WO2021143923A1 - 硼酸衍生物 - Google Patents

硼酸衍生物 Download PDF

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WO2021143923A1
WO2021143923A1 PCT/CN2021/072666 CN2021072666W WO2021143923A1 WO 2021143923 A1 WO2021143923 A1 WO 2021143923A1 CN 2021072666 W CN2021072666 W CN 2021072666W WO 2021143923 A1 WO2021143923 A1 WO 2021143923A1
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alkyl
dichloromethane
cycloalkyl
acid
nmr
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PCT/CN2021/072666
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English (en)
French (fr)
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商现星
张晓军
王业柳
杨斌
陈昌俊
张权浩
陈曦
孙颖慧
李红娟
郭慧萍
朱岩
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首药控股(北京)股份有限公司
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Priority to CN202180010730.8A priority Critical patent/CN115151553A/zh
Publication of WO2021143923A1 publication Critical patent/WO2021143923A1/zh

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    • 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
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    • C—CHEMISTRY; METALLURGY
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    • 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

Definitions

  • This patent relates to a new type of boric acid derivative represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • This article also provides pharmaceutical compositions containing such compounds and methods for their preparation.
  • the compounds described in this patent can be used to treat or prevent diseases related to immune proteasomes.
  • the ubiquitin-proteasome system is present in all eukaryotic cells and is responsible for the degradation of misfolding or redundant proteins in the cell. By regulating the level of protein level, it can regulate almost all important life activities, such as signal transduction, transcription regulation, cell differentiation and apoptosis.
  • 26S proteasome the sedimentation coefficient of proteasome density gradient centrifugation is 26S, so it is also called 26S proteasome
  • the unfolded protein is unfolded, and the unfolded protein is finally delivered to the 20S core particle for degradation.
  • the 20S proteasome has a barrel-like structure composed of 4 rings.
  • the two outer rings each of which contains seven alpha subunits, on the one hand act as the binding part of the regulatory particle, and on the other hand play the role of a "gate" to prevent unregulated entry of proteins into the core particle.
  • the two inner rings each ring contains seven ⁇ subunits, including the protease active subunits ⁇ 1c, ⁇ 2c and ⁇ 5c, which are used for proteolysis.
  • LMP7 is encoded by the PSMB8 gene, with a total of 276 amino acids, and is a small protein of about 30kDa. LMP7 is the core catalytic subunit of the immune proteasome.
  • the function of the immune proteasome in the immune process has been thoroughly studied, especially its antigen presentation function.
  • the catalytic subunits of the immune proteasome are hydrolyzed to produce polypeptides, which are presented to the cell surface by histocompatibility complex (MHC)-1, causing cytotoxic T lymphocyte responses (CTLs).
  • MHC histocompatibility complex
  • CTLs cytotoxic T lymphocyte responses
  • immune proteasomes can hydrolyze proteins and present antigens more efficiently, and the generated antigens can cause more intense CTLs.
  • Some studies have shown that immune proteasomes can regulate the production of cytokines. Small molecule inhibitors are used to selectively inhibit LMP7. IL-23 in monocytes and TNF- ⁇ and IL-6 in T cells will be inhibited.
  • immune proteasomes play a role in maintaining protein homeostasis in the oxidative stress response caused by cytokines. Oxidative stress will release free radicals, leading to the accumulation of a large number of damaged proteins, exceeding the scavenging ability of ordinary proteasomes, and ultimately leading to cell death.
  • the immune proteasome can efficiently remove protein accumulation and maintain cell homeostasis.
  • LMP7/ ⁇ 5i- and LMP2/ ⁇ 1i-deficient mice oxidized and polyubiquitinated proteins were observed to accumulate in the liver and brain [U. Seifert et al., Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress , Cell, 142(4), 613-24, 2010].
  • Immune proteasomes are associated with many diseases. Studies have shown that immunoproteasomes are highly expressed in blood cancers, and selective inhibition of ⁇ 1i and LMP7 can effectively inhibit the growth of patient-derived cells and tumor models [U. Seifert et al., Immunoproteasomes preserve protein homeostasis upstream interferon-induced oxidative stress, Cell, 142(4), 613-24, 2010]. In a study of 668 breast cancer patients, 40% of patients had high expression of LMP7 in their tumors [M. Lee et al., Expression of Immunoproteasome Subunit LMP7in Breast Cancer and Its Association with Immune-Related Markers, Cancer Research and Treatment, 51(1) ,2018].
  • Immune proteasomes promote the occurrence and development of the colorectal, and inhibitors of LMP7 can effectively inhibit the formation of colorectal cancer in mouse models [J. Koerner et al., Inhibition and deficiency of the immunoproteasome subunit LMP7 suppression, the development and progression of colorectal cancer in mice, Oncotarget, 8(31):50873-50888, 2017]. Recently, there is new evidence that the immune proteasome is related to autoimmune diseases, and it is expected to become a popular target for the treatment of such diseases.
  • Immune proteasomes are highly expressed in autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel diseases [Tissue-specific up-regulation of the proteasome subunit ⁇ 5i (LMP7) in Sjogren's syndrome, Arthritis Rheum, 54( 5), 1501-8, 2006].
  • LMP7 proteasome subunit ⁇ 5i
  • selective inhibitors of LMP7 can reduce the degree of inflammatory infiltration and cytokine levels, and alleviate the symptoms of arthritis [J. Koerner et al., Inhibition and deficiency of the immunoproteasome subunit LMP7suppress the development and progression of colorectal cancer in mice, Oncotarget, 8(31):50873-50888,2017].
  • LMP7 of the immune proteasome as a target to treat a variety of diseases is an innovative field and has a broad space for development. Compared with broad-spectrum proteasome inhibitors, LMP7 selective inhibitors have absolute advantages in safety. Patents such as WO2019099582A1 and WO2019038250A1 disclose some LMP7 inhibitors and methods of using them to treat related diseases.
  • This patent describes a class of boronic acid derivatives, which have good inhibitory activity on LMP7, and at the same time have good selectivity for other proteasomes. Moreover, these compounds have excellent oral bioavailability, plasma protein adsorption, pharmacokinetic characteristics, CYP-inhibition and stability.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof,
  • R a and R b are each independently selected from H and C 1-6 alkyl, or R a and R b can be joined together to form a 3-10 membered heterocyclic ring;
  • X is a bond, -O-, or -NR 4 -;
  • Y is a key or -(CR 4 R 5 ) m -;
  • R 4 and R 5 are each independently selected from H, C 1-6 alkyl and C 3-8 cycloalkyl;
  • n 1, 2, or 3;
  • R 2 is selected from H and C 1-6 alkyl
  • R 3 is selected from C 6-10 aryl and C 5-10 heteroaryl, and the aryl and heteroaryl may be optionally substituted by halogen, -OH, -NH 2 , -OC 1-6 alkyl,- N(C 1-6 alkyl)(C 1-6 alkyl), -CN, NO 2 , C 1-6 alkyl, C 3-8 cycloalkyl, or C 3-8 heterocycloalkyl substituted;
  • R 1 is selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, the alkyl, cycloalkane Group, heterocycloalkyl, aryl and heteroaryl are One of them is substituted by halogen, -OH, -NH 2 , -(CH 2 ) 1-3 -C 3-8 cycloalkyl, -(CH 2 ) 0-6 -CF 3 ,- OC 1-6 alkyl, -NR 9 R 8 , -CN, NO 2 , C 1-6 alkyl, -(CH 2 ) 0-3 -(CO)-R 8 , -(CH 2 ) 0-3 -(CO)-NH-R 8 , -(CH 2 ) 0-3 -NH-(CO)-R 8 , or R 10 substitution;
  • R 6a and R 6b are each independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, so
  • the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups can be optionally substituted by halogen, C 1-6 alkyl, C 3-8 cycloalkyl, -OH, -NH 2 , -OC 1-6 alkyl, -NR 9 R 8 , -NO 2 , or -CN substitution, or
  • R 6a and R 6b can be joined together to form a 3-8 membered heterocyclic ring
  • R 7 is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, the alkyl group, Cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups can be optionally substituted by halogen, C 1-6 alkyl, C 3-8 cycloalkyl, -OH, -NH 2 , -OC 1-6 alkane Group, -NR 9 R 8 , -NO 2 , or -CN substitution;
  • R 8 is selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, the alkyl, cycloalkane Groups, heterocycloalkyl, aryl and heteroaryl groups can be optionally substituted by halogen, C 1-6 alkyl, -OC 1-6 alkyl, C 6-10 aryl, or C 5-10 heteroaryl replace;
  • R 9 is selected from H and C 1-6 alkyl
  • R 10 is selected from C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, the cycloalkyl, heterocycloalkyl, aryl and Heteroaryl groups can be optionally substituted by halogen, -OH, -NH 2 , -OC 1-6 alkyl, -N (C 1-6 alkyl) (C 1-6 alkyl), -CN, NO 2 , Or C 1-6 alkyl substitution;
  • R a and R b is H
  • X is a bond, -O-, or -NR 4 -, and R 4 is H;
  • Y is a bond or -(CR 4 R 5 ) m -, R 4 and R 5 are each independently selected from H and C 1-6 alkyl, and m is 1, 2, or 3;
  • Y is a bond or -(CR 4 R 5 ) m -, R 4 and R 5 are H, and m is 1, 2, or 3;
  • Y is a bond or -(CR 4 R 5 ) m -, R 4 and R 5 are each independently selected from H and C 1-6 alkyl, and m is 1 or 2;
  • Y is a bond or -(CR 4 R 5 ) m -, R 4 and R 5 are H, and m is 1 or 2;
  • Y is a bond or -(CR 4 R 5 ) m -, R 4 and R 5 are each independently selected from H and C 1-6 alkyl, and m is 1;
  • Y is a bond or -(CR 4 R 5 ) m -, R 4 and R 5 are H, and m is 1;
  • R 2 is H
  • R 3 is selected from C 5-10 heteroaryl groups, which can be optionally substituted by halogen, NO 2 , C 1-6 alkyl, C 3-8 cycloalkyl, or C 3-8 heterocycloalkyl substitution;
  • R 3 is Said May be optionally substituted by halogen, NO 2 , C 1-6 alkyl, C 3-8 cycloalkyl, or C 3-8 heterocycloalkyl;
  • R 1 is selected from C 3-8 cycloalkyl, C 6-10 aryl, and C 5-10 heteroaryl, and the cycloalkyl, aryl and heteroaryl are One of them is substituted by halogen, -CF 3 , -OC 1-6 alkyl, NO 2 , C 1-6 alkyl, -(CO)-R 8 , -(CO)-NH- R 8 , or R 10 substitution;
  • R 6a and R 6b are each independently selected from C 1-6 alkyl and C 3-8 cycloalkyl, or R 6a and R 6b may be joined together to form a 3-8 membered heterocyclic ring;
  • R 7 is selected from H, C 1-6 alkyl and C 3-8 cycloalkyl
  • R 8 is selected from a C 1-6 alkyl group and a C 3-8 cycloalkyl group, and the cycloalkyl group may be optionally substituted by a C 1-6 alkyl group;
  • R 10 is selected from C 3-8 cycloalkyl and C 3-8 heterocycloalkyl, the cycloalkyl and heterocycloalkyl may be optionally substituted by C 1-6 alkyl;
  • the present invention provides the following compounds or pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof:
  • the present invention provides the following compounds or pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof:
  • the compound of formula (I) of the present invention can be used to treat diseases related to lmp7; in some embodiments, the diseases related to lmp7 activity are hematological malignancies, solid tumors, or abnormal immune regulation, more preferably multiple bone marrow.
