, chloro C 1 -4 alkylphenyl, bromo C1-4 alkylphenyl, C1-4 alkylphenyl, cyanophenyl, C1-4 alkoxyphenyl, biphenyl, C1-4 Alkyl sulfonyl phenyl, phenyl C 1-4 alkoxy phenyl,
  • R 1 is selected from H, fluoromethylphenyl, chloromethylphenyl, bromomethylphenyl, fluoroethylphenyl, chloroethylphenyl, bromoethylphenyl phenyl, fluoropropylphenyl, chloropropylphenyl, bromopropylphenyl, fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, ethylphenyl, propylphenyl, n is an integer selected from 1-5, m and m' are the same or different and each independently is an integer selected from 0-2, the optionally substituted with methyl, ethyl, propyl or phenyl;
  • R 2 and R 3 are each independently selected from OH, or R 2 and R 3 are formed together with the B atom to which they are attached.
  • R 4 is selected from methyl, ethyl, propyl, phenyl, fluorophenyl, chlorophenyl, bromophenyl, cyanophenyl, methylphenyl, ethylphenyl, propylphenyl , methoxyphenyl, ethoxyphenyl, propoxyphenyl, biphenyl, methylsulfonylphenyl, ethylsulfonylphenyl, propylsulfonylphenyl, phenylmethoxybenzene base, phenylethoxyphenyl, phenylpropoxyphenyl,
  • X is selected from O, S, -OS(O) 2- or -NHS(O) 2- .
  • a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from:
  • the present application relates to a pharmaceutical composition, which contains the above-mentioned compound represented by formula I, a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • composition of the present application can be prepared in any form, such as capsules, tablets, aerosols, solutions, suspensions, sugar coatings, lozenges, syrups, emulsions, ointments, ointments, injections, powders , granules, pastes, sustained release agents, foams.
  • the medicament of the present application can be prepared into oral administration preparations, nasal administration preparations, pulmonary administration preparations, buccal preparations, subcutaneous administration preparations, intradermal administration preparations, and transdermal administration preparations , parenteral preparations, rectal preparations, depot preparations, intravenous preparations, intraurethral preparations, intramuscular preparations, intranasal preparations, ocular preparations, Epidural formulations or topical formulations.
  • excipients described herein can be any pharmaceutically acceptable excipients, such as, but not limited to, solvents, propellants, solubilizers, co-solvents, emulsifiers, colorants, disintegrants, fillers, lubricants, wetting agents, Osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, antioxidants, penetration enhancers, pH regulators, surfactants, diluents, etc.
  • solvents such as, but not limited to, solvents, propellants, solubilizers, co-solvents, emulsifiers, colorants, disintegrants, fillers, lubricants, wetting agents, Osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, antioxidants, penetration enhancers, pH regulators, surfactants, diluents, etc.
  • the present application relates to the use of the above-mentioned compound represented by Formula I, a pharmaceutically acceptable salt or a stereoisomer thereof, or the above-mentioned pharmaceutical composition in the preparation of a proteasome inhibitor.
  • the proteasome inhibitor can be prepared as a medicament for the treatment or alleviation of proteasome-related diseases (eg, tumors, Plasmodium infection, asthma, Alzheimer's disease, etc.).
  • the present application relates to a method for treating or alleviating a disease associated with the proteasome, comprising administering to a subject in need a therapeutically effective amount of the compound shown in the above-mentioned formula I, its pharmaceutically acceptable The salt or its stereoisomer, or the above-mentioned pharmaceutical composition.
  • the present application relates to the above-mentioned compound of formula I, a pharmaceutically acceptable salt or a stereoisomer thereof, or the above-mentioned medicine for treating or alleviating a disease associated with the proteasome combination.
  • patient refers to a human or non-human animal (eg, primate, rodent, etc.).
  • the aqueous layer was extracted with ethyl acetate (10 ml ⁇ 2), and the combined organic layers were washed with brine (50 ml), dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure, and the obtained crude product was used for the next reaction. No further purification was required.
  • step 3 The crude product obtained in step 3 was dissolved in toluene (25 mL), and DDQ (0.454 g, 2 mmol) was added thereto. The resulting solution was stirred at 100°C for 12 hours and then cooled to room temperature. The solids were removed by filtration, and to the filtrate were added water (25 mL) and potassium carbonate (0.276 g, 2 mmol) and stirred for 30 min. The organic layer was separated, washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 . After purification by column chromatography (silica gel, 10% ethyl acetate in petroleum ether), 0.78 g of a yellow liquid was obtained (75.3% yield).
  • Step 4 To a mixture of the product obtained in Step 4 (0.78 g, 1.47 mmol) with tetrahydrofuran (15 mL) and water (15 mL) was added 3N aqueous LiOH solution (2 mL). After stirring for 30 min, additional water (15 ml) was added and the tetrahydrofuran was removed under reduced pressure and low temperature. The residue was acidified with 4N HCl to pH 2-3, the precipitate was filtered and washed with water until pH 6-7. The title compound (0.69 g, 93.5%) was obtained and used in the next reaction without further purification.
  • the unsalted form 29-5 of compound 29 was obtained in 30.6% yield using the procedure shown in step 6 and step 7 in Preparation Example 1.
  • Compound 29-5 (0.10 g, 0.21 mmol) was suspended in ethyl acetate (10 mL), and 2N hydrogen chloride in ethyl acetate (2 mL) was added. The mixture was stirred at room temperature for 12 hours. The precipitate was filtered and washed with ethyl acetate. Compound 29 (85.7 mg) was finally obtained as a white solid. mp: 146-148°C.
  • CellTiter-Glo assay was used to detect the effect of compounds on tumor cell proliferation.
  • Cell lines such as human melanoma cell A375, non-small cell lung cancer cell A549, human lung adenocarcinoma cell H1299, colorectal cancer cell line HCT116, liver cancer cell line HepG2 and gastric cancer cell MGC80-3 were cultured in vitro. The cells were collected, centrifuged at 1000 rpm for 5 min, the supernatant was discarded, suspended in an appropriate amount of medium, and the cell concentration was adjusted to 2 ⁇ 10 4 /mL.
  • the cell suspension was inoculated on a 384-well cell culture plate, 50 ⁇ L per well, and placed in a cell incubator (37°C, 5% CO 2 ) for 24 hours, and 5 ⁇ L of the drug diluted in cell culture medium was added to each well of the administration group. There are three duplicate wells for each drug. After culturing in the incubator for 72 h, 20 ⁇ L of CellTiter-Glo was added to each well and placed at 37°C for 20 min. The relative luminescence units (RLU) were measured using Multimode Microplate Reader Varioskan Flash (Thermo Scientific, USA) and compared with the RLU of the control group. The inhibition rate and IC50 value were calculated using SigmaPlot 10.0 software. The results are shown in the table below:
  • the activity of target compounds on the 20S proteasome was measured using the Proteasome-Glo TM Cell-Based Assay Kit (Promega, USA).
  • the human chronic myeloid leukemia cell line (K562, 6000 cells/well) was seeded in 384-well plates at 20 ⁇ L/well. Cells were then equilibrated at 37°C, 5% CO2 for 2 h. Each 384-well plate was set up with blank control group and administration group.
  • RLU Relative luminescence units
  • This experiment included PO group and IV group, three animals in each group.
  • PO group about 0.25 mL of whole blood was collected from the orbital venous plexus before administration, 15min, 30min, 1h, 2h, 4h, 7h, and 24h after administration.
  • 5min, 15min, 30min, 1h, 2h, 4h, 7h, 24h about 0.25mL of whole blood from orbital vein was put into heparin anticoagulation tube.
  • After blood collection invert the blood collection tube containing anticoagulant several times to mix thoroughly, and place on wet ice before centrifugation. Within 60 minutes after blood collection, centrifuge at 8000 rpm for 10 minutes at 2 to 8° C. to separate red blood cells to obtain plasma samples.
  • Plasma samples were transferred to cryovials and stored at -75 ⁇ 15°C until analysis. Take 50 ⁇ L of plasma sample, add 5 ⁇ L acetonitrile:water (1:1, v/v), add 200 ⁇ L 0.1% formic acid acetonitrile, centrifuge (12000 rpm, 15 min), and dilute the supernatant with ultrapure water 1:1 to obtain. Plasma drug concentrations were analyzed using an LC-MS/MS method. Using Microsoft EXCEL to describe the experimental data using mean, deviation %, standard deviation (SD). Pharmacokinetic parameter calculations were performed with WinNonlin 8.1 software.
  • Table 4 Mean pharmacokinetic parameters in plasma after single intravenous injection of 1 mg/kg compound 39 and oral administration of 10 mg/kg compound 39 in male SD rats
  • the area under the plasma concentration-time curve (AUC 0-t ) was 186 ⁇ 147 h ⁇ ng/mL, and the peak concentration (C max ) was 74.8 ⁇ 82.0 ng/ mL, the time to peak (T max ) was 0.33 ⁇ 0.14h, the elimination half-life (T 1/2 ) in vivo was 1.63 ⁇ 0.36h, and the bioavailability was 2.42 ⁇ 1.91%.
  • Pharmacokinetic studies showed that compound 39 was widely distributed in male SD rats, with moderate clearance and rapid absorption.
  • the activity of compound 30 was evaluated by MTT method against seven tumor cell models A549, A375, HCT116, MDA-MB-231, HepG2, PC3 and MCF-7. All cells used for the study were cultured at a concentration of 3.5 x 103 cells/mL, and each 100 mL of cell suspension was seeded in 96-well microtiter plates for 24 hours (37°C, 5% CO2 ). Then different concentrations of compound 30 were added and incubated for 72 h, and the control group was added with an equivalent concentration of DMSO (final concentration 0.5%).
  • the number of viable cells was determined by MTT method (3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide), and the OD value at 492/620 nm was recorded. Using the results of triplicate experiments, IC50 values were calculated by Prism-Graphpad software.
  • Compound 30 has significant inhibitory activity on the growth of seven tumor cells, and the IC 50 of HCT116 and MCF-7 reached 0.63 ⁇ M and 0.69 ⁇ M, respectively.
  • the Bel7404 model of human liver cancer transplanted into 6-week-old male BALB/c athymic nude mice (purchased from Shanghai Slack Laboratory Animal Co., Ltd.) weighing 18-20 g was used to study the antitumor effect of compound 30.