  • Tumor acute myelogenous leukemia, myeloid leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, plasmacytoma, follicular lymphoma, immunocytoma, breast cancer, Liver cancer, colorectal cancer, ovarian cancer, esophageal cancer, lung cancer, head and neck cancer, pancreatic cancer, kidney cancer, stomach cancer, thyroid cancer, prostate cancer, bladder cancer, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, Multiple sclerosis, scleroderma, joint adhesive spondylitis, atherosclerosis, Behcet's disease, Crohn's disease, inflammatory bowel disease, ulcerative colitis, autoimmune hepatitis, Sjogren's syndrome, lupus nephritis , Asthma, Amyotrophic Lateral Sclerosis (ALS),
  • Another aspect of the present invention also relates to a pharmaceutical composition, which comprises the compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier;
  • the present invention provides a method for treating diseases associated with lmp7 activity, the method comprising administering to a subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isoform of the present invention.
  • the disease associated with lmp7 activity is multiple myeloma, acute myelogenous leukemia, myeloid leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, and acute lymphocytic leukemia.
  • Leukemia diffuse large B-cell lymphoma, plasmacytoma, follicular lymphoma, immunocytoma, breast cancer, liver cancer, colorectal cancer, ovarian cancer, esophageal cancer, lung cancer, head and neck cancer, pancreatic cancer, kidney cancer, gastric cancer , Thyroid cancer, prostate cancer, bladder cancer, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, scleroderma, joint adhesive spondylitis, atherosclerosis, Behcet's disease, Crohn's disease, inflammatory bowel disease, ulcerative colitis, autoimmune hepatitis, Sjogren's syndrome, lupus nephritis, asthma, amyotrophic lateral sclerosis (ALS), psoriasis, type A immunoglobulin nephropathy, allergic Purpura, Alzheimer's disease (AD);
  • ALS amyotrophic lateral s
  • the objects involved in the present invention are mammals including humans;
  • the present invention provides the use of the compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof in the preparation of a medicament for treating diseases related to lmp7 activity; in
  • the disease associated with lmp7 activity is multiple myeloma, acute myelogenous leukemia, myeloid leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, Plasmacytoma, follicular lymphoma, immunocytoma, breast cancer, liver cancer, colorectal cancer, ovarian cancer, esophageal cancer, lung cancer, head and neck cancer, pancreatic cancer, kidney cancer, stomach cancer, thyroid cancer, prostate cancer, bladder cancer , Rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, scleroderma, joint adhesive spondylitis
  • optionally substituted alkyl means “unsubstituted alkyl” or "substituted alkyl”.
  • the optionally substituted group can be unsubstituted (for example: -CH 2 CH 3 ), fully substituted (for example: -CF 2 CF 3 ), monosubstituted (for example: -CH 2 CH 2 F) or Any level between single substitution and complete substitution (for example: -CH 2 CHF 2 , -CF 2 CH 3 , -CFHCHF 2, etc.).
  • any substitution or substitution pattern that is impossible to exist in space and/or cannot be synthesized will not be introduced.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • substituent -CH 2 O- is equivalent to -OCH 2 -.
  • group and "chemical group” as used herein refer to a specific part or functional group of a molecule. Chemical groups are often thought of as chemical entities embedded in or attached to a molecule.
  • C 1 -C 6 alkyl describes an alkyl group, as defined below, having a total of from 1 to 6 carbon atoms.
  • the total number of carbon atoms shown in the abbreviated notation does not include the carbon atoms on the possible substituents.
  • halogen refers to bromine, chlorine, fluorine or iodine.
  • aromatic refers to a planar ring or ring part of multiple rings, which has 4n+2 Delocalized electronic conjugate system of electrons, where n is an integer.
  • the aromatic ring can be formed by 5, 6, 7, 8, 9, or more than 9 atoms.
  • the aromatic compound may be optionally substituted, and may be a single ring or a polycyclic ring of condensed rings.
  • aromatic compound includes all carbocyclic rings (such as benzene rings) and rings containing one or more heteroatoms (such as pyridine).
  • heteroatom or “hetero” as used herein alone or as part of other ingredients refers to atoms other than carbon and hydrogen.
  • the heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but are not limited to these atoms.
  • the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.
  • fused or "fused ring” used herein alone or in combination refers to a cyclic structure in which two or more rings share one or more bonds.
  • spiro or "spiro ring” used herein alone or in combination refers to a cyclic structure in which two or more rings share one or more atoms.
  • alkyl refers to an optionally substituted linear or optionally substituted branched monovalent saturated hydrocarbon, which has 1-12 Carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, are connected to other parts of the molecule through a single bond, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, etc.
  • cycloalkyl refers to a stable monovalent non-aromatic monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms, and may include fused rings, spiro rings or bridges.
  • the ring system contains 3-15 ring-forming carbon atoms, preferably 3-10 ring-forming carbon atoms, more preferably 3-8 ring-forming carbon atoms, which may be saturated or unsaturated, and is connected to other parts of the molecule through a single bond Connected.
  • Non-limiting examples of "cycloalkyl” include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • heterocyclyl refers to a stable 3-18 membered monovalent non-aromatic ring, including 2-12 carbon atoms, 1 -6 heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heterocyclic group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain a fused ring, a spiro ring or a bridged ring system.
  • the nitrogen, carbon or sulfur on the heterocyclic group can be selected The nitrogen atom can be selectively quaternized, and the heterocyclic group can be partially or fully saturated.
  • the heterocyclic group can be connected to the rest of the molecule through a single bond through a carbon atom or heteroatom on the ring.
  • the heterocyclic group containing a condensed ring may contain one or more aromatic or heteroaromatic rings, as long as the atom on the non-aromatic ring is connected to the rest of the molecule.
  • the heterocyclic group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable A 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • Non-limiting examples of heterocyclic groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, indolinyl, dioxolane, 1,1 -Dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, Piperazinyl, piperidinyl, 4-piperidinone, pyranyl, pyrazolidinyl, pyrrolidinyl, quinazinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like.
  • aryl refers to an all-carbon monocyclic or fused ring with a fully conjugated ⁇ -electron system, which has 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms .
  • the aryl group may be unsubstituted or substituted by one or more substituents. Examples of the substituents include but are not limited to alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, sulfonyl , Sulfinyl, phosphoryl and heteroalicyclic groups.
  • substituents include but are not limited to alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, sulfonyl , Sulfinyl, phosphoryl and heteroalicyclic groups.
  • Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl,
  • heteroaryl refers to a monocyclic or condensed ring of 5-12 ring atoms, with 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, including 1, 2, 3, or 4 ring atoms selected from N, O, S, the remaining ring atoms are C, and have a fully conjugated ⁇ -electron system. Heteroaryl groups can be unsubstituted or substituted. The substituents include but are not limited to alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl and hetero Alicyclic group.
  • Non-limiting examples of non-substituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, iso Quinolinyl, tetrazolyl, triazinyl.
  • polymorph or “polymorph (phenomenon)" used in the present invention means that the compound of the present invention has multiple crystal lattice forms. Some compounds of the present invention may have more than one crystal form, and the present invention covers all polymorphic forms or mixtures thereof.
  • the olefin double bond contained in the compound of the present invention includes E and Z isomers.
  • the compounds of the present invention may contain asymmetric centers. These asymmetric centers can independently be in the R or S configuration. Some of the compounds of the present invention may also show cis-trans isomerism, which is obvious to those skilled in the art. It should be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers and their mixtures, including racemic mixtures. These isomers can be separated from their mixtures by implementing or modifying known methods such as chromatography techniques and recrystallization techniques, or they can be prepared separately from appropriate isomers of their intermediates.
  • pharmaceutically acceptable salt includes both acid salts and alkali salts.
  • “Pharmaceutically acceptable salt addition” refers to those that retain the biological effectiveness and characteristics of the free base of the compound, are not undesirable biologically or otherwise, and are related to inorganic acids, such as, but not limited to, hydrochloric acid, hydrogen Bromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids, such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, Salts formed by capric acid, caproic acid, carbonic acid, cinnamic acid, citric acid, etc.
  • inorganic acids such as, but not limited to, hydrochloric acid, hydrogen Bromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
  • organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, al
  • “Pharmaceutically acceptable alkali-added salts” refer to those salts that retain the biological efficacy and properties of the free acid of the compound, and are not biologically or otherwise undesirable. These salts are prepared by reacting free acids with inorganic or organic bases. Salts formed by reaction with inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and manganese salts.
  • Organic bases that form salts include, but are not limited to, primary amines, secondary amines, tertiary amines, cyclic amines, etc., such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, etc. , Dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline and caffeine, etc.
  • Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
  • solvate refers to a complex composed of one or more molecules of the compound of the present invention and one or more solvent molecules.
  • the solvent may be water, in which case the solvate is a hydrate. It can also be an organic solvent. Therefore, the compounds of the present invention can exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, etc., and the corresponding solvated forms.
  • the compound of the present invention may be a true solvate, but in other cases, the compound of the present invention may only accidentally retain water or a mixture of water and some other solvents.
  • the compound of the present invention can be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the present invention are also included in the scope of the present invention.
  • composition refers to a formulation mixed with a compound of the present invention and a medium generally accepted in the art for delivering a compound with biological activity to a mammal (such as a human).
  • This medium contains all pharmaceutically acceptable carriers.
  • the term "acceptable" in connection with a formulation, composition or ingredient means that it does not have a lasting harmful effect on the overall health of the subject being treated.
  • the term "pharmaceutically acceptable” refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing undesirable biological activity. Reacts or interacts in an undesirable manner with any components included in the composition.
  • “Pharmaceutically acceptable carriers” include, but are not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, which have been approved by relevant government administrative departments and can be used in humans and domesticated animals.
  • subject refers to an individual suffering from a disease, disorder, or condition, etc., including mammals and non-mammals.
  • mammals include, but are not limited to, any member of the class Mammals: humans, non-human primates (such as chimpanzees and other apes and monkeys); domestic animals such as cows, horses, sheep, goats, pigs; domestic animals , Such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs.
  • non-human mammals include, but are not limited to, birds, fish, and the like.
  • the mammal is a human.
  • treatment refers to the treatment of related diseases or disorders in mammals, especially humans, including
  • disease and disorder used herein can be substituted for each other or have different meanings, because some specific diseases or conditions have no known causative factors (so the cause of the disease is not clear), so they cannot be recognized as The disease can only be regarded as an unwanted condition or syndrome, and more or less specific symptoms of the syndrome have been confirmed by clinical researchers.
  • an "effective amount” for treatment is the amount of the composition containing the compound disclosed herein that is required to provide significant disease relief clinically. Techniques such as dose escalation tests can be used to determine the effective amount suitable for any individual case.
  • administration refers to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral route, transduodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • the compounds and compositions discussed herein are administered orally.
  • the temperature is in Celsius.
  • the reagents were purchased from commercial suppliers such as Sinopharm Chemical Reagent Beijing Co., Ltd., Alfa Aesar, or Beijing Bailingwei Technology Co., Ltd., and these reagents can be used directly without further purification unless otherwise specified.
  • reaction flask is equipped with a rubber septum so that substrates and reagents can be added via a syringe; glassware is dried And/or heat and dry.
  • 200-300 mesh silica gel from Qingdao Ocean Chemical Factory is used for column chromatography purification; Thin layer chromatography silica gel prefabricated plate (HSGF254) produced by Yantai Chemical Industry Research Institute is used for preparation of thin layer chromatography; Thermo LCQ is used for MS measurement Fleet type (ESI) liquid chromatography-mass spectrometer; SGW-3 automatic polarimeter, Shanghai Shenguang Instrument Co., Ltd. was used for polarimetric determination.
  • ESI MS measurement Fleet type
  • Nuclear magnetic data ( 1 H NMR) was run at 400 MHz using Varian equipment.
  • the solvents used in NMR data include CDCl 3 , CD 3 OD, D 2 O, DMSO-d 6, etc., based on tetramethylsilane (0.00ppm) or based on residual solvents (CDCl 3 : 7.26 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d 6 -DMSO: 2.50 ppm).
  • the following abbreviations indicate different peak shapes: s (single peak), d (doublet), t (triplet), q (quartet), m (multiple peak), br (broad peak) ), dd (double doublet), dt (double triplet). If the coupling constant is given, use Hertz (Hz) as the unit.
  • the methanol (200 mL) solution containing benzofuran-3-yl formaldehyde (15.0 g) was cooled to 0° C., and sodium borohydride (5.9 g) was added to the system in batches. After the natural temperature returned to room temperature After stirring for 2 hours, after monitoring the completion of the reaction, the solvent was removed by rotary evaporation. The residue was partitioned between ethyl acetate and 1mol/L aqueous hydrochloric acid solution. The organic phase was dried with anhydrous sodium sulfate, filtered and the solvent was evaporated to dryness to obtain the product ( 14.8g).
  • the dichloromethane (100mL) solution containing benzofuran-3-ylmethanol (10.0g) was cooled to 0°C, and phosphorus pentachloride (18.2g) was added to the system in batches. After the addition, it returned to room temperature naturally. After stirring for 1 hour, water was added to quench the reaction. The organic phase was washed with saturated aqueous sodium bicarbonate solution and saturated brine in turn, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to obtain the product (12.1 g).
  • Step D Benzofuran-3-ylmethylboronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step E 2-(benzofuran-3-yl)-1-(S)-chloroethylboronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step F 2-((benzofuran-3-yl)-1-(R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-di Alcohol ester hydrochloride
  • Step G (R)-2-(((chlorocarbonyl)oxy)methyl)pyrrolidine-1-carboxylate tert-butyl ester
  • Step H ((1R)-2-(benzofuran-3-yl)-1-(((((2R)-N-tert-butoxycarbonyl-pyrrolidin-2-yl)methoxy)carbonyl) Amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • the 2-(benzofuran-3-yl)-1-(R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester salt The acid salt (470mg) and diisopropylethylamine (273mg) were added to dry dichloromethane, protected by nitrogen and cooled to 0°C, and (R)-2-(((chlorocarbonyl) was added dropwise to the reaction solution.
  • the dichloromethane solution of tert-butyl oxy)methyl)pyrrolidine-1-carboxylate was returned to room temperature and stirred for 2 hours. The reaction was quenched with water and extracted with dichloromethane.
  • Step J ((1R)-2-(benzofuran-3-yl)-1-((((((2R)-pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid- (1S,2S,3R,5S)-(+)-Pinane-2,3-diol ester trifluoroacetate
  • Step K N-(tert-butyl)benzenesulfinamide
  • Step M ((1R)-2-(benzofuran-3-yl)-1-(((((2R)-1-(N-(tert-butyl)phenylsulfonimido)pyrrolidine -2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step N ((1R)-2-(benzofuran-3-yl)-1-(((((2R)-1-(N-(tert-butyl)phenylsulfonimido)pyrrolidine -2-yl)methoxy)carbonyl)amino)ethyl)boronic acid
  • Step A N-sulfinyl tritylamine
  • Step D (2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(S-methylsulfonimido)pyrrolidine
  • Step E (2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(N,S-dimethylsulfonimido)pyrrolidine
  • Step F ((2R)-1-(N,S-Dimethylsulfonimido)pyrrolidin-2-yl)methanol
  • Step G ((1R)-2-(benzofuran-3-yl)-1-(((((2R)-1-(N,S-dimethylsulfonimido)pyrrolidinyl- 2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • the 2-(benzofuran-3-yl)-1-(R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester salt The acid salt (150mg) and triethylamine (162mg) were added to dry dichloromethane, protected by nitrogen and cooled to -60°C, and the dichloride of bis(trichloromethyl) carbonate (47mg) was added dropwise to the reaction solution.
  • Step H ((1R)-2-(benzofuran-3-yl)-1-(((((2R)-1-(N,S-dimethylsulfonimido)pyrrolidinyl- 2-yl)methoxy)carbonyl)amino)ethyl)boronic acid
  • Step B (R)-2-(benzofuran-3-yl)-1-(2-(3-dimethylsulfinimidophenyl)acetamido)ethylboronic acid-(1S, 2S,3R,5S)-(+)-Pinane-2,3-diol ester
  • Step C (R)-(2-(benzofuran-3-yl)-1-(2-(3-dimethylsulfinimidophenyl)acetamido)ethyl)boronic acid
  • Step A ((6-Bromopyridin-2-yl)imino)dimethyl- ⁇ 6 -sulfinimide
  • Step B ((6-Aminopyridin-2-yl)imino)dimethyl- ⁇ 6 -sulfinimide
  • Step C Benzyl boronic acid pinacol ester
  • step C in Example 1 using benzyl chloride, cuprous iodide, pinacol diborate, triphenylphosphine and lithium tert-butoxide as raw materials to obtain the product (2.5 g).
  • Step D Benzylboronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • step D in Example 1 take the benzyl boronic acid pinacol ester and (1S,2S,3R,5S)-(+)-pinene-2,3-diol as the main raw material to react to obtain the product (2.0 g).
  • Step E 1-(S)-Chloro-2-phenylethylboronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • step E in Example 1 Refer to the method of step E in Example 1 with benzylboronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester, dichloromethane, butyllithium and zinc chloride
  • the tetrahydrofuran solution was used as the main raw material to react to obtain a light yellow oily crude product (2.3g) which was directly used in the next reaction.