  • the doses of compound 30 were 50mg/kg (30H group), 25mg/kg (30M group), 12.5mg/kg (30L group), 2 times a week by intravenous injection, a total of 5 times; -FU is a control drug, intraperitoneally injected twice a week, for a total of 7 times (5 mice in each group of compound 30 administration group, 5 mice in 5FU administration group; 8 mice were used as blank control group) .
  • the long diameter of the tumor a (mm) and the perpendicular short diameter b (mm) of the tumor were measured with a digital electronic caliper.
  • the animals were sacrificed, weighed, the tumor mass was dissected and weighed, and the tumor inhibition rate (tumor inhibition rate, %) was calculated according to the following formula:
  • the results of in vivo anti-tumor activity are shown in Table 6.
  • the tumor inhibition rates of compound 30 against human liver cancer Bel7404 were 61.29%, 36.55% and 24.89% at doses of 50 mg/kg, 25 mg/kg and 12.5 mg/kg, respectively.
  • the tumor animal model obtained by subcutaneous xenotransplantation of cell lines in female NOD/SCID mice (purchased from Speifu Biotechnology Co., Ltd.) was used to study the antitumor effect in vivo.
  • RPMI 8226 cells were subcutaneously inoculated into NOD/SCID mice, and a subcutaneous tumor model of human multiple myeloma was successfully established 9 days after inoculation.
  • the test was divided into vehicle (0.3mL DMSO, 0.27mL Tween-80, 2.43mL normal saline) control group, compound 30 low dose group (20mg/kg), compound 30 medium dose group (30mg/kg), compound 30 high dose group (40 mg/kg), compound 39 low-dose group (5 mg/kg), compound 39 medium-dose group (10 mg/kg), compound 39 high-dose group (15 mg/kg), and bortezomib (purchased from Yangzijiang Pharmaceutical Co., Ltd.) Raw material drug) as a positive control group (0.5 mg/kg); each group of 5 tumor-bearing mice constructed above was administered by tail vein, twice a week, for a total of nine times.
  • the long diameter a (mm) of the tumor and the short diameter b (mm) of the tumor perpendicular to the long diameter were measured twice a week with a digital electronic caliper.
  • V o is the measurement of the mice in each group and the first administration (ie, d1)
  • the tumor volume of , Vt is the tumor volume measured at the last dose.
  • the animals were sacrificed 31 days after inoculation with RPMI 8226 cells (d22), the body weight was weighed, the tumor mass was dissected and weighed, and the tumor inhibition rate was calculated according to the following formula:
  • the in vivo antitumor activity results of compound 30 are shown in Table 8.
  • the tumor inhibition rates of compound 30 on human multiple myeloma RPMI 8226 at doses of 20 mg/kg, 30 mg/kg and 40 mg/kg were 72.45%, 82.53% and 92.07%.
  • the results of the in vivo antitumor activity of compound 39 are shown in Table 9.
  • the tumor inhibition rates of compound 39 on human multiple myeloma RPMI 8226 at doses of 5 mg/kg, 10 mg/kg and 15 mg/kg were 83.82%, 93.35% and 96.14%.
  • the compounds prepared in the examples of the present invention can exhibit excellent antitumor activity.

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Abstract

本申请涉及下述式I所示的吡唑硼酸类化合物、其药学上可接受的盐或其立体异构体，包含其的药物组合物及它们的用途。所述化合物、其药学上可接受的盐或其立体异构体以及包含其的药物组合物可用于制备蛋白酶体抑制剂。

Description

吡唑硼酸类化合物、包含其的药物组合物及它们的用途 技术领域
本申请属于医药领域，具体而言，涉及式I所示的吡唑硼酸类化合物、其药学上可接受的盐或其立体异构体以及包含其的药物组合物，并涉及它们在制备蛋白酶体抑制剂中的用途。
背景技术
作为水解细胞内蛋白质的主要场所，蛋白酶体在细胞周期调控、细胞应激反应和免疫反应上发挥着重要的作用。因此，蛋白酶体已经成为治疗多种疾病的理想靶点，这些疾病包括肿瘤、疟原虫、哮喘等。
目前有多款蛋白酶体抑制剂上市，例如硼替佐米、MLN9708(商品名Ninlaro；31)、卡非佐米和NPI0052(商品名Marizomib)等。然而，现有蛋白酶体抑制剂存在生物选择性差、体内外稳定性较差、实体瘤抑制效果不佳、毒副作用大等缺点，限制了其在临床上的应用。
发明内容
本申请涉及一种式I所示的化合物、其药学上可接受的盐或其立体异构体：
Figure PCTCN2021113533-appb-000001
其中，R 1选自H、苯基、C 1-4烷基、含有1-3个选自N或O或S的杂原子的5元或6元杂环、或者
Figure PCTCN2021113533-appb-000002
所述苯基任选被卤素、卤代C 1-4烷基和/或C 1-4烷基取代，所述Z 1为C 1-10链烃基或者C 1-10链烃基中的一个或多个碳原子被选自O、S或N的杂原子取代的杂链烃基，所述R a和R b各自独立地选自H或C 1-4烷基，或者R a和R b与其连接的N原子一起形成5元至10元饱和杂环，所述5元至10元饱和杂环除所述N原子外还可含有0-3个选自N、O或S的杂原子，所述5元至10元饱和杂环任选被C 1-4烷基、苯基、或者含有1-3个杂原子的5元或6元杂环取代；
R 2和R 3各自独立地选自OH、C 1-4烷基或O(O)C 1-4烷基，或者R 2、R 3与其连接的B原子一起形成4-15元的环
Figure PCTCN2021113533-appb-000003
所述R c和R d各自独立地选自O、S、NH、NR e、-CO、-NHCO、-NR fCO、-OS(O) 2、-NHS(O) 2或者-NR g-SO 2，所述Z 2为C 1-10链烃基、或者C 1-10链烃基中的一个或多个碳原子被选自O、S或N的杂原子取代的杂链烃基、或者为1个或多个R c和/或R d；
所述R e、R f和R g各自独立地选自卤素、C 1-10烷基、C 1-10烷氧基或C 1-10卤代烷基；
R 4选自C 1-4烷基、苯基、或者含有1-3个选自N或O或S的杂原子的5元或6元杂环，所述苯基任选被卤素、氰基、C 1-4烷基、C 1-4烷氧基、苯基、C 1-4烷基砜基和/或苯基C 1-4烷氧基取代；
X选自NH、O、S、-OS(O) 2-或-NHS(O) 2-。
本申请另一方面涉及一种药物组合物，其含有上述的式I所示的化合物、其药学上可接受的盐或其立体异构体和药学上可接受的辅料。
本申请另一方面涉及上述的式I所示的化合物、其药学上可接受的盐或其立体异构体或者上述的药物组合物在制备蛋白酶体抑制剂中的用途。优选地，所述蛋白酶体抑制剂可用于治疗或缓解与蛋白酶体相关的疾病，例如肿瘤、疟原虫感染、哮喘或阿尔茨海默症等。或者，本申请另一方面涉及治疗或缓解与蛋白酶体相关的疾病的方法，包括向有需要的受试者给予治疗有效量的上述的式I所示的化合物、其药学上可接受的盐或其立体异构体、或者上述的药物组合物。或者，本申请另一方面涉及用于治疗或缓解与蛋白酶体相关的疾病的上述的式I所示的化合物、其药学上可接受的盐或其立体异构体、或者上述的药物组合物。
具体实施方式
本领域技术人员能够理解的是，下述的实施方式仅作为示例的目的给出，而并不旨在以任何方式限制本申请的保护范围。本申请可涵盖下述多个实施方式的任意组合或不同实施方式的多个特征的任意组合。
在本文中，术语“C m-n”是指由该术语修饰的该部分中具有m-n个碳原子(n大于m，且二者为整数)。 例如，C 1-10表示其修饰的部分中具有1-10个碳原子，例如1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。