  • Step F 2-Phenyl-1-(R)-aminoethylboronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester hydrochloride
  • step F in Example 1 Refer to the method of step F in Example 1, with 1-(S)-chloro-2-phenylethylboronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol Ester, lithium bistrimethylsilylamide tetrahydrofuran solution and 1,4-dioxane solution of hydrogen chloride as main raw materials are reacted to obtain the product (0.70g).
  • Step G (R)-(1-(3-(6-((Dimethyl(oxo)- ⁇ 6 -sulfinyl)amino)pyridin-2-yl)ureido)-2-phenyl Ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step H (R)-(1-(3-(6-((Dimethyl(oxo)- ⁇ 6 -sulfinyl)amino)pyridin-2-yl)ureido)-2-phenyl Ethyl) boric acid
  • the aqueous phase was washed three times with dichloromethane and then acidified with 3 mol/L hydrochloric acid to make the pH acidic. After three extractions with dichloromethane, the organic phase It was dried with sodium sulfate, filtered and concentrated at 30°C to remove the solvent to obtain the product (10 mg).
  • Step A ((1R)-1-(((((((2R)-1-(N,S-dimethylsulfonimido)pyrrolidin-2-yl)methoxy)carbonyl)amino)- 2-Phenylethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step B ((1R)-1-(((((2R)-1-(N,S-dimethylsulfonimido)pyrrolidin-2-yl)methoxy)carbonyl)amino)- 2-phenylethyl)boronic acid
  • Step A ((R)-2-(benzofuran-3-yl)-1-(2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetamido)ethyl Yl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step B ((R)-2-(benzofuran-3-yl)-1-(2-((R)-pyrrolidin-2-yl)acetamido)ethyl)boronic acid-(1S,2S ,3R,5S)-(+)-Pinane-2,3-diol ester trifluoroacetate
  • Step C ((1R)-2-(benzofuran-3-yl)-1-(2-((2R)-1-(N-(tert-butyl)phenylsulfonimido)pyrrolidine -2-yl)acetamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step D ((1R)-2-(benzofuran-3-yl)-1-(2-((2R)-1-(N-(tert-butyl)phenylsulfonimido)pyrrolidine -2-yl)acetamido)ethyl)boronic acid
  • Step B (2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(propyl-2-ylsulfonimido)pyrrolidine
  • N-tritylpropane-2-sulfenamide (8g) into dry dichloromethane (50mL), cool to 0°C, and add tert-butyl hypochlorite ( 2.48g), stirred at 0°C for 1 hour, and then the reaction solution was added dropwise to (R)-2-(((tert-butylbenzylsilyl)oxy)methyl)pyrrolidine (3.12g) And triethylamine (4.6g) in dichloromethane (50mL) solution, stir overnight at room temperature under nitrogen protection, add p-toluenesulfonic acid monohydrate (19.8g), stir at room temperature for 30 minutes, add 1mol/L sodium hydroxide The pH of the aqueous solution was adjusted to 9-10 and extracted with dichloromethane.
  • Step D ((2R)-1-(N-methylpropane-2-ylsulfonimido)pyrrolidin-2-yl)methanol
  • Step E ((1R)-2-(benzofuran-3-yl)-1-(((((2R)-1-(N-methylpropane-2-ylsulfonimido)pyrrolidine -2-yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step F ((1R)-2-(benzofuran-3-yl)-1-(((((2R)-1-(N-methylpropane-2-ylsulfonimido)pyrrolidine -2-yl)methoxy)carbonyl)amino)ethyl)boronic acid
  • Step B (2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(cyclohexanesulfonimido)pyrrolidine
  • Step C (2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(N-methylcyclohexanesulfonimido)pyrrolidine
  • Step D ((2R)-1-(N-methylcyclohexanesulfonimido)pyrrolidin-2-yl)methanol
  • Step E ((1R)-2-(benzofuran-3-yl)-1-(((((2R)-1-(N-methylcyclohexanesulfonimido)pyrrolidine-2 -Yl)methoxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinane-2,3-diol ester
  • Step F ((1R)-2-(benzofuran-3-yl)-1-(((((2R)-1-(N-methylcyclohexanesulfonimido)pyrrolidine-2 -(Yl)methoxy)carbonyl)amino)ethyl)boronic acid
  • Methyl 2-(2-dimethylsulfinimido)acetate (800mg) was dissolved in a mixed solvent of methanol (5mL) and water (2mL), sodium hydroxide (160mg) was added, and the temperature was raised to 70°C Stir for 4 hours, reduce to room temperature, adjust the pH to 5-6 with 1mol/L dilute hydrochloric acid, directly evaporate the solvent, dry the residue in vacuum, beat with 1:10 methanol/dichloromethane, filter, and concentrate the filtrate under reduced pressure to obtain Product (756mg).
  • Step C (R)-2-(benzofuran-3-yl)-1-(2-(2-dimethylsulfinimido)acetamido)ethylboronic acid-(1S,2S, 3R,5S)-(+)-Pinane-2,3-diol ester
  • Step D (R)-2-(benzofuran-3-yl)-1-(2-(2-dimethylsulfinimido)acetamido)ethylboronic acid
  • Step A ethyl 2-(3-dimethylsulfinimidophenyl)acetate
  • Step C (R)-(2-(benzofuran-3-yl)-1-(2-(4-dimethylsulfinimidophenyl)acetamido)ethyl)boronic acid-( 1S,2S,3R,5S)-(+)-pinane-2,3-diol ester
  • Step D (R)-(2-(benzofuran-3-yl)-1-(2-(4-dimethylsulfinimidophenyl)acetamido)ethyl)boronic acid
  • Step D (R)-2-(benzofuran-3-yl)-1-(2-(3-chloro-4-dimethylsulfinimidophenyl)acetamido)ethylboronic acid -(1S,2S,3R,5S)-(+)-Pinane-2,3-diol ester
  • Step E (R)-(2-(benzofuran-3-yl)-1-(2-(3-chloro-4-dimethylsulfinimidophenyl)acetamido)ethyl Boric acid
  • Step B 2-(3-Fluoro-4-dimethylsulfinimidophenyl)acetonitrile
  • Step D (R)-2-(benzofuran-3-yl)-1-(2-(3-fluoro-4-dimethylsulfinimidophenyl)acetamido)ethylboronic acid -(1S,2S,3R,5S)-(+)-Pinane-2,3-diol ester
  • Step E (R)-(2-(benzofuran-3-yl)-1-(2-(3-fluoro-4-dimethylsulfinimidophenyl)acetamido)ethyl Boric acid
  • Step F (R)-2-(benzofuran-3-yl)-1-(2-(3-methoxy-4-dimethylsulfinimidophenyl)acetamido)ethyl Boric acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • step D with 2-(3-methoxy-4-dimethylsulfinimidophenyl)acetic acid (170mg) and 2-(benzofuran-3-yl)-1 -(R)-Aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester hydrochloride (230mg) was used as the raw material to obtain the product (180mg).
  • Step G (R)-(2-(benzofuran-3-yl)-1-(2-(3-methoxy-4-dimethylsulfinimidophenyl)acetamido) Ethyl boric acid
  • step E in Example 10 (R)-2-(benzofuran-3-yl)-1-(2-(3-methoxy-4-dimethylsulfinimidobenzene) (1S,2S,3R,5S)-(+)-pinene-2,3-diol ester (180mg) was used as the raw material to obtain the product (32mg).
  • Step D (R)-2-(benzofuran-3-yl)-1-(2-(2-chloro-4-dimethylsulfinimidophenyl)acetamido)ethylboronic acid -(1S,2S,3R,5S)-(+)-Pinane-2,3-diol ester
  • Step G (R)-(2-(benzofuran-3-yl)-1-(2-(3-methoxy-4-dimethylsulfinimidophenyl)acetamido) Ethyl boric acid
  • step E in Example 10 to (R)-2-(benzofuran-3-yl)-1-(2-(2-chloro-4-dimethylsulfinimidophenyl) Acetamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester (280mg) was used as the raw material to obtain the product (30mg).
  • Step B 2-(3-Dimethylsulfinimido-5-methoxyphenyl)acetonitrile
  • Step D (R)-(2-(benzofuran-3-yl)-1-(2-(3-dimethylsulfinimido-5-methoxyphenyl)acetamido) Ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step E (R)-(2-(benzofuran-3-yl)-1-(2-(3-(dimethylsulfinimido)-5-methoxyphenyl)acetamide (Yl)ethyl)boronic acid
  • Step A 4-(2-Dimethylsulfinimidopyridine) ethyl acetate
  • Step B 4-(2-Dimethylsulfinimidopyridine)acetic acid
  • Step C (R)-2-(benzofuran-3-yl)-1-(4-(2-dimethylsulfinimidopyridine)acetamido)ethylboronic acid-(1S,2S ,3R,5S)-(+)-Pinane-2,3-diol ester
  • Step D (R)-(2-(benzofuran-3-yl)-1-(4-(2-dimethylsulfinimidopyridine)acetamido)ethylboronic acid
  • Step B 2-(5-Dimethylsulfinimido-pyridin-2-yl)acetic acid
  • Step C (R)-(2-(benzofuran-3-yl)-1-(2-(5-(dimethylsulfinimido)pyridin-2-yl)acetamido)ethyl Yl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step D (R)-(2-(benzofuran-3-yl)-1-(2-(5-(dimethylsulfinimido)pyridin-2-yl)acetamido)ethyl Base) boric acid
  • Step C (R)-2-(benzofuran-3-yl)-1-(3-(dimethylsulfinimidophenyl)propionamido)ethylboronic acid-(1S,2S, 3R,5S)-(+)-Pinane-2,3-diol ester
  • Step D (R)-(2-(benzofuran-3-yl)-1-(3-(dimethylsulfinimidophenyl)propionamido)ethylboronic acid
  • Step B 4-(Dimethylsulfinimidophenyl)propionic acid
  • Step C (R)-2-(benzofuran-3-yl)-1-(4-(dimethylsulfinimidophenyl)propionamido)ethylboronic acid-(1S,2S, 3R,5S)-(+)-Pinane-2,3-diol ester
  • Step D (R)-(2-(benzofuran-3-yl)-1-(4-(dimethylsulfinimidophenyl)propionamido)ethylboronic acid
  • Step E Imino(methyl)(2-((((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)- ⁇ 6 -sulfone
  • Step F Methyl(methylimino)(2-((((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)- ⁇ 6 -sulfone
  • Methyl(methylimino)(2-((((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)- ⁇ 6 -sulfone 180mg was dissolved in methanol (10mL ), add p-toluenesulfonic acid (12mg), heat to 45°C and stir overnight. Add water and extract with dichloromethane, the extract is concentrated under reduced pressure, and the residue is purified on a silica gel preparation plate (1:30 methanol/dichloromethane) Get the product (100mg).
  • Step H 2-(benzofuran-3-yl)-1-(R)-(3-acetylbenzenesulfonamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-pine Alkyl-2,3-diol ester
  • Step I (R)-(2-(benzofuran-3-yl)-1-((((2-(N,S-dimethylsulfonimido)benzyl)oxy)carbonyl) Amino) ethylboronic acid
  • the 2-(benzofuran-3-yl)-1-(R)-(3-acetylbenzenesulfonamido)ethylboronic acid-(1S,2S,3R,5S)-(+)-Pinane- 2,3-diol ester (90 mg) was dissolved in a mixed solvent of methanol (5 mL) and n-hexane (5 mL), isobutylboronic acid (98 mg), 1 mol/L dilute hydrochloric acid (0.2 mL) were added, and the mixture was stirred at room temperature overnight. The methanol phase was separated and washed with n-hexane. The methanol phase was collected and concentrated under reduced pressure. The residue was purified on a silica gel preparation plate (1:10 methanol/dichloromethane) to obtain the product (29 mg).
  • reaction was quenched by adding water, then 1mol/L sodium hydroxide aqueous solution (100mL) was added, extracted with ethyl acetate, the organic phase was washed with 1mol/L hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure A colorless oily product (1.50 g) was obtained, which was directly used in the next reaction.
  • Step C Imino(3-((((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)- ⁇ 6 -methyl sulfone
  • Step D Imino(3-hydroxymethylphenyl)- ⁇ 6 -methyl sulfone
  • Step E (R)-2-(benzofuran-3-yl)-1-N-(3-(S-methylsulfonylimino)phenylmethoxyoxo)aminoethylboronic acid-( 1S,2S,3R,5S)-(+)-pinane-2,3-diol ester
  • the 2-(benzofuran-3-yl)-1-(R)-aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester salt The acid salt (300mg) was dissolved in dichloromethane (5mL), cooled to -78°C, triphosgene (100mg) was added to the reaction solution, and stirred at this temperature for 30 minutes, and then imino (3-hydroxymethyl A solution of phenyl)- ⁇ 6 -methyl sulfone (200 mg) in dichloromethane (2 mL). Warm to room temperature and stir overnight.
  • the reaction was quenched by adding water, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified with a silica gel preparation plate (1:20 methanol/dichloromethane) to obtain the product (208 mg).
  • Step F (R)-2-(benzofuran-3-yl)-1-N-(3-(S-methylsulfonylimino)phenylmethoxyoxo)aminoethylboronic acid
  • Step A 4-(2-Methoxy-(dimethylsulfinimidophenyl))acetonitrile
  • 4-bromo-2-methoxybenzeneacetonitrile (620mg) was dissolved in 1,4-dioxane (50mL), and dimethylsulfinimide (308mg), tris( Dibenzylideneacetone)dipalladium (125mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (238mg) and cesium carbonate (1.7g), heated to 110°C and stirred overnight.
  • Step B 4-(2-Methoxy-(dimethylsulfinimidophenyl))acetic acid
  • Step C (R)-2-(benzofuran-3-yl)-1-(4-(2-methoxy-(dimethylsulfinimidophenyl))acetamido)ethyl Boric acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step D (R)-(2-(benzofuran-3-yl)-1-(4-(2-methoxy-(dimethylsulfinimidophenyl))acetamido) Ethyl boric acid
  • Step B 4-(3-Chloro-(dimethylsulfinimidophenyl))propionic acid
  • Step C (R)-2-(benzofuran-3-yl)-1-(4-(3-chloro-(dimethylsulfinimidophenyl))propionamido)ethylboronic acid -(1S,2S,3R,5S)-(+)-Pinane-2,3-diol ester
  • Step D (R)-(2-(benzofuran-3-yl)-1-(4-(3-chloro-(dimethylsulfinimidophenyl))propionamido)ethyl Boric acid
  • Methyl 3-(methylthio)benzoate (1.82g) was dissolved in anhydrous tetrahydrofuran (50mL) and cooled to 0°C under nitrogen protection. A toluene solution (30 mL) of 1 mol/L diisopropylaluminum hydride was added dropwise into the system. After returning to room temperature and stirring for 3 hours, ethyl acetate (150 mL) and 1 mol/L sodium hydroxide aqueous solution (70 mL) were slowly added to the system. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to evaporate the solvent to obtain the target product (1.51 g).
  • Step C (3-(chloromethyl)phenyl)methyl sulfide
  • Step F 2-(3-(N,S-Dimethylsulfonimido)phenyl)acetic acid
  • Step G (1R)-2-(benzofuran-3-yl)-1-(2-(3-(N,S-dimethylsulfinimido)phenyl)acetamido)ethyl Boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step H (1R)-2-(benzofuran-3-yl)-1-(2-(3-(N,S-dimethylsulfinimido)phenyl)acetamido)ethyl Boronic acid
  • Step C (4-Dimethylsulfinimido-3-chlorophenyl)methyl acrylate
  • Step D (4-Dimethylsulfinimido-3-chlorophenyl) methyl propionate
  • Step F (R)-2-(benzofuran-3-yl)-1-(3-(4-dimethylsulfinimido-3-chlorophenyl)propylamino)ethylboronic acid- (1S,2S,3R,5S)-(+)-pinane-2,3-diol ester
  • Step G (R)-2-(benzofuran-3-yl)-1-(3-(4-dimethylsulfinimido-3-chlorophenyl)propylamino)ethylboronic acid
  • Step B Methyl 2-(4-(S-methylsulfonimido)phenyl)acetate
  • Step C 2-(4-(N,S-Dimethylsulfonimido)phenyl)acetic acid
  • Step D (R)-2-(benzofuran-3-yl)-1-(2-(4-(N,S-dimethylsulfonimido)phenyl)acetamido)ethyl Boric acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • step D in Example 10 2-(4-(N,S-dimethylsulfonimido)phenyl)acetic acid (228mg) and 2-(benzofuran-3-yl)-1 -(R)-Aminoethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester hydrochloride (376mg) was used as a raw material to obtain a product (100mg).
  • Step E (R)-2-(benzofuran-3-yl)-1-(2-(4-(N,S-dimethylsulfonimido)phenyl)acetamido)ethyl Boric acid
  • Methyl 3-(S-methylsulfonimido)benzoate 500 mg
  • paraformaldehyde 210 mg
  • the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (10% methanol/dichloromethane mixture) to obtain the product (0.31 g).
  • Step C (3-(hydroxymethyl)phenyl)(methyl)(methylimino)- ⁇ 6 -sulfone
  • Methyl 3-(N,S-dimethylsulfonimido)benzoate (300mg) was dissolved in anhydrous tetrahydrofuran (10mL) and cooled to 0°C under nitrogen protection.
  • a toluene solution (4.0 mL) of 1 mol/L diisopropyl aluminum hydride was added dropwise into the system. After returning to room temperature, it was stirred until the reaction was complete, and ethyl acetate (50 mL) and 1 mol/L sodium hydroxide aqueous solution (30 mL) were slowly added to the system.
  • the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to evaporate the solvent to obtain the target product (105 mg).
  • Step D ((1R)-2-(benzofuran-3-yl)-1-((((3-(N,S-dimethylsulfonimido)benzyl)oxy)carbonyl) Amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step E ((1R)-2-(benzofuran-3-yl)-1-((((3-(N,S-dimethylsulfonimido)benzyl)oxy)carbonyl) (Amino) ethyl) boric acid
  • Step E 2-(4-((Dimethyl(oxo)- ⁇ 6 -sulfinylimino)amino)-3-(dimethylamino)phenyl)acetonitrile
  • Step F 2-(4-((Dimethyl(oxo)- ⁇ 6 -sulfimido)amino)-3-(dimethylamino)phenyl)acetic acid
  • Step G (R)-(2-(benzofuran-3-yl)-1-(2-(4-((dimethyl(oxy)- ⁇ 6 -sulfaamino)amino)-3-( Dimethylamino)phenyl)acetamido)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step H (R)-(2-(benzofuran-3-yl)-1-(2-(4-((dimethyl(oxy)- ⁇ 6 -sulfaamino)amino)-3-( Dimethylamino)phenyl)acetamido)ethyl)boronic acid
  • Step D Ethyl 3-(2-(dimethylsulfonimido)phenyl)propionate
  • Step E 3-(2-(Dimethylsulfonimido)phenyl)propionic acid
  • Step F (R)-2-(benzofuran-3-yl)-1-(3-(2-(dimethylsulfinimido)phenyl)propionamido)ethylboronic acid-( 1S,2S,3R,5S)-(+)-pinane-2,3-diol ester
  • the reaction was quenched by adding water (100 mL).
  • the aqueous phase was extracted three times with dichloromethane, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure.
  • the residue was purified on a silica gel preparation plate (21:1 dichloromethane/methanol) to obtain the product (179 mg).