在本文中，除非另有说明，使用的术语“链烃基”是指由C和H组成的链状基团，其包括直链或支链、饱和或不饱和的链烃基，包括但不限于C 1-10链烃基、C 1-9链烃基、C 1-8链烃基、C 1-7链烃基、C 1-6链烃基、C 1-5链烃基、C 1-4链烃基、C 1-3链烃基、C 1-2链烃基和C 1链烃基。在本文中，除非另有说明，使用的术语“杂链烃基”是指链烃基中的1个或多个(例如2个、3个、4个、5个、6个、7个、8个、9个、10个等)、例如1-3个或1-5个或1-10个碳原子被选自N、O或S中的杂原子取代而形成的链状基团。
在本文中，除非另有说明，使用的术语“烷基”是指仅由碳原子和氢原子组成的饱和烃基，包括但不限于，C 1-10烷基、C 1-9烷基、C 1-8烷基、C 1-7烷基、C 1-6烷基、C 1-5烷基、C 1-4烷基、C 1-3烷基、C 1-2烷基和C 1烷基。作为烷基的非限制性实例，可以列举以下直链或支链的饱和烃基：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基及其另外七种异构体、正己基及其另外十六种异构体。例如，C 1-7烷基包括甲基、乙基、丙基、丁基、戊基、己基、庚基及其全部异构体。
在本文中，除非另有说明，术语“杂环”包括脂杂环和芳杂环，是指由碳原子和独立地选自N、O或S中的1-3个杂原子组成的饱和或不饱和环系，并且可以是取代的或未取代的。在本文中，除非另有说明，术语“饱和杂环”是指由碳原子和独立地选自N、O或S中的1-3个杂原子组成的杂环，并且可以是取代的或未取代的。作为杂环的非限制性实例，可列举吡咯基、噻吩基、噻唑基、咪唑基、吡嗪基、哌啶基、哌嗪基、嘧啶基、吡咯烷基、吗啉基、呋喃基、四氢呋喃基、四氢吡喃基、环氧乙烷基、吡喃基、吡啶基或四氢吡啶基，但不仅限于此。
在本文中，除非另有说明，使用的术语“烷氧基”是指氧原子与上述烷基相连、并且通过该氧原子以单键连接至分子其余部分的基团，其涵盖了各种可能的几何异构基团与立体异构基团。作为烷氧基的非限制性实例，可以列举甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基及其另外七种异构体、正己氧基及其另外十六种异构体。
在本文中，除非另有说明，使用的术语“卤素”是指氟、氯、溴或碘。在本文中，除非另有说明，使用的术语“卤代烷基”是指被一个或多个、优选1-5个(例如1个、2个、3个、4个或5个)卤素原子取代的如上定义的烷基。卤代烷基包括单卤代烷基、二卤代烷基、三卤代烷基、全卤代烷基等，如氯代甲基、二氯甲基、二氟甲基、二溴甲基、三氟甲基、2,2,2-三氟乙基、全氟乙基、2,2,2-三氟-1,1-二氯乙基等。
在本文中，除非另有说明，使用的术语“药学上可接受的”是指在合理医学判断范围内，适用于与人类和动物组织接触而没有过量毒性、刺激、过敏反应或其它问题或并发症，与合理的利益/风险比相称的那些化合物、材料、组合物和/或剂型。例如，本文使用的术语“药学上可接受的盐”是指式1所示的化合物与药学上可接受的游离酸或游离碱形成的酸加成盐或碱加成盐。酸加成盐由以下酸获得：如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、亚硝酸、亚磷酸、乙酸、苯甲酸、柠檬酸、乳酸、马来酸、葡萄糖酸、甲磺酸、苯磺酸、对甲苯磺酸、酒石酸、富马酸、苹果酸、草酸、琥珀酸等。碱加成盐包括钠盐、钾盐、钙盐、铵盐、或镁盐等。
除非另有说明，本文中使用楔形的实线键和虚线键
Figure PCTCN2021113533-appb-000004
表示一个立体中心的绝对构型。除非另有说明，本文提到的立体异构体包括几何异构体和对映异构体，所有这些异构体都在本申请的范围之内。
在本文中，除非另有说明，术语“任选”是指其所修饰的对象或事件存在或不存在、出现或不出现。例如，某一基团“任选被取代”是指该基团可被取代的或未被取代的。
在一个实施方式中，本申请涉及一种式I所示的化合物、其药学上可接受的盐或其立体异构体：
Figure PCTCN2021113533-appb-000005
其中，R 1选自H、苯基、C 1-4烷基、含有1-3个选自N或O或S的杂原子的5元或6元杂环、或者
Figure PCTCN2021113533-appb-000006
所述苯基任选被卤素、卤代C 1-4烷基和/或C 1-4烷基取代，所述Z 1为C 1-10链烃基或者C 1-10链烃基中的一个或多个碳原子被选自O、S或N的杂原子取代的杂链烃基，所述R a和R b各自独立地选自H或C 1-4烷基， 或者R a和R b与其连接的N原子一起形成5元至10元饱和杂环，所述5元至10元饱和杂环除所述N原子外还含有0-3个选自N、O或S的杂原子，所述5元至10元饱和杂环任选被C 1-4烷基、苯基、或者含有1-3个杂原子的5元或6元杂环取代；
R 2和R 3各自独立地选自OH、C 1-4烷基或O(O)C 1-4烷基，或者R 2、R 3与其连接的B原子一起形成4-15元的环
Figure PCTCN2021113533-appb-000007
所述R c和R d各自独立地选自O、S、NH、NR e、-CO、-NHCO、-NR fCO、-OS(O) 2、-NHS(O) 2或者-NR g-SO 2，所述Z 2为C 1-10链烃基、或者C 1-10链烃基中的一个或多个碳原子被选自O、S或N的杂原子取代的杂链烃基、或者为1个或多个R c和/或R d；
所述R e、R f和R g各自独立地选自卤素、C 1-10烷基、C 1-10烷氧基或C 1-10卤代烷基；
R 4选自C 1-4烷基、苯基、或者含有1-3个选自N或O或S的杂原子的5元或6元杂环，所述苯基任选被卤素、氰基、C 1-4烷基、C 1-4烷氧基、苯基、C 1-4烷基砜基和/或苯基C 1-4烷氧基取代；
X选自NH、O、S、-OS(O) 2-或-NHS(O) 2-。
在一些实施方式中，R 1选自H、苯基、卤代苯基、卤代C 1-4烷基苯基、C 1-4烷基苯基、含有1-3个选自N或O或S的杂原子的5元或6元不饱和杂环、或者
Figure PCTCN2021113533-appb-000008
所述Z 1为C 1-10烷基，所述R a和R b各自独立地选自C 1-4烷基，或者R a和R b与其连接的N原子一起形成5元至7元饱和杂环，所述5元至7元饱和杂环任选被C 1-4烷基或者苯基取代。
在一些实施方式中，R 1选自H、苯基、卤代苯基、卤代C 1-4烷基苯基、C 1-4烷基苯基、
Figure PCTCN2021113533-appb-000009
Figure PCTCN2021113533-appb-000010
Figure PCTCN2021113533-appb-000011
所述Z 1为C 1-6烷基，所述R a和R b各自独立地选自C 1-4烷基，或者R a和R b与其连接的N原子一起形成5元或6元饱和杂环，所述5元或6元饱和杂环任选被C 1-4烷基或者苯基取代。
在一些实施方式中，R 1选自H、卤代C 1-4烷基苯基、氟代苯基、氯代苯基、溴代苯基、C 1-4烷基苯基、
Figure PCTCN2021113533-appb-000012
Figure PCTCN2021113533-appb-000013
n为选自1-6的整数，m和m’相同或不同且各自独立地为选自0-3的整数，所述
Figure PCTCN2021113533-appb-000014
Figure PCTCN2021113533-appb-000015
任选被C 1-4烷基或者苯基取代。
在一些实施方式中，R 2和R 3各自独立地选自OH、C 1-3烷基或O(O)C 1-3烷基，或者R 2、R 3与其连接的B原子一起形成6-10元的环
Figure PCTCN2021113533-appb-000016
所述R c和R d各自独立地选自O、S、-CO或-OS(O) 2，所述Z 2为C 1-5链烃基、或者C 1-5链烃基中的1-3个碳原子被选自O、S或N的杂原子取代的杂链烃基。
在一些实施方式中，R 2和R 3各自独立地选自OH、C 1-3烷基或O(O)C 1-3烷基，或者R 2、R 3与其连接的B原子一起形成
Figure PCTCN2021113533-appb-000017
Figure PCTCN2021113533-appb-000018
在一些实施方式中，R 4选自C 1-4烷基、苯基、卤代苯基、卤代C 1-4烷基苯基、C 1-4烷基苯基、氰基苯基、C 1-4烷氧基苯基、联苯基、C 1-4烷基砜基苯基、苯基C 1-4烷氧基苯基、或者含有1-3个选自N或O或S的杂原子的5元或6元不饱和杂环。
在一些实施方式中，R 4选自C 1-4烷基、苯基、氟代苯基、氯代苯基、溴代苯基、氟代C 1-4烷基苯基、氯代C 1-4烷基苯基、溴代C 1-4烷基苯基、C 1-4烷基苯基、氰基苯基、C 1-4烷氧基苯基、联苯基、C 1-4烷基砜基苯基、苯基C 1-4烷氧基苯基、或者含有1-2个选自N或O或S的杂原子的5元或6元不饱和杂环。
在一些实施方式中，R 4选自C 1-4烷基、苯基、氟代苯基、氯代苯基、溴代苯基、氟代C 1-4烷基苯基、氯代C 1-4烷基苯基、溴代C 1-4烷基苯基、C 1-4烷基苯基、氰基苯基、C 1-4烷氧基苯基、联苯基、C 1-4烷基砜基苯基、苯基C 1-4烷氧基苯基、
Figure PCTCN2021113533-appb-000019
Figure PCTCN2021113533-appb-000020
在一些实施方式中，R 1选自H、氟代甲基苯基、氯代甲基苯基、溴代甲基苯基、氟代乙基苯基、氯代乙基苯基、溴代乙基苯基、氟代丙基苯基、氯代丙基苯基、溴代丙基苯基、氟代苯基、氯代苯基、溴代苯基、甲基苯基、乙基苯基、丙基苯基、
Figure PCTCN2021113533-appb-000021
Figure PCTCN2021113533-appb-000022
Figure PCTCN2021113533-appb-000023
n为选自1-5的整数，m和m’相同或不同且各自独立地为选自0-2的整数，所述
Figure PCTCN2021113533-appb-000024
Figure PCTCN2021113533-appb-000025
任选被甲基、乙基、丙基或者苯基取代；
R 2和R 3各自独立地选自OH，或者R 2、R 3与其连接的B原子一起形成
Figure PCTCN2021113533-appb-000026
R 4选自甲基、乙基、丙基、苯基、氟代苯基、氯代苯基、溴代苯基、氰基苯基、甲基苯基、乙基苯基、丙基苯基、甲氧基苯基、乙氧基苯基、丙氧基苯基、联苯基、甲基砜基苯基、乙基砜基苯基、丙基砜基苯基、苯基甲氧基苯基、苯基乙氧基苯基、苯基丙氧基苯基、
Figure PCTCN2021113533-appb-000027
Figure PCTCN2021113533-appb-000028
X选自O、S、-OS(O) 2-或-NHS(O) 2-。
在一些实施方式中，在本申请涉及的上述的式I所示的化合物、其药学上可接受的盐或其立体异构体中，所述化合物选自：
(1)(R)-(3-甲基-1-(2-(5-苯基-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
(2)(R)-(3-甲基-1-(2-(5-苯基-3-(2-(((4-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
(3)(R)-(3-甲基-1-(2-(5-苯基-3-(2-(((2-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
(4)(R)-(1-(2-(3-(2-((3-氟苯基)磺酰基)氧基)苯基)-5-苯基-1H-吡唑-1-基)-乙酰胺基)-3-甲基丁基)硼酸；
(5)(R)-(1-(2-(3-(2-(((3-氯苯基)磺酰基)氧基)苯基)-5-苯基-1H-吡唑-1-基)-乙酰胺基)-3-甲基丁基)硼酸；