  • Step G (R)-2-(benzofuran-3-yl)-1-(3-(2-(dimethylsulfinimido)phenyl)propionamido)ethylboronic acid
  • 6-(Methylthio)picolinic acid (750mg) was dissolved in anhydrous tetrahydrofuran (20mL) and cooled to 0°C under nitrogen protection.
  • a toluene solution (14 mL) of 1 mol/L diisopropyl aluminum hydride was added dropwise into the system. After returning to room temperature, it was stirred until the reaction was complete, and ethyl acetate (100 mL) and 1 mol/L sodium hydroxide aqueous solution (50 mL) were slowly added to the system.
  • the organic phase was separated, dried with anhydrous sodium sulfate, and the solvent was evaporated to obtain the target product (320 mg).
  • Step C (6-(Hydroxymethyl)pyridin-2-yl)(imino)(methyl)- ⁇ 6 -sulfone
  • Step D ((1R)-2-(benzofuran-3-yl)-1-((((6-(S-methylsulfonimido)pyridin-2-yl)methoxy)carbonyl )Amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step E ((1R)-2-(benzofuran-3-yl)-1-((((6-(S-methylsulfonimido)pyridin-2-yl)methoxy)carbonyl )Amino)ethyl)boronic acid
  • Step B (R)-2-(benzofuran-3-yl)-1-((((2-(S-methylsulfonimido)benzyl)oxy)carbonyl)amino)ethyl Boric acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step C (R)-2-(benzofuran-3-yl)-1-((((2-(S-methylsulfonimido)benzyl)oxy)carbonyl)amino)ethyl Boric acid
  • the methanol phase was separated by liquid separation, and washed with n-hexane (20 mL) three times and concentrated to dryness under reduced pressure. The residue was purified on a silica gel preparation plate (1:10 methanol/dichloromethane) to obtain the product (3 mg).
  • Step A (6-(Hydroxymethyl)pyridin-2-yl)(methylimino)(methyl)- ⁇ 6 -sulfone
  • Step B ((1R)-2-(benzofuran-3-yl)-1-((((6-(N,S-methylsulfonimido)pyridin-2-yl)methoxy )Carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step C ((1R)-2-(benzofuran-3-yl)-1-((((6-(N,S-dimethylsulfonimido)pyridin-2-yl)methoxy (Yl)carbonyl)amino)ethyl)boronic acid
  • Step A 5-chloro-2-(methylthio)-benzoic acid methyl ester
  • Step C (4-Chloro-2-(hydroxymethyl)phenyl)(imino)(methyl)- ⁇ 6 -sulfone
  • Step D (4-Chloro-2-(hydroxymethyl)phenyl)(methylimino)(ethyl)- ⁇ 6 -sulfone
  • Step E ((1R)-2-(benzofuran-3-yl)-1-((((5-chloro-2-(N-methyl-ethylsulfonimido)benzyl)oxy (Yl)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step F ((1R)-2-(benzofuran-3-yl)-1-((((5-chloro-2-(N-methyl-ethylsulfonimido)benzyl)oxy (Yl)carbonyl)amino)ethyl)boronic acid
  • Butylboric acid (89mg), 1mol/L hydrochloric acid (0.3mL) and n-hexane (5mL) were stirred overnight at room temperature, separated to remove the upper n-hexane, and the methanol phase was washed with n-hexane and concentrated at 30°C to give the product (41mg ).
  • Step D (4-Cyclopropyl-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)(imino)(methyl)- ⁇ 6 -sulfone
  • Step E (4-Cyclopropyl-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)(methylimino)(methyl)- ⁇ 6- Sulfone
  • Step F (4-Cyclopropyl-2-(hydroxymethyl)phenyl)(methylimino)(methyl)- ⁇ 6 -sulfone
  • Step G ((1R)-2-(benzofuran-3-yl)-1-((((5-cyclopropyl-2-(N,S-dimethylsulfonimido)benzyl )Oxy)carbonyl)amino)ethyl)boronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester
  • Step H ((1R)-2-(benzofuran-3-yl)-1-((((5-cyclopropyl-2-(N,S-dimethylsulfonimido)benzyl )Oxy)carbonyl)amino)ethyl)boronic acid
  • LMP7 is the catalytic subunit of the immune proteasome. This experiment uses its hydrolase activity to establish an enzymatic detection method platform and uses it for the activity detection of compounds. Using Ac-ANW-AMC (BonstonBiochem, Cat#S-320) as the substrate of LMP7, the fluorescent group AMC (7-Amino-4-methylcoumarin, 7-amino-4-methylcoumarin) released after hydrolysis The amount can reflect the enzymatic activity.
  • MOLT-4 cells are human acute lymphoblastic leukemia cells and have been identified as cells with high expression of LMP7. We used MOLT-4 cell lysate as the enzyme source for LMP7 to establish an enzymatic detection method for compounds on LMP7 and tested the compound's inhibitory activity (half inhibitory concentration, IC 50 ).
  • MOLT-4 cells were cultured in RPMI-1640 (Biological Industries) medium containing 10% fetal bovine serum (Biological Industries) and 1% Pen Strep (Gibco) in a 75cm 2 cell culture flask (Corning) (37°C, 95°C). % Air and 5% CO 2 ), passage 2-3 times a week. Collect 1 ⁇ 10 7 MOLT-4 cells, resuspend them in 1 ml PBS (Solarbio), centrifuge at 3000 rpm for 5 minutes. Aspirate the supernatant.
  • the compound was diluted 5-fold with 100% DMSO, a total of 9 concentrations, 2 ⁇ l of each concentration was added to 48 ⁇ l of reaction buffer (20mM Tris, pH 8.0, 0.5mM EDTA) and mixed, as 4* compound (final The concentration is 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256, 0nM) for use.
  • reaction buffer to prepare 4*MOLT-4 cell lysate with a final concentration of 20ng/ ⁇ l and 2*Ac-ANW-AMC with a final concentration of 100 ⁇ M.
  • ⁇ 5 is the catalytic subunit of the proteasome. This experiment uses its hydrolase activity to establish an enzymatic detection method platform and uses it for the activity detection of compounds. Using Ac-WLA-AMC (BonstonBiochem, Cat#S-330) as the substrate of ⁇ 5, the fluorescent group AMC (7-Amino-4-methylcoumarin, 7-amino-4-methylcoumarin) released after hydrolysis The amount can reflect the enzymatic activity.
  • HEK-293 is a human embryonic kidney cell that expresses proteasome constitutively, but does not express immune proteasome.
  • HEK-293 cell lysate as the enzyme source of ⁇ 5 to establish an enzymatic detection method of compounds against ⁇ 5 and tested the compound's inhibitory activity (half inhibitory concentration, IC 50 ).
  • the enzymatic inhibitory activity of the compound on ⁇ 5 is used as an indicator of compound selectivity.
  • HEK-293 cells were cultured with DMEM (Biological Industries) medium containing 10% fetal bovine serum (Biological Industries) and 1% Pen Strep (Gibco) in a 75cm 2 cell culture flask (Corning) (37°C, 95% air And 5% CO 2 ), passage 2-3 times a week. Collect 1 ⁇ 10 7 HEK-293 cells, resuspend them in 1 ml PBS (Solarbio), centrifuge at 3000 rpm for 5 minutes. Aspirate the supernatant.
  • DMEM Biological Industries
  • Pen Strep Gibco
  • the compound was diluted 5-fold with 100% DMSO, a total of 9 concentrations, 2 ⁇ l of each concentration was added to 48 ⁇ l of reaction buffer (20mM Tris, pH 8.0, 0.5mM EDTA) and mixed, as 4* compound (final The concentration is 100000, 20000, 4000, 800, 160, 32, 6.4, 1.28, 0nM) for use.
  • reaction buffer to prepare 4*HEK-293 cell lysate with a final concentration of 25ng/ ⁇ l and 2*Ac-WLA-AMC with a final concentration of 20 ⁇ M.

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Abstract

公开了式(I)化合物或其药学上可接受的盐、溶剂化物、多晶型物或异构体、包含这些化合物的药物组合物，以及此类化合物在治疗跟LMP7相关的疾病中的用途。

Description

硼酸衍生物
相关申请的交叉引用
本申请要求2020年1月19日提交、申请号为202010058216.9的中国专利申请的优先权，其所公开的内容作为参考全文并入本申请。
技术领域
本专利涉及如式(I)所示的一类新型硼酸衍生物或其药学上可接受的盐。本文还提供了含有此类化合物的药物组合物及其制备方法。本专利所描述化合物可用于治疗或者预防与免疫蛋白酶体相关的疾病的治疗。
背景技术
泛素-蛋白酶体系统(UPS)存在于所有的真核细胞中，负责细胞内错误折叠或者冗余蛋白的降解。通过调节蛋白水平稳态，调控几乎所有重要的生命活动，比如信号转导、转录调控、细胞分化和凋亡等。26S蛋白酶体(蛋白酶体密度梯度离心的沉降系数为26S，故又称其为26S蛋白酶体)在结构上可分为19S调节颗粒和20S核心颗粒两部分，19S调节颗粒负责识别带有泛素标记的蛋白及对其进行去折叠，并最终将去折叠的蛋白传送至20S核心颗粒中进行降解。20S蛋白酶体有一个桶状结构，由4个环组成。外部的两个环，每个环都含有七个α亚基，一方面作为调节颗粒的结合部，另一方面发挥“门”的作用，阻止蛋白质不受调控地进入核心颗粒的内部。内部的两个环，每个环都含有七个β亚基，包含蛋白酶活性亚基β1c、β2c和β5c，用于蛋白质水解反应。在造血细胞和被干扰素(IFN)-γ或肿瘤坏死因子(TNF)-α刺激的细胞中，这些活性亚基会被β1i(LMP2，低分子量的多肽2)、β2i(MECL-1，多催化内肽酶复合物类似物-1)和β5i(LMP7)取代，形成免疫蛋白酶体【Michael Basler等人，EMBO reports,2018】。LMP7由PSMB8基因编码，共276个氨基酸，是一个约30kDa的小分子蛋白。LMP7是免疫蛋白酶体的核心催化亚基，具有胰凝乳蛋白酶活性，在免疫蛋白酶体水解蛋白的过程中发挥重要作用【A.Arkhjami等人，Immune and non-immune functions of the immunoproteasome，Frontiers in Bioscience,17(1):1904,2012】。
免疫蛋白酶体在免疫过程中的功能已经研究得很透彻，尤其是它的抗原呈递功能。免疫蛋白酶体的催化亚基水解产生多肽，由组织相容性复合物(MHC)-1呈递到细胞表面，引起细胞毒性T淋巴细胞反应(CTLs)。与蛋白酶体相比，免疫蛋白酶体能更加高效地水解蛋白和呈递抗原，产生的抗原能够引起更加强烈的CTLs。一些研究证明免疫蛋白酶体可以调控细胞因子的产生。用小分子抑制剂选择性地抑制LMP7，单核细胞中的IL-23以及T细胞中TNF-α和IL-6都会被抑制，在风湿性关节炎的动物模型中也观察到类似的现象【T.Muchamuel等人，A selective inhibitor of the immunoproteasome subunit LMP7blocks cytokine production and attenuates progression of experimental arthritis，Nat Med,15(7),781-7,2009】。另外，免疫蛋白酶体在T细胞分化，增殖和凋亡中的功能也在一些研究 中得到验证【C.M.Caudill等人，T cells lacking immunoproteasome subunits MECL-1and LMP7hyperproliferate in response to polyclonal mitogens，J.Immunol,176(7),4075-82,2006】。除了免疫功能，免疫蛋白酶体在细胞因子引起的氧化应激反应中发挥维持蛋白稳态的作用。氧化应激反应会释放自由基，导致大量受损的蛋白累积，超出普通蛋白酶体的清除能力，最终导致细胞死亡。免疫蛋白酶体可以高效地清除蛋白累积，维持细胞内稳态。在LMP7/β5i-和LMP2/β1i-缺陷的小鼠中，观察到氧化的和多泛素化的蛋白在肝脏和脑中累积【U.Seifert等人，Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress，Cell,142(4),613-24,2010】。
免疫蛋白酶体与多种疾病相关。研究表明免疫蛋白酶体在血癌中高表达，选择性的抑制β1i和LMP7可以有效地抑制病人来源的细胞和肿瘤模型的生长【U.Seifert等人，Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress，Cell,142(4),613-24,2010】。对668名乳腺癌患者进行研究，40％的患者肿瘤中LMP7高表达【M.Lee等人，Expression of Immunoproteasome Subunit LMP7in Breast Cancer and Its Association with Immune-Related Markers，Cancer Research and Treatment,51(1),2018】。免疫蛋白酶体促进结直肠的发生和发展，LMP7的抑制剂可以有效地抑制小鼠模型结直肠癌的形成【J.Koerner等人，Inhibition and deficiency of the immunoproteasome subunit LMP7suppress the development and progression of colorectal carcinoma in mice，Oncotarget,8(31):50873-50888,2017】。近期有新的证据证明免疫蛋白酶体与自身免疫疾病相关，有望成为治疗此类疾病的一个热门靶点。免疫蛋白酶体在自身免疫疾病中高表达，比如类风湿性关节炎和炎症性肠类疾病【T.Egerer等人，Tissue-specific up-regulation of theproteasome subunitβ5i(LMP7)in Sjogren's syndrome,Arthritis Rheum,54(5),1501-8,2006】。在两种关节炎小鼠模型中，LMP7的选择性抑制剂会降低炎性浸润程度和细胞因子水平，缓解关节炎的症状【J.Koerner等人，Inhibition and deficiency of the immunoproteasome subunit LMP7suppress the development and progression of colorectal carcinoma in mice，Oncotarget,8(31):50873-50888,2017】。有文章报道免疫蛋白酶体与神经退行性疾病相关，在阿尔兹海默症患者的大脑中免疫蛋白酶体高表达【M.DíazHernández等人，Neuronal Induction of the Immunoproteasome in Huntington's Disease，Journal of Neuroscience,23(37):11653-11661,2003】。
以免疫蛋白酶体的催化亚基LMP7作为靶点治疗多种疾病，是一个创新领域，具有广阔的发展空间。与广谱的蛋白酶体抑制剂相比，LMP7选择性抑制剂在安全性上有绝对的优势。WO2019099582A1和WO2019038250A1等专利公开了一些LMP7抑制剂和使用它们治疗相关疾病的方法。
本专利描述了一类硼酸衍生物，它们对LMP7有着很好的抑制活性，同时对其他蛋白酶体有着很好的选择性。并且，此类化合物有着优异的口服生物利用度，血浆蛋白吸附，药代动力学特征，CYP-抑制和稳定性。
发明概述
在一个方面，本发明提供了式I化合物、或其药学上可接受的盐、溶剂化物、多晶型物或异构体，
Figure PCTCN2021072666-appb-000001
其中，
R a和R b各自独立地选自H和C 1-6烷基，或者R a和R b可以连到一起形成一个3-10元杂环；
X为键、-O-、或者-NR 4-；
Y为键或者-(CR 4R 5) m-；
R 4和R 5各自独立地选自H、C 1-6烷基和C 3-8环烷基；
m为1、2、或者3；
R 2选自H和C 1-6烷基；
R 3选自C 6-10芳基和C 5-10杂芳基，所述芳基和杂芳基可任选地被卤素、-OH、-NH 2、-O-C 1-6烷基、-N(C 1-6烷基)(C 1-6烷基)、-CN、NO 2、C 1-6烷基、C 3-8环烷基、或者C 3-8杂环烷基取代；
R 1选自C 1-6烷基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基和C 5-10杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基被
Figure PCTCN2021072666-appb-000002
中的一个取代，并且可任选地被卤素、-OH、-NH 2、-(CH 2) 1-3-C 3-8环烷基、-(CH 2) 0-6-CF 3、-O-C 1-6烷基、-NR 9R 8、-CN、NO 2、C 1-6烷基、-(CH 2) 0-3-(CO)-R 8、-(CH 2) 0-3-(CO)-NH-R 8、-(CH 2) 0-3-NH-(CO)-R 8、或者R 10取代；
R 6a和R 6b各自独立地选自C 1-6烷基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基和C 5-10杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基可任选地被卤素、C 1-6烷基、C 3-8环烷基、-OH、-NH 2、-O-C 1-6烷基、-NR 9R 8、-NO 2、或者-CN取代，或者
R 6a和R 6b可以连在一起形成一个3-8元杂环；
R 7选自H、C 1-6烷基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基和C 5-10杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基可任选地被卤素、C 1-6烷基、C 3-8环烷基、-OH、-NH 2、-O-C 1-6烷基、-NR 9R 8、-NO 2、或者-CN取代；
R 8选自C 1-6烷基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基和C 5-10杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基可任选地被卤素、C 1-6烷基、-O-C 1-6烷基、C 6-10芳基、或者C 5-10杂芳基取代；
R 9选自H和C 1-6烷基；
R 10选自C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基和C 5-10杂芳基，所述环烷基、杂环烷基、芳基和杂芳基可任选地被卤素、-OH、-NH 2、-O-C 1-6烷基、-N(C 1-6烷基)(C 1-6烷基)、-CN、NO 2、或者C 1-6烷基取代；