(6)(R)-(1-(2-(3-(2-(((3-溴苯基)磺酰基)氧基)苯基)-5-苯基-1H-吡唑-1-基)-乙酰胺基)-3-甲基丁基)硼酸；
(7)(R)-(1-(2-(3-(2-(((2,5-二氯苯基)磺酰基)氧基)苯基)-5-苯基-1H-吡唑-1-基)-乙酰胺基)-3-甲基丁基)硼酸；
(8)(R)-(3-甲基-1-(2-(5-苯基-3-(2-((间-甲苯基磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
(9)(R)-(3-甲基-1-(2-(5-苯基-3-(2-((噻吩-2-基磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
(10)(R)-(1-(2-(3-(2-((吡啶-2-基磺酰基)氧基)苯基)-5-苯基-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
(11)(R)-(3-甲基-1-(2-(5-苯基-3-(3-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
(12)(R)-(3-甲基-1-(2-(5-苯基-3-(4-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
(13)(R)-(1-(2-(5-(4-溴苯基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
(14)(R)-(1-(2-(5-(3-溴苯基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
(15)(R)-(1-(2-(5-(2-溴-苯基)-3-(2-(((3-三氟甲基苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)异丁基)硼酸；
(16)(R)-(1-(2-(5-(4-氟苯基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
(17)(R)-(1-(2-(5-(4-氯苯基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
(18)(R)-(1-(2-(5-(4-氰基苯基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
(19)(R)-(1-(2-(5-(4-(甲基磺酰基)苯基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
(20)(R)-(1-(2-(5-(4-甲基-苯基)-3-(2-(((3-三氟甲基苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)异丁基)硼酸；
(21)(R)-(1-(2-(5-(4-甲氧基苯基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
(22)(R)-(1-(2-(5-([1,1’-联苯基]-4-基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
(23)(R)-(1-(2-(5-(4-(苄氧基)苯基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
(24)(R)-(1-(2-(5-(呋喃-2-基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
(25)(R)-(3-甲基-1-(2-(5-(噻吩-2-基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
(26)(R)-(3-甲基-1-(2-(5-甲基-3-(3-(((3-三氟甲基苯基)磺酰胺基)苯基)-1H-吡唑-1-基)乙酰胺基)异丁基)硼酸；
(27)(R)-(1-(2-(3-(3-羟基苯基)-5-苯基-1H-吡唑-1-基)乙酰胺基)3-甲基丁基)硼酸；
(28)(R)-(3-甲基-1-(2-(5-苯基-3-(3-((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
(29)(R)-(1-(2-(3-(3-(2-(二甲基氨基)乙氧基)苯基)-5-苯基-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸盐酸盐；
(30)(R)-(3-甲基-1-(2-(3-(3-(2-吗啉乙氧基)苯基)-5-苯基-1H-吡唑-1-基)-乙酰氨基-)丁基)硼酸盐酸盐；
(31)(R)-(3-甲基-1-(2-(3-(3-(3-吗啉丙氧基)苯基)-5-苯基-1H-吡唑-1-基)乙酰氨基)丁基)硼酸盐酸盐；
(32)(R)-(1-(2-(3-(N,N-二乙基乙氧基)苯基)-5-苯基-1H-吡唑-1-基)乙酰胺基)异丁基)硼酸盐酸盐；
(33)(R)-(3-甲基-1-(2-(5-苯基-3-(3-(2-(吡咯烷基-1-基)乙氧基)苯基)-1H-吡唑-1-基)乙酰胺基)异丁基)硼酸盐酸盐；
(34)(R)-(3-甲基-1-(2-(5-苯基-3-(3-(2-(哌啶烷基-1-基)乙氧基)苯基)-1H-吡唑-1-基)乙酰胺基)异丁基)硼酸盐酸盐；
(35)(R)-(3-甲基-1-(2-(3-(3-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)苯基)-5-苯基-1H-吡唑-1-基)乙酰氨基)丁基)硼酸盐酸盐；
(36)((1R)-1-(2-(3-(3-(2-(2,6-二甲基吗啉代)乙氧基)苯基)-5-苯基-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸盐酸盐；
(37)((1R)-1-(2-(3-(3-(2-(S,S-2,6-二甲基吗啉代)乙氧基)苯基)-5-苯基-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸盐酸盐；
(38)((1R)-1-(2-(3-(3-(2-(S,R-2,6-二甲基吗啉代)乙氧基)苯基)-5-苯基-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸盐酸盐；
(39)(R)-(3-甲基-1-(2-(5-苯基-3-(3-(2-(4-苯基哌嗪-1-基)乙氧基)苯基)-1H-吡唑-1-基)乙酰氨基)丁基)硼酸盐酸盐；
(40)(R)-(3-甲基-1-(2-(5-苯基-3-(3-(3-(4-苯基哌嗪-1-基)丙氧基)苯基)-1H-吡唑-1-基)乙酰氨基)丁基)硼酸二盐酸盐；
(41)(R)-(3-甲基-1-(2-(5-苯基-3-(3-(4-(4-苯基哌嗪-1-基)丁氧基)苯基)-1H-吡唑-1-基)乙酰氨基)丁基)硼酸二盐酸盐；
(42)(R)-(3-甲基-1-(2-(5-苯基-3-(3-((5-(4-苯基哌嗪-1-基)戊基)氧基)苯基)-1H-吡唑-1-酰基)乙酰胺基)丁基)硼酸二盐酸盐。
在一个实施方式中，本申请涉及一种药物组合物，其含有上述的式I所示的化合物、其药学上可接受的盐或其立体异构体和药学上可接受的辅料。
本申请的药物组合物可以制成任何形式的制剂，例如胶囊剂、片剂、气雾剂、溶液剂、悬浮剂、糖衣剂、锭剂、糖浆剂、乳剂、软膏剂、膏剂、注射剂、散剂、颗粒剂、糊剂、缓释剂、泡沫剂。根据给药途径，本申请的药物可以制成口服给药制剂、鼻部给药制剂、肺部给药制剂、口腔含化制剂、皮下给药制剂、皮内给药制剂、经皮给药制剂、胃肠外给药制剂、直肠给药制剂、储库式给药制剂、静脉内给药制剂、尿道内给药制剂、肌内给药制剂、鼻内给药制剂、眼部给药制剂、硬膜外给药制剂或局部给药制剂。
本文所述的辅料可为药学上可接受的任何辅料，例如但不限于溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、抗氧剂、渗透促进剂、pH值调节剂、表面活性剂、稀释剂等。关于其它可用的药学上可接受的药用辅料，可参见例如《药用辅料手册》(第4版)，R.C.罗等著，郑泽民主译，2005年，化学工业出版社。
在一个实施方式中，本申请涉及上述的式I所示的化合物、其药学上可接受的盐或其立体异构体、或者上述的药物组合物在制备蛋白酶体抑制剂中的用途。优选地，所述蛋白酶体抑制剂可被制备成用于治疗或缓解与蛋白酶体相关的疾病(例如肿瘤、疟原虫感染、哮喘和阿尔茨海默症等)的药物。在可选的实施方式中，本申请涉及治疗或缓解与蛋白酶体相关的疾病的方法，包括向有需要的受试者给予治疗有效量的上述的式I所示的化合物、其药学上可接受的盐或其立体异构体、或者上述的药物组合物。在可选的实施方式中，本申请涉及用于治疗或缓解与蛋白酶体相关的疾病的上述的式I所示的化合物、其药学上可接受的盐或其立体异构体、或者上述的药物组合物。
除非另有说明，在本文中，术语“患者”、“受试者”和“个体”可互换使用，并且表示人或非人动物(例如灵长类动物、啮齿动物等)。
除非另有说明，在本文中，代表成分的量或理化性质或者反应条件等的参数值应当被理解为在所有情况下均由术语“约”修饰。当用术语“约”描述本发明时，术语“约”表示存在的误差值，例如表示在某一特定值的±10％、例如±1％或±0.1％的范围内变化。
除非另有说明，在本文中，单数术语涵盖复数术语，并且复数术语涵盖单数术语。类似地，除非上下文另有明确指示，词语“或”意在包括“和”。
在本文中，除非另有说明，术语“包含、包括和含有”或等同物为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
实施例
接下来通过实施例对本申请进行详细说明，但本申请不仅限于这些实施例。除非另外说明，下述实施例中使用的各试剂、材料、设备均为可商购的；并且，各试剂均为市售化学纯或者分析纯的。
路线1：化合物1-化合物26的合成
Figure PCTCN2021113533-appb-000029
制备例1：化合物1的合成
步骤1：中间体1-2的合成
向处于95％EtOH(125mL)中的KOH(16.8g，300mmol)的溶液中加入1-(2-羟基苯基)乙烷-1-酮(13.6g，100mmol)和苯甲醛(10.6g，100mmol)。在室温下搅拌该溶液12小时，直到通过TLC监测反应完全，倒入冰水(1000mL)中，并用4N HCl酸化至pH 2-3。静置后，将沉淀物过滤并用水冲洗，直到pH值达到6-7，并在真空中干燥，得到黄色固体粗品(23.1g，收率95.1％)。
步骤2：中间体1-3的合成
将步骤1得到的粗品(8.69g，40mmol)和肼基乙酸乙酯盐酸盐(7.74g，48mmol)悬浮在EtOH(150mL)中。将该溶液加热回流12h，然后减压浓缩。将剩余物溶解在乙酸乙酯(100mL)和水(100mL)中，然后用柠檬酸酸化至pH 5-6。将有机层分离并用盐水(50ml×3)洗涤，用无水Na 2SO 4干燥。经柱层析法(硅胶，处于石油醚中的3.3％乙酸乙酯)纯化后，得到7.2g的黄色油(收率55.6％)。
步骤3：中间体1-4的合成
在冰浴和氩气气氛下，向处于四氢呋喃(15mL)中的步骤2的产物(0.648g，2mmol)的溶液中加入60％NaH(0.16g，4mmol)。加入3-(三氟甲基)苯磺酰氯(0.732g，3mmol)。将溶液在冰浴中搅拌30分钟，然后滴加水(2mL)和4N HCl水性溶液(2mL)。将产生的混合物在减压下浓缩。将剩余物溶解 在乙酸乙酯(20mL)中并用水(20mL)洗涤。将水层用乙酸乙酯(10ml×2)萃取，并将合并后的有机层用盐水(50ml)洗涤，用无水Na 2SO 4干燥，减压浓缩，得到的粗品用于下一步反应而无需进一步纯化。
步骤4：中间体1-5的合成
将步骤3得到的粗品溶解于甲苯(25mL)中，并向其中加入DDQ(0.454g，2mmol)。将所得溶液在100℃下搅拌12小时，然后冷却至室温。通过过滤去除固体，并向滤液中加入水(25mL)和碳酸钾(0.276g，2mmol)，并搅拌30min。将有机层分离，用盐水(20mL)洗涤并用无水Na 2SO 4干燥。经柱层析法(硅胶，处于石油醚中的10％乙酸乙酯)纯化后，得到0.78g的黄色液体(收率75.3％)。
步骤5：中间体1-6的合成
向步骤4得到的产物(0.78g，1.47mmol)与四氢呋喃(15mL)和水(15mL)的混合物中加入3N LiOH水性溶液(2mL)。搅拌30min后，加入另外的水(15ml)，并在减压和低温下移除四氢呋喃。将剩余物用4N HCl酸化至pH 2-3，将沉淀物过滤并用水洗涤，直到pH 6-7。得到题述化合物(0.69g，93.5％)，用于下一步反应而无需进一步纯化。
步骤6：中间体1-7的合成
向处于CH 2Cl 2(30mL)中的步骤5的产物(0.52g，1mmol)的经搅拌的悬液中加入EDCI(0.23g，1.2mmol)和HOBT(0.15g，1.1mmol)。然后加入频哪醇亮氨酸硼酸盐酸盐(0.25g，1mmol)和DIPEA(0.15g，1.2mmol)。将混合物搅拌12h。在减压下去除溶剂，并将剩余物溶解在乙酸乙酯(20mL)中。将有机层用0.1N HCl、盐水、5％NaHCO 3和盐水洗涤。将有机相用无水Na 2SO 4干燥。将溶剂蒸发以产生题述化合物(0.60g，含杂质的粗品)，无需进一步纯化而用于下一步。
步骤7：化合物1的合成
向处于乙醚(15mL)中的上述步骤6获得的产物(0.60g，0.86mmol)溶液中加入二乙醇胺(0.105g，1mmol)，并将反应混合物在室温下搅拌12h。将所得沉淀物过滤，用乙醚洗涤，然后用乙酸乙酯(20mL)和水(20mL)的混合物进行处理。在搅拌下向该悬液中加入4N HCl，并再搅拌12h。将有机层分离并用盐水、饱和NaHCO 3和盐水洗涤，并用无水Na 2SO 4干燥。将有机溶剂在减压下去除，以提供作为白色固体的化合物1(0.33g，总收率32.7％)。mp:98-100℃。 1H NMR(400MHz,DMSO)δ8.75(s,1H),7.97(d,J＝7.8Hz,1H),7.84(d,J＝7.9Hz,1H),7.78(s,1H),7.67(t,J＝6.9Hz,3H),7.57–7.47(m,2H),7.36(dq,J＝21.4,7.2Hz,5H),6.46(s,1H),4.58(q,J＝17.0Hz,2H),2.57(s,1H),1.44(dt,J＝12.9,6.4Hz,1H),1.14(ddd,J＝19.4,14.3,6.8Hz,2H),0.70(d,J＝6.3Hz,6H)； 13C NMR(101MHz,DMSO)δ169.6,150.4,146.4,139.5,136.2,132.9,132.5,132.0,132.0(dd,J＝3.5Hz),131.7,131.6,130.7(dd,J＝33.5Hz),128.9,128.5,128.2,125.5,124.3(dd,J＝7.3,3.4Hz),123.9,123.9,123.2(dd,J＝273.1Hz),105.4,50.5,43.0,40.7,25.8,23.3,22.8。HRMS(ESI+ve)m/z calculated for C 30H 30BF 3N 3O 5S(M+MeOH-H 2O+H) +:612.1961,found 612.19455。
制备例2-制备例26：按照路线1所示，采用与化合物1的合成相同的步骤，得到白色固体的化合物2-化合物26，各化合物如下表所示：
Figure PCTCN2021113533-appb-000030
Figure PCTCN2021113533-appb-000031
Figure PCTCN2021113533-appb-000032
Figure PCTCN2021113533-appb-000033
Figure PCTCN2021113533-appb-000034
路线2：化合物27的合成
Figure PCTCN2021113533-appb-000035
制备例27：化合物27的合成
步骤1：中间体27-2的合成
在冰浴和氩气气氛下，向处于四氢呋喃(15mL)中的2-(3-(3-羟基苯基)-5-苯基-4,5-二氢-1H-吡唑-1-基)乙酸乙酯的溶液中加入60％NaH(0.16g，4mmol)的四氢呋喃溶液。添加乙酰氯(0.24g，3mmol)。将溶液在冰浴下搅拌30分钟，然后滴加水(2mL)和4N HCl水性溶液(2mL)。将得到的混合物在减压下浓缩。将剩余物溶解在乙酸乙酯(20mL)中并用水(20mL)洗涤。将水层用乙酸乙酯(10mL×2)萃取，并将合并后的有机层用盐水(50mL)洗涤，用无水Na 2SO 4干燥，减压浓缩，从而得到中间体27-2的粗品，无需进一步纯化而直接用于下一步反应。
步骤2：中间体27-3的合成
向处于PhMe(50mL)中的中间体27-2的粗品的溶液中加入DDQ(0.453g，2mmol)。将所得溶液在100℃下搅拌12小时，然后冷却至室温。通过过滤除去固体，并向滤液中加入水(25mL)和碳酸钾(0.276g，2mmol)，搅拌30min。将有机层分离，用盐水(20mL)洗涤，用无水Na 2SO 4干燥并浓缩以产生中间体27-3的粗品(收率75.3％)，无需进一步纯化而直接用于下一步反应。
步骤3：中间体27-4的合成
向处于四氢呋喃(15mL)和水(15mL)中的中间体27-3的粗品的溶液中加入3N NaOH(2mL)。将混合物在50℃下搅拌12小时，然后减压浓缩以除去四氢呋喃。向剩余物加入另外的水(15mL)并用4N HCl酸化至pH 2-3。将沉淀过滤并用水洗涤，直到pH值达到6-7。得到中间体27-4(0.53g，89.4％)，无需进一步纯化而直接用于下一步反应。
步骤4：化合物27的合成
按照制备例1的步骤6和步骤7所示的程序，从中间体27-4起始制备得到白色固体的化合物27，收率66.0％。mp:127-129℃。 1H NMR(400MHz,DMSO)δ7.56(d,J＝7.0Hz,2H),7.47(d,J＝6.2Hz,3H),7.22(dd,J＝16.0,8.0Hz,3H),6.80(s,1H),6.73(d,J＝7.6Hz,1H),4.76(s,2H),3.14(dd,J＝9.3,5.3Hz,1H),1.55(dd,J＝12.9,6.4Hz,1H),1.32(m,2H),0.84(dd,J＝10.7,6.5Hz,6H)； 13C NMR(101MHz,DMSO)δ166.8,157.8,150.2,145.8,134.8,130.4,130.1,129.2,129.2,128.9,116.7,115.1,112.3,103.7,52.7,38.2,25.2,23.7,22.3.HRMS(ESI+ve)m/z calculated for C 23H 27BN 3O 3(M+MeOH–H 2O) +:404.2140,found 404.2146。
路线3：化合物28的合成
Figure PCTCN2021113533-appb-000036
制备例28：化合物28的合成
步骤1：中间体28-2的合成
在冰浴下，向处于CH 2Cl 2(200mL)中的间-氨基苯乙酮(2.70g，20mmol)的溶液中滴加Et 3N(3.03g，30mmol)和3-(三氟甲基)苯磺酰氯(4.86g，20mmol)。将该溶液在室温下搅拌12小时，用盐水洗涤，用无水Na 2SO 4干燥，并在减压下蒸发，得到作为白色固体的中间体28-2(6.28g，91.6％)。
步骤2：中间体28-3的合成
采用与制备例1的步骤1相同的程序，得到黄色固体，收率78.9％。
步骤3：中间体28-4的合成
将中间体28-3(4.31g，10mmol)和肼基乙酸乙酯盐酸盐(1.94g，12mmol)悬浮在EtOH(100mL)中。将溶液在回流下搅拌12小时，然后在减压下浓缩。将剩余物溶解在乙酸乙酯(100mL)和水(100mL)中，然后用柠檬酸酸化至pH 5-6。将有机层分离并用盐水(50mL×3)洗涤，用无水Na 2SO 4干燥。经柱层析法(硅胶，处于石油醚中的8％乙酸乙酯)纯化后，得到2.39g作为黄色液体的中间体28-4(收率45.0％，具有杂质的粗品)。
步骤4：化合物28的合成
采用制备例1的步骤3至步骤7所示的程序，得到白色固体的化合物28，收率53.1％。mp:119-120℃. 1H NMR(400MHz,DMSO)δ8.04(m,3H),7.82(t,J＝7.8Hz,1H),7.63(s,1H),7.55(m,3H),7.49(dd,J＝9.4,4.7Hz,3H),7.31(t,J＝7.9Hz,1H),7.05(dd,J＝8.0,1.3Hz,1H),6.77(s,1H),4.77(s,2H),3.15(dd,J＝9.6,5.4Hz,1H),1.55(dd,J＝13.4,6.6Hz,1H),1.34(m,2H),0.84(dd,J＝9.8,6.6Hz,6H)； 13C NMR(101MHz,DMSO)δ166.7,149.3,146.0,140.9,137.8,134.6,131.4,131.2,130.3(d,J＝32.6Hz),130.3,130.2,130.1(d,J＝3.1Hz),130.1,129.2,128.9,123.7(d,J＝273.0Hz),123.7(d,J＝3.7Hz),122.3,120.4,117.8,103.7,52.8,38.2,25.2,23.7,22.3。HRMS(ESI+ve)m/z calculated for C 30H 31BF 3N 4O 4S(M+MeOH–H 2O) +:611.2106,found611.2100。
路线4：化合物29-化合物42的合成
Figure PCTCN2021113533-appb-000037
制备例29：化合物29的合成
步骤1：中间体Y-2(29-2)的合成
向处于EtOH(50mL)中的2-(3-(3-乙酰氧基苯基)-5-苯基-1H-吡唑-1-基)乙酸乙酯的粗品(5mmol)的溶液中加入浓盐酸(2mL)。将混合物加热回流4小时，然后冷却至室温。在减压下除去EtOH，将剩余物溶解在乙酸乙酯(30mL)中并用盐水洗涤，用无水Na 2SO 4干燥。经柱层析法(硅胶，处于石油醚中的12％乙酸乙酯)纯化后，获得1.05g作为白色固体的中间体29-2(收率52.0％)。
步骤2：中间体Y-3(29-3)的合成
向处于丙酮(10mL)和DMF(10mL)中的中间体29-2(0.32g，1mmol)的溶液中加入K 2CO 3(0.28g，2mmol)和2-二甲氨基氯乙烷盐酸盐(0.28g，2mmol)。将混合物加热回流12小时，冷却至室温，然后在减压下浓缩。将剩余物溶解在乙酸乙酯(30mL)中并用盐水洗涤，用无水Na 2SO 4干燥。经柱层析法(硅胶，石处于油醚中的30％乙酸乙酯)纯化后，得到0.35g作为黄色油的中间体29-3(收率89.1％)。
步骤3：中间体Y-4(29-4)的合成
将中间体29-3(0.35g，0.89mmol)悬浮于4N HCl(15mL)中，然后加热回流12h。将所得混合物在减压下蒸发，得到中间体29-4的粗品，无需进一步纯化而用于下一步反应。
步骤4：化合物29的合成
采用制备例1中的步骤6和步骤7所示的程序得到化合物29的未成盐形式29-5，收率为30.6％。将化合物29-5(0.10g，0.21mmol)悬浮于乙酸乙酯(10mL)中，并加入2N氯化氢乙酸乙酯溶液(2mL)。将混合物在室温下搅拌12小时。将沉淀物过滤并用乙酸乙酯洗涤。最终获得白色固体的化合物29(85.7mg)。mp:146-148℃。 1H NMR(400MHz,DMSO)δ7.57(dd,J＝7.6,1.9Hz,2H),7.51(dd,J＝10.7,5.8Hz,6H),7.39(t,J＝7.9Hz,1H),6.99(dd,J＝8.2,1.9Hz,1H),6.93(d,J＝2.3Hz,1H),4.80(s,2H),4.40(m,2H),3.55(m,2H),3.14(dd,J＝9.6,5.3Hz,1H),2.89(s,6H),1.55(m,1H),1.34(m,2H),0.85(dd,J＝11.0,6.6Hz,6H)； 13C NMR(101MHz,DMSO)δ166.8,158.3,149.8,146.0,134.9,130.4,130.2,129.3,128.9,119.0,114.6,111.7,103.9,62.6,55.9,52.7,43.2,38.2,25.2,23.7,22.2。HRMS(ESI+ve)m/z calculated for C 27H 36BN 4O 3(M+MeOH–H 2O) +:475.2875,found 475.2870。
制备例30-制备例42：按照路线4所示，采用与化合物29的合成相同的步骤制备化合物30-化合物42，各化合物如下表所示：
Figure PCTCN2021113533-appb-000038
Figure PCTCN2021113533-appb-000039
Figure PCTCN2021113533-appb-000040
药理实验
1)细胞活性测试
采用CellTiter-Glo法检测化合物对肿瘤细胞增殖的影响。体外培养人黑色素瘤细胞A375、非小细胞肺癌细胞A549、人肺腺癌细胞H1299、结直肠癌细胞HCT116、肝癌细胞株HepG2和胃癌细胞MGC80-3等细胞株，细胞生长至对生长期后，收集细胞，1000rpm离心5min，弃上清，适量培养基悬浮，调整细胞浓度至2×10 4/mL。将细胞悬液接种到384孔细胞培养板上，每孔50μL，放置细胞培养箱(37℃，5％CO 2)中培养24h后，给药组每孔加入细胞培养基稀释的药物5μL，每种药物设三个复孔。培养箱中培养72h后，每孔加入CellTiter-Glo 20μL，于37℃放置20min，使用Multimode Microplate Reader Varioskan Flash(Thermo Scientific，USA)测量相对发光单位(RLU)，并与对照组的RLU比较。运用SigmaPlot 10.0软件计算抑制率和IC 50值。结果见下表：
表1 化合物对三种肿瘤细胞生长的抑制率
Figure PCTCN2021113533-appb-000041
表2 化合物对一些肿瘤细胞的抑制作用
Figure PCTCN2021113533-appb-000042
Figure PCTCN2021113533-appb-000043
2)酶活性测试
目标化合物对20S蛋白酶体的活性测定使用Proteasome-Glo TM Cell-Based测定试剂盒(Promega，USA)。将人慢性髓样白血病细胞系(K562,6000个细胞/孔)以20μL/孔接种在384孔板中。然后将细胞在37℃、5％CO 2下平衡2h。每块384孔板设置空白对照组和给药组，给药组每孔分别加入5μL终浓度为40μM、13.3μM、4.44μM、1.48μM、0.49μM、0.16μM、0.055μM、0.0183μM、0.0030μM、0.0061μM的化合物溶液，将细胞与药物在37℃、5％CO 2下一起温育2h，然后每孔分别加入25μL相应的Proteasome-Glo TM Cell-Based试剂。15min后使用Multimode Microplate Reader Varioskan Flash(Thermo Scientific，USA)测量相对发光单位(RLU)，并与对照组的RLU比较。采用SigmaPlot 10.0软件计算IC 50值。结果见下表：
表3 化合物30和39对蛋白酶体各亚基的抑制活性
Figure PCTCN2021113533-appb-000044
药代动力学测试
本实验包括PO组和IV组，每组三只动物，PO组于给药前、给药后15min、30min、1h、2h、4h、7h、24h从眼眶静脉丛取全血约0.25mL，IV组于给药前、5min、15min、30min、1h、2h、4h、7h、24h从眼眶静脉全血约0.25mL，置肝素抗凝管中。采血后将含抗凝剂的采血管反复颠倒数次以充分混匀，离心前放在湿冰上。采血后60分钟内，在2至8℃下8000rpm，离心10分钟，分离红细胞，得到血浆样品。血浆样品转移至冻存管，-75±15℃条件下保存直至分析。取血浆样本50μL加入5μL乙腈：水(1:1，v/v)，加入200μL 0.1％甲酸乙腈，离心(12000rpm，15min)，上清用超纯水1:1稀释，即得。使用LC-MS/MS方法分析血浆药物浓度。采用Microsoft EXCEL对实验数据采用均值(mean)、偏差％、标准偏差(SD)进行统计描述。用WinNonlin 8.1软件进行药代动力学参数计算。计算以下药代动力学参数：CL(清除率)、V d(表观分布容积)、T 1/2(消除半衰期)、C max(达峰浓度)、T max(达峰时间)、AUC(血药浓度-时间曲线下面积)、F％(生物利用度)。
表4 雄性SD大鼠单次静脉注射1mg/kg化合物39和口服给予10mg/kg化合物39后血浆中的平均药代动力学参数
Figure PCTCN2021113533-appb-000045
NA：不适用。
由表4可知，SD大鼠单次尾静脉注射给予1mg/kg化合物39后，血药浓度-时间曲线下面积(AUC 0-t)为767±117h·ng/mL，表观分布容积(V d)为13.9±2.8L/kg，高于SD大鼠的总体液量，表明药物在体内分布较广；清除率(CL)为21.0±3.4mL/min/kg，属于中等清除率的化合物；体内消除半衰期(T 1/2)为7.63±0.30 h。SD大鼠口服灌胃给予10mg/kg化合物39后，血药浓度-时间曲线下面积(AUC 0-t)为186±147h·ng/mL，达峰浓度(C max)为74.8±82.0ng/mL，达峰时间(T max)为0.33±0.14h，体内消除半衰期(T 1/2)为1.63±0.36h，生物利用度为2.42±1.91％。药代动力学研究表明，化合物39在雄性SD大鼠体内分布较广，属于中等清除率，吸收迅速。
抗肿瘤谱研究
针对A549、A375、HCT116、MDA-MB-231、HepG2、PC3和MCF-7七种肿瘤细胞模型，采用MTT法对化合物30进行了活性评价。所有用于研究的细胞均以3.5×10 3细胞/mL浓度培养，每100mL细胞悬液接种于96孔微滴度板上24小时(37℃，5％CO 2)。然后加入不同浓度的化合物30，孵育72h，对照组加入等效浓度的DMSO(最终浓度0.5％)。MTT法(3-(4,5-二甲基噻唑-2-基)-二苯基四唑溴盐)测定存活细胞数，记录492/620nm处的OD值。利用三重复实验的结果，经Prism-Graphpad软件计算IC 50值。
结果如表5所示，化合物30对七种肿瘤细胞的生长均有显著的抑制活性，其中对HCT116和MCF-7的IC 50分别达到了0.63μM和0.69μM。
表5 化合物30对七种肿瘤细胞的活性
Figure PCTCN2021113533-appb-000046
体内抗肿瘤活性研究
本试验选用移植于体重为18-20g的6周龄雄性BALB/c无胸腺裸鼠(购自上海斯莱克实验动物有限责任公司)的人肝癌Bel7404模型进行化合物30的抗肿瘤作用研究。化合物30的给药剂量分别为50mg/kg(30H组)、25mg/kg(30M组)、12.5mg/kg(30L组)，每周2次静脉注射，共给药5次；同时，以5-FU为对照药物，每周2次腹腔注射，共给药7次(化合物30给药组每组5只小鼠，5FU给药组5只小鼠；采用8只小鼠作为空白对照组)。每周2次用数显电子卡尺测量肿瘤长径a(mm)及相垂直的肿瘤短径b(mm)，肿瘤体积计算公式为：TV＝ab 2/2，相对肿瘤体积计算公式为：RTV＝Vt/Vo，Vo为给药的第一天(d1)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积。给药的第22天(d22)处死动物，称体重，解剖取瘤块，称瘤重，根据以下公式计算肿瘤抑制率(抑瘤率，％)：
Figure PCTCN2021113533-appb-000047
体内抗肿瘤活性结果如表6所示，化合物30在剂量分别为50mg/kg、25mg/kg、12.5mg/kg时对人体肝癌Bel7404的抑瘤率为61.29％、36.55％、24.89％。
表6 化合物30静脉注射对移植于裸鼠的人体肝癌Bel7404的抑瘤作用
Figure PCTCN2021113533-appb-000048
Figure PCTCN2021113533-appb-000049
与空白对照组比较：*P<0.05，**P<0.01。
小鼠体内最大耐受剂量研究
选用健康非荷肿瘤雌性NOD/SCID小鼠(购自斯贝福生物技术有限公司)进行最大耐受剂量实验(Maximum Tolerated Dose,MTD)。向NOD/SCID小鼠直接单次尾静脉注射给药化合物39，以溶媒(0.3mL DMSO,0.27mL Tween-80,2.43mL生理盐水)为对照组，根据化合物39的给药剂量将给药组分为低剂量组(10mg/kg)、中剂量组(20mg/kg)、高剂量组(30mg/kg)三组，每组7只小鼠。观察给药后小鼠体重及生存健康状况(给药前1天记为“第0天”)，确定小鼠最大耐受剂量。每天一次测量小鼠体重，数据如表7所示。
表7 小鼠平均体重变化
Figure PCTCN2021113533-appb-000050
结果表明，化合物39在剂量30mg/kg以下给药是安全的，小鼠平均体重变化不超过5％。
体内人源多发性骨髓瘤RPMI 8226药效学研究
采用细胞株皮下异种移植雌性NOD/SCID小鼠(购自斯贝福生物技术有限公司)得到的肿瘤动物模型进行体内抗肿瘤作用的研究。
向NOD/SCID小鼠皮下接种RPMI 8226细胞，接种细胞9天后成功建立人源多发性骨髓瘤皮下移植肿瘤模型。试验分为溶媒(0.3mL DMSO,0.27mL Tween-80,2.43mL生理盐水)对照组、化合物30低剂量组(20mg/kg)、化合物30中剂量组(30mg/kg)、化合物30高剂量组(40mg/kg)、化合物39低剂量组(5mg/kg)、化合物39中剂量组(10mg/kg)、化合物39高剂量组(15mg/kg)，并以硼替佐米(购自扬子江药业原料药)作为阳性对照组(0.5mg/kg)；每组5只上述构建的荷瘤小鼠，尾静脉给药，一周两次，共给药九次。每周2次用数显电子卡尺测量肿瘤长径a(mm)及与长径垂直的肿瘤短径b(mm)。肿瘤体积计算公式为：TV＝ab 2/2，相对肿瘤体积计算公式为：RTV＝V t/V o，V o为将各组小鼠分笼并第一次给药时(即d1)测量的肿瘤体积，V t为最后一次给药时测量的肿瘤体积。接种RPMI 8226细胞后31天(d22)处死动物，称体重，解剖取瘤块，称瘤重，根据以下公式计算肿瘤抑制率：
Figure PCTCN2021113533-appb-000051
化合物30的体内抗肿瘤活性结果如表8所示，化合物30在剂量分别为20mg/kg、30mg/kg和40mg/kg时对人源多发性骨髓瘤RPMI 8226的肿瘤抑制率分别为72.45％、82.53％和92.07％。
表8.化合物30在RPMI 8226人源多发性骨髓瘤模型中的体内抗肿瘤结果
Figure PCTCN2021113533-appb-000052
1.数据以“平均值±标准误差”表示；
2.T/C％＝T RTV/C RTV×100％或T/C％＝T TV/C TV×100％；TGI％＝(1-T/C％)×100％(T RTV：治疗组平均RTV；C RTV：对照组平均RTV；T TV：治疗组平均TV；C TV：对照组平均TV)。
化合物39的体内抗肿瘤活性结果如表9所示，化合物39在剂量分别为5mg/kg、10mg/kg和15mg/kg时对人源多发性骨髓瘤RPMI 8226的肿瘤抑制率分别为83.82％、93.35％和96.14％。
表9.化合物39在RPMI 8226人源多发性骨髓瘤模型中的体内抗肿瘤结果
Figure PCTCN2021113533-appb-000053
Figure PCTCN2021113533-appb-000054
1.数据以“平均值±标准误差”表示；
2.T/C％＝T RTV/C RTV×100％或T/C％＝T TV/C TV×100％；TGI％＝(1-T/C％)×100％(T RTV：治疗组平均RTV；C RTV：对照组平均RTV；T TV：治疗组平均TV；C TV：对照组平均TV)。
由此可见，本发明实施例中制备的化合物可表现出的出色的抗肿瘤活性。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
本领域技术人员将认识到，本申请的范围并不限于上文描述的各种具体实施方式和实施例，而是能够在不脱离本申请的精神的情况下，进行各种修改、替换、或重新组合，这都落入了本申请的保护范围内。

Claims (15)

  1. 一种式I所示的化合物、其药学上可接受的盐或其立体异构体：
    Figure PCTCN2021113533-appb-100001
    其中，R 1选自H、苯基、C 1-4烷基、含有1-3个选自N或O或S的杂原子的5元或6元杂环、或者
    Figure PCTCN2021113533-appb-100002
    所述苯基任选被卤素、卤代C 1-4烷基和/或C 1-4烷基取代，所述Z 1为C 1-10链烃基或者C 1-10链烃基中的一个或多个碳原子被选自O、S或N的杂原子取代的杂链烃基，所述R a和R b各自独立地选自H或C 1-4烷基，或者R a和R b与其连接的N原子一起形成5元至10元饱和杂环，所述5元至10元饱和杂环除所述N原子外还含有0-3个选自N、O或S的杂原子，所述5元至10元饱和杂环任选被C 1-4烷基、苯基、或者含有1-3个杂原子的5元或6元杂环取代；
    R 2和R 3各自独立地选自OH、C 1-4烷基或O(O)C 1-4烷基，或者R 2、R 3与其连接的B原子一起形成4-15元的环
    Figure PCTCN2021113533-appb-100003
    所述R c和R d各自独立地选自O、S、NH、NR e、-CO、-NHCO、-NR fCO、-OS(O) 2、-NHS(O) 2或者-NR g-SO 2，所述Z 2为C 1-10链烃基、或者C 1-10链烃基中的一个或多个碳原子被选自O、S或N的杂原子取代的杂链烃基、或者为1个或多个R c和/或R d；
    所述R e、R f和R g各自独立地选自卤素、C 1-10烷基、C 1-10烷氧基或C 1-10卤代烷基；
    R 4选自C 1-4烷基、苯基、或者含有1-3个选自N或O或S的杂原子的5元或6元杂环，所述苯基任选被卤素、氰基、C 1-4烷基、C 1-4烷氧基、苯基、C 1-4烷基砜基和/或苯基C 1-4烷氧基取代；
    X选自NH、O、S、-OS(O) 2-或-NHS(O) 2-。
  2. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，R 1选自H、苯基、卤代苯基、卤代C 1-4烷基苯基、C 1-4烷基苯基、含有1-3个选自N或O或S的杂原子的5元或6元不饱和杂环、或者
    Figure PCTCN2021113533-appb-100004
    所述Z 1为C 1-10烷基，所述R a和R b各自独立地选自C 1-4烷基，或者R a和R b与其连接的N原子一起形成5元至7元饱和杂环，所述5元至7元饱和杂环任选被C 1-4烷基或者苯基取代。
  3. 如权利要求1或2所述的化合物、其药学上可接受的盐或其立体异构体，其中，R 1选自H、苯基、卤代苯基、卤代C 1-4烷基苯基、C 1-4烷基苯基、
    Figure PCTCN2021113533-appb-100005
    Figure PCTCN2021113533-appb-100006
    Figure PCTCN2021113533-appb-100007
    或者
    Figure PCTCN2021113533-appb-100008
    所述Z 1为C 1-6烷基，所述R a和R b各自独立地选自C 1-4烷基，或者R a和R b与其连接的N原子一起形成5元或6元饱和杂环，所述5元或6元饱和杂环任选被C 1-4烷基或者苯基取代。
  4. 如权利要求1-3中任一项所述的化合物、其药学上可接受的盐或其立体异构体，其中，R 1选自H、卤代C 1-4烷基苯基、氟代苯基、氯代苯基、溴代苯基、C 1-4烷基苯基、
    Figure PCTCN2021113533-appb-100009
    Figure PCTCN2021113533-appb-100010
    Figure PCTCN2021113533-appb-100011
    n为选自1-6的整数，m和m’相同或不同且各自独立地为选自0-3的整数，所述
    Figure PCTCN2021113533-appb-100012
    Figure PCTCN2021113533-appb-100013
    Figure PCTCN2021113533-appb-100014
    任选被C 1-4烷基或者苯基取代。
  5. 如权利要求1-4中任一项所述的化合物、其药学上可接受的盐或其立体异构体，其中，R 2和R 3各自独立地选自OH、C 1-3烷基或O(O)C 1-3烷基，或者R 2、R 3与其连接的B原子一起形成6-10元的环
    Figure PCTCN2021113533-appb-100015
    所述R c和R d各自独立地选自O、S、-CO或-OS(O) 2，所述Z 2为C 1-5链烃基、或者C 1-5链烃基中的1-3个碳原子被选自O、S或N的杂原子取代的杂链烃基。
  6. 如权利要求1-5中任一项所述的化合物、其药学上可接受的盐或其立体异构体，其中，R 2和R 3各自独立地选自OH、C 1-3烷基或O(O)C 1-3烷基，或者R 2、R 3与其连接的B原子一起形成
    Figure PCTCN2021113533-appb-100016
    Figure PCTCN2021113533-appb-100017
  7. 如权利要求1-6中任一项所述的化合物、其药学上可接受的盐或其立体异构体，其中，R 4选自C 1-4烷基、苯基、卤代苯基、卤代C 1-4烷基苯基、C 1-4烷基苯基、氰基苯基、C 1-4烷氧基苯基、联苯基、C 1-4烷基砜基苯基、苯基C 1-4烷氧基苯基、或者含有1-3个选自N或O或S的杂原子的5元或6元不饱和杂环。
  8. 如权利要求1-7中任一项所述的化合物、其药学上可接受的盐或其立体异构体，其中，R 4选自C 1-4烷基、苯基、氟代苯基、氯代苯基、溴代苯基、氟代C 1-4烷基苯基、氯代C 1-4烷基苯基、溴代C 1-4烷基苯基、C 1-4烷基苯基、氰基苯基、C 1-4烷氧基苯基、联苯基、C 1-4烷基砜基苯基、苯基C 1-4烷氧基苯基、或者含有1-2个选自N或O或S的杂原子的5元或6元不饱和杂环。
  9. 如权利要求1-8中任一项所述的化合物、其药学上可接受的盐或其立体异构体，其中，R 4选自C 1-4烷基、苯基、氟代苯基、氯代苯基、溴代苯基、氟代C 1-4烷基苯基、氯代C 1-4烷基苯基、溴代C 1-4烷基苯基、C 1-4烷基苯基、氰基苯基、C 1-4烷氧基苯基、联苯基、C 1-4烷基砜基苯基、苯基C 1-4烷氧基苯基、
    Figure PCTCN2021113533-appb-100018
    Figure PCTCN2021113533-appb-100019
    Figure PCTCN2021113533-appb-100020
  10. 如权利要求1-9中任一项所述的化合物、其药学上可接受的盐或其立体异构体，其中，R 1选自H、氟代甲基苯基、氯代甲基苯基、溴代甲基苯基、氟代乙基苯基、氯代乙基苯基、溴代乙基苯基、氟代丙基苯基、氯代丙基苯基、溴代丙基苯基、氟代苯基、氯代苯基、溴代苯基、甲基苯基、乙基苯基、丙基苯基、
    Figure PCTCN2021113533-appb-100021
    或者
    Figure PCTCN2021113533-appb-100022
    Figure PCTCN2021113533-appb-100023
    Figure PCTCN2021113533-appb-100024
    n为选自1-5的整数，m和m’相同或不同且各自独立地为选自0-2的整数，所述
    Figure PCTCN2021113533-appb-100025
    Figure PCTCN2021113533-appb-100026
    任选被甲基、乙基、丙基或者苯基取代；
    R 2和R 3各自独立地选自OH，或者R 2、R 3与其连接的B原子一起形成
    Figure PCTCN2021113533-appb-100027
    R 4选自甲基、乙基、丙基、苯基、氟代苯基、氯代苯基、溴代苯基、氰基苯基、甲基苯基、乙基苯基、丙基苯基、甲氧基苯基、乙氧基苯基、丙氧基苯基、联苯基、甲基砜基苯基、乙基砜基苯基、丙基砜基苯基、苯基甲氧基苯基、苯基乙氧基苯基、苯基丙氧基苯基、
    Figure PCTCN2021113533-appb-100028
    X选自O、S、-OS(O) 2-或-NHS(O) 2-。
  11. 如权利要求1-10中任一项所述的化合物、其药学上可接受的盐或其立体异构体，其中，所述化合物选自：
    (1)(R)-(3-甲基-1-(2-(5-苯基-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
    (2)(R)-(3-甲基-1-(2-(5-苯基-3-(2-(((4-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
    (3)(R)-(3-甲基-1-(2-(5-苯基-3-(2-(((2-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
    (4)(R)-(1-(2-(3-(2-((3-氟苯基)磺酰基)氧基)苯基)-5-苯基-1H-吡唑-1-基)-乙酰胺基)-3-甲基丁基)硼酸；
    (5)(R)-(1-(2-(3-(2-(((3-氯苯基)磺酰基)氧基)苯基)-5-苯基-1H-吡唑-1-基)-乙酰胺基)-3-甲基丁基)硼酸；
    (6)(R)-(1-(2-(3-(2-(((3-溴苯基)磺酰基)氧基)苯基)-5-苯基-1H-吡唑-1-基)-乙酰胺基)-3-甲基丁基)硼酸；
    (7)(R)-(1-(2-(3-(2-(((2,5-二氯苯基)磺酰基)氧基)苯基)-5-苯基-1H-吡唑-1-基)-乙酰胺基)-3-甲基丁基)硼酸；
    (8)(R)-(3-甲基-1-(2-(5-苯基-3-(2-((间-甲苯基磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
    (9)(R)-(3-甲基-1-(2-(5-苯基-3-(2-((噻吩-2-基磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
    (10)(R)-(1-(2-(3-(2-((吡啶-2-基磺酰基)氧基)苯基)-5-苯基-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
    (11)(R)-(3-甲基-1-(2-(5-苯基-3-(3-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
    (12)(R)-(3-甲基-1-(2-(5-苯基-3-(4-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
    (13)(R)-(1-(2-(5-(4-溴苯基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
    (14)(R)-(1-(2-(5-(3-溴苯基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基 丁基)硼酸；
    (15)(R)-(1-(2-(5-(2-溴-苯基)-3-(2-(((3-三氟甲基苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)异丁基)硼酸；
    (16)(R)-(1-(2-(5-(4-氟苯基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
    (17)(R)-(1-(2-(5-(4-氯苯基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
    (18)(R)-(1-(2-(5-(4-氰基苯基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
    (19)(R)-(1-(2-(5-(4-(甲基磺酰基)苯基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
    (20)(R)-(1-(2-(5-(4-甲基-苯基)-3-(2-(((3-三氟甲基苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)异丁基)硼酸；
    (21)(R)-(1-(2-(5-(4-甲氧基苯基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
    (22)(R)-(1-(2-(5-([1,1’-联苯基]-4-基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
    (23)(R)-(1-(2-(5-(4-(苄氧基)苯基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
    (24)(R)-(1-(2-(5-(呋喃-2-基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸；
    (25)(R)-(3-甲基-1-(2-(5-(噻吩-2-基)-3-(2-(((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
    (26)(R)-(3-甲基-1-(2-(5-甲基-3-(3-(((3-三氟甲基苯基)磺酰胺基)苯基)-1H-吡唑-1-基)乙酰胺基)异丁基)硼酸；
    (27)(R)-(1-(2-(3-(3-羟基苯基)-5-苯基-1H-吡唑-1-基)乙酰胺基)3-甲基丁基)硼酸；
    (28)(R)-(3-甲基-1-(2-(5-苯基-3-(3-((3-(三氟甲基)苯基)磺酰基)氧基)苯基)-1H-吡唑-1-基)乙酰胺基)丁基)硼酸；
    (29)(R)-(1-(2-(3-(3-(2-(二甲基氨基)乙氧基)苯基)-5-苯基-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸盐酸盐；
    (30)(R)-(3-甲基-1-(2-(3-(3-(2-吗啉乙氧基)苯基)-5-苯基-1H-吡唑-1-基)-乙酰氨基-)丁基)硼酸盐酸盐；
    (31)(R)-(3-甲基-1-(2-(3-(3-(3-吗啉丙氧基)苯基)-5-苯基-1H-吡唑-1-基)乙酰氨基)丁基)硼酸盐酸盐；
    (32)(R)-(1-(2-(3-(N,N-二乙基乙氧基)苯基)-5-苯基-1H-吡唑-1-基)乙酰胺基)异丁基)硼酸盐酸盐；
    (33)(R)-(3-甲基-1-(2-(5-苯基-3-(3-(2-(吡咯烷基-1-基)乙氧基)苯基)-1H-吡唑-1-基)乙酰胺基)异丁基)硼酸盐酸盐；
    (34)(R)-(3-甲基-1-(2-(5-苯基-3-(3-(2-(哌啶烷基-1-基)乙氧基)苯基)-1H-吡唑-1-基)乙酰胺基)异丁基)硼酸盐酸盐；
    (35)(R)-(3-甲基-1-(2-(3-(3-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)苯基)-5-苯基-1H-吡唑-1-基)乙酰氨基)丁基)硼酸盐酸盐；
    (36)((1R)-1-(2-(3-(3-(2-(2,6-二甲基吗啉代)乙氧基)苯基)-5-苯基-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸盐酸盐；
    (37)((1R)-1-(2-(3-(3-(2-(S,S-2,6-二甲基吗啉代)乙氧基)苯基)-5-苯基-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸盐酸盐；
    (38)((1R)-1-(2-(3-(3-(2-(S,R-2,6-二甲基吗啉代)乙氧基)苯基)-5-苯基-1H-吡唑-1-基)乙酰胺基)-3-甲基丁基)硼酸盐酸盐；
    (39)(R)-(3-甲基-1-(2-(5-苯基-3-(3-(2-(4-苯基哌嗪-1-基)乙氧基)苯基)-1H-吡唑-1-基)乙酰氨基)丁基)硼酸盐酸盐；
    (40)(R)-(3-甲基-1-(2-(5-苯基-3-(3-(3-(4-苯基哌嗪-1-基)丙氧基)苯基)-1H-吡唑-1-基)乙酰氨基)丁基)硼酸二盐酸盐；
    (41)(R)-(3-甲基-1-(2-(5-苯基-3-(3-(4-(4-苯基哌嗪-1-基)丁氧基)苯基)-1H-吡唑-1-基)乙酰氨基)丁基)硼酸二盐酸盐；或
    (42)(R)-(3-甲基-1-(2-(5-苯基-3-(3-((5-(4-苯基哌嗪-1-基)戊基)氧基)苯基)-1H-吡唑-1-酰基)乙酰胺基)丁基)硼酸二盐酸盐。
  12. 一种药物组合物，包含权利要求1-11中任一项所述的化合物、其药学上可接受的盐或其立体异构体和药学上可接受的辅料。
  13. 如权利要求12所述的药物组合物，其中，所述药学上可接受的辅料选自溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、抗氧剂、渗透促进剂、pH值调节剂、表面活性剂或稀释剂。
  14. 用于治疗或缓解与蛋白酶体相关的疾病的权利要求1-11中任一项所述的化合物、其药学上可接受的盐或其立体异构体、或者权利要求12或13所述的药物组合物。
  15. 如权利要求14所述的用于治疗或缓解与蛋白酶体相关的疾病的化合物、其药学上可接受的盐或其立体异构体、或者药物组合物，其中，所述与蛋白酶体相关的疾病为肿瘤、疟原虫感染、哮喘或阿尔茨海默症。
PCT/CN2021/113533 2020-08-19 2021-08-19 吡唑硼酸类化合物、包含其的药物组合物及它们的用途 Ceased WO2022037648A1 (zh)

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KR1020237009128A KR20230074722A (ko) 2020-08-19 2021-08-19 피라졸 보론산 화합물, 이를 함유하는 약학적 조성물, 및 이의 용도
AU2021328979A AU2021328979B2 (en) 2020-08-19 2021-08-19 Pyrazole boronic acid compound, pharmaceutical composition containing same, and uses thereof
JP2023512421A JP7853957B2 (ja) 2020-08-19 2021-08-19 ピラゾールボロン酸化合物、それを含有する医薬組成物、及びそれらの使用

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5563127A (en) * 1993-03-24 1996-10-08 The Dupont Merck Pharmaceutical Company Boronic acid and ester inhibitors of thrombin
CN104321060A (zh) * 2011-12-22 2015-01-28 阿雷斯贸易股份有限公司 α-氨基硼酸衍生物,选择性免疫蛋白酶体抑制剂
CN105622658A (zh) * 2016-03-18 2016-06-01 中国药科大学 非肽类蛋白酶体抑制剂、其药物组合物、制备方法和应用
CN107108660A (zh) * 2014-10-01 2017-08-29 默克专利股份公司 硼酸衍生物
WO2020020858A1 (en) * 2018-07-26 2020-01-30 Merck Patent Gmbh Boronic acid derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7576206B2 (en) * 2003-08-14 2009-08-18 Cephalon, Inc. Proteasome inhibitors and methods of using the same

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5563127A (en) * 1993-03-24 1996-10-08 The Dupont Merck Pharmaceutical Company Boronic acid and ester inhibitors of thrombin
CN104321060A (zh) * 2011-12-22 2015-01-28 阿雷斯贸易股份有限公司 α-氨基硼酸衍生物,选择性免疫蛋白酶体抑制剂
CN107108660A (zh) * 2014-10-01 2017-08-29 默克专利股份公司 硼酸衍生物
CN105622658A (zh) * 2016-03-18 2016-06-01 中国药科大学 非肽类蛋白酶体抑制剂、其药物组合物、制备方法和应用
WO2020020858A1 (en) * 2018-07-26 2020-01-30 Merck Patent Gmbh Boronic acid derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
R.C. ROWE ET AL.: "Handbook of Pharmaceutical Excipients", CHEMICAL INDUSTRY PRESS
See also references of EP4201941A4

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