在一些实施方式中，R a和R b为H；
在一些实施方式中，X为键、-O-、或者-NR 4-，R 4为H；
在一些实施方式中，Y为键或者-(CR 4R 5) m-，R 4和R 5各自独立地选自H和C 1-6烷基，m为1、2、或者3；
在一些实施方式中，Y为键或者-(CR 4R 5) m-，R 4和R 5为H，m为1、2、或者3；
在一些实施方式中，Y为键或者-(CR 4R 5) m-，R 4和R 5各自独立地选自H和C 1-6烷基，m为1或2；
在一些实施方式中，Y为键或者-(CR 4R 5) m-，R 4和R 5为H，m为1或2；
在一些实施方式中，Y为键或者-(CR 4R 5) m-，R 4和R 5各自独立地选自H和C 1-6烷基，m为1；
在一些实施方式中，Y为键或者-(CR 4R 5) m-，R 4和R 5为H，m为1；
在一些实施方式中，R 2为H；
在一些实施方式中，R 3选自C 5-10杂芳基，所述杂芳基可任选地被卤素、NO 2、C 1-6烷基、C 3-8环烷基、或者C 3-8杂环烷基取代；
在一些实施方式中，R 3为
Figure PCTCN2021072666-appb-000003
所述
Figure PCTCN2021072666-appb-000004
可任选地被卤素、NO 2、C 1-6烷基、C 3-8环烷基、或者C 3-8杂环烷基取代；
在一些实施方式中，R 1选自C 3-8环烷基、C 6-10芳基和C 5-10杂芳基，所述环烷基、芳基和杂芳基被
Figure PCTCN2021072666-appb-000005
中的一个取代，并且可任选地被卤素、-CF 3、-O-C 1-6烷基、NO 2、C 1-6烷基、-(CO)-R 8、-(CO)-NH-R 8、或者R 10取代；
R 6a和R 6b各自独立地选自C 1-6烷基和C 3-8环烷基，或者R 6a和R 6b可以连在一起形成一个3-8元杂环；
R 7选自H、C 1-6烷基和C 3-8环烷基；
R 8选自C 1-6烷基和C 3-8环烷基，所述环烷基可任选地被C 1-6烷基取代；
R 10选自C 3-8环烷基和C 3-8杂环烷基，所述环烷基和杂环烷基可任选地被C 1-6烷基取代；
在一些实施方式中，本发明提供以下化合物或其药学上可接受的盐、溶剂化物、多晶型物或异构体：
Figure PCTCN2021072666-appb-000006
在一些实施方式中，本发明提供以下化合物或其药学上可接受的盐、溶剂化物、多晶型物或异构体：
Figure PCTCN2021072666-appb-000007
本发明的式(I)化合物可以用于治疗跟lmp7相关的疾病；在一些实施方式中，所述跟lmp7活性相关的疾病为恶性血液病、固体肿瘤或免疫调节异常，更 优选为多发性骨髓瘤、急性骨髓性白血病、髓细胞白血病、套細胞淋巴瘤、慢性淋巴细胞白血病、急性淋巴细胞白血病、弥漫大B细胞淋巴瘤、浆细胞瘤、滤泡性淋巴瘤、免疫细胞瘤、乳腺癌、肝癌、结直肠癌、卵巢癌、食道癌、肺癌、头颈癌、胰腺癌、肾癌、胃癌、甲状腺癌、前列腺癌、膀胱癌、类风湿性关节炎、系统性红斑狼疮、炎性肠病、多发性硬化、硬皮病、关节黏连性脊椎炎、动脉粥样硬化、白塞病、克罗恩病、炎性肠病、溃疡性结肠炎、自身免疫性肝炎、干燥综合症、狼疮肾炎、哮喘、肌萎缩性侧索硬化(ALS)、牛皮癣、A型免疫球蛋白肾病、过敏性紫癜、阿兹海默氏症(AD)；
本发明另一方面还涉及药物组合物，其包含本发明化合物或其药学上可接受的盐、溶剂化物、多晶型物或异构体，以及药学上可接受的载体；
在另一方面，本发明提供了治疗跟lmp7活性相关的疾病的方法，所述方法包含给对象施用有效量的本发明化合物或其药学上可接受的盐、溶剂化物、多晶型物或异构体、或者上述组合物；在一些实施方式中，所述跟lmp7活性相关的疾病为多发性骨髓瘤、急性骨髓性白血病、髓细胞白血病、套細胞淋巴瘤、慢性淋巴细胞白血病、急性淋巴细胞白血病、弥漫大B细胞淋巴瘤、浆细胞瘤、滤泡性淋巴瘤、免疫细胞瘤、乳腺癌、肝癌、结直肠癌、卵巢癌、食道癌、肺癌、头颈癌、胰腺癌、肾癌、胃癌、甲状腺癌、前列腺癌、膀胱癌、类风湿性关节炎、系统性红斑狼疮、炎性肠病、多发性硬化、硬皮病、关节黏连性脊椎炎、动脉粥样硬化、白塞病、克罗恩病、炎性肠病、溃疡性结肠炎、自身免疫性肝炎、干燥综合症、狼疮肾炎、哮喘、肌萎缩性侧索硬化(ALS)、牛皮癣、A型免疫球蛋白肾病、过敏性紫癜、阿兹海默氏症(AD)；
在本发明的一些实施方式中，本发明涉及的所述对象为包括人类的哺乳动物；
在另一方面，本发明提供了本发明化合物或其药学上可接受的盐、溶剂化物、多晶型物或异构体在制备用来治疗跟lmp7活性相关的疾病的药物中的用途；在一些实施方式中，所述跟lmp7活性相关的疾病为多发性骨髓瘤、急性骨髓性白血病、髓细胞白血病、套細胞淋巴瘤、慢性淋巴细胞白血病、急性淋巴细胞白血病、弥漫大B细胞淋巴瘤、浆细胞瘤、滤泡性淋巴瘤、免疫细胞瘤、乳腺癌、肝癌、结直肠癌、卵巢癌、食道癌、肺癌、头颈癌、胰腺癌、肾癌、胃癌、甲状腺癌、前列腺癌、膀胱癌、类风湿性关节炎、系统性红斑狼疮、炎性肠病、多发性硬化、硬皮病、关节黏连性脊椎炎、动脉粥样硬化、白塞病、克罗恩病、炎性肠病、溃疡性结肠炎、自身免疫性肝炎、干燥综合症、狼疮肾炎、哮喘、肌萎缩性侧索硬化(ALS)、牛皮癣、A型免疫球蛋白肾病、过敏性紫癜、阿兹海默氏症(AD)。
发明详述
在下文的发明详述中陈述了利用本发明原理的示例性实施方式。通过参考以下发明内容可更好地理解本发明的特征和优点。
应理解本发明各个方面的保护范围由权利要求书决定，并且这些权利要求范围内的方法和结构以及其等价的方法和结构均在本权利要求书涵盖的范围之内。
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解，上述简述和下文的详述都是示例性的、解释性的，而不是对任何本发明主题的限制。除非另有具体说明，否则使用单数形式时也包括复数。除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
某些化学术语
术语“任选”、“任选的”或“任选地”是指随后描述的事件或情况可能发生也可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，“任选取代的烷基”表示“未取代的烷基”或“取代的烷基”。并且，任选取代的基团可以是未取代的(例如：-CH 2CH 3)、完全取代的(例如：-CF 2CF 3)、单取代的(例如：-CH 2CH 2F)或者介于单取代和完全取代之间的任意层级(例如：-CH 2CHF 2、-CF 2CH 3、-CFHCHF 2等)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、核磁、高效液相色谱、红外和紫外/可见光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和医药化学的有关术语以及实验步骤和技术是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送、以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。
本文所用术语“基团”、“化学基团”是指分子的一个特定的部分或官能团。化学基团经常被认作为嵌入或附加到一个分子中的化学实体。
一些在此命名的化学基团可以用简略记号表示碳原子的总个数。例如，C 1-C 6烷基描述了一个烷基基团，如下定义的那样，具有总共1到6个碳原子。简略记号所示碳原子总个数不包括可能的取代基上的碳原子。
术语“卤素”、“卤代”或“卤化物”是指溴、氯、氟或碘。
本文使用的术语“芳香”、“芳香环”、“芳香的”、“芳香性的”、“芳香环的”是指平面的一个环或多个环的环部分，其具有含4n+2个电子的离域化电子共扼体系，其中n为整数。芳环可由5、6、7、8、9或9个以上的原子形成。芳族化合物可被任选地取代，并可为单环或稠合环的多环。术语芳族化合物包括所有碳环(如苯环)和含一个或多个杂原子的环(如吡啶)。
本文单独或作为其它成分的一部分使用的术语“杂原子”或“杂”是指除碳和氢之外的原子。杂原子独立地选自氧、氮、硫、磷、硅、硒和锡，但不限于这些原子。在出现两个或更多杂原子的实施方案中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的一些或全部彼此不同。
本文单独或组合使用的术语“稠”或“稠环”是指两个或更多个环共享一个或更多个键的环状结构。
本文单独或组合使用的术语“螺”或“螺环”是指两个或更多个环共享一个或更多个原子的环状结构。
本文单独或作为其它组分的一部分(比如：单烷基氨基)使用的术语“烷基”是指任选取代的直链或任选取代的支链的一价饱和烃，其具有1-12个碳原子，优选1-8个碳原子，更优选1-6个碳原子，通过单键与分子的其它部分相连，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基、正庚基、2-甲基己基、3甲基己基、正辛基，正壬基、正癸基等。
本文单独或组合使用的术语“烯基”是指任选取代的直链或任选取代的支链的一价烃基，其具有一个或多个C＝C双键并具有2-约10个碳原子，更优选2-约6个碳原子。这些基团中的双键可以为顺式或反式构象，并应被理解为包含所述两种异构体。实例包括但不限于乙烯基(CH＝CH 2)、1-丙烯基(CH 2CH＝CH 2)、异丙烯基(C(CH3)＝CH 2)、丁烯基和1,3-丁二烯基等。
本文单独或作为其它成分的一部分使用的术语“环烷基”是指稳定的单价非芳香单环或多环碳氢基团，只包含碳原子和氢原子，可能包括稠环、螺环或桥环系统，包含3-15个成环碳原子，优选包含3-10个成环碳原子，更优选包含3-8个成环碳原子，可饱和也可不饱和，通过单键与分子的其它部分相连。“环烷基”的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基和环庚基等。
本文单独或作为其它成分的一部分使用的术语“杂环基”、“杂环烷基”、“杂环”是指稳定的3-18元单价非芳香环，包括2-12个碳原子，1-6个选自氮、氧和硫的杂原子。除非另作说明，杂环基基团可以是单环、双环、三环或四环系统，其可能包含稠环、螺环或桥环系统，杂环基上的氮、碳或硫可选择性的被氧化，氮原子可选择性的被季铵化，杂环基可以部分或完全饱和。杂环基可以通过环上的碳原子或杂原子与分子的其余部分通过一个单键连接。包含稠环的杂环基中可以包含一个或多个芳环或杂芳环，只要与分子的其余部分连接的是非芳香环上的原子。为了本申请，杂环基优选的是一个稳定的4-11元单价非芳香单环或二环，其包含1-3个选自氮、氧和硫的杂原子，更优选的是一个稳定的4-8元单价非芳香单环，其包含1-3个选自氮、氧和硫的杂原子。杂环基的的非限制性实例包括氮杂环庚烷基、氮杂环丁基、十氢异喹啉基、二氢呋喃基、二氢吲哚基、二氧戊烷基、1,1-二氧-硫代吗啉基、咪唑烷基、咪唑啉基、异噻唑烷基、异恶唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、恶嗪基、哌嗪基、哌啶基、4-哌啶酮基、吡喃基、吡唑烷基、吡咯烷基、喹嗪基、奎宁环基、四氢呋喃基、四氢吡喃基等。
术语“芳基”是指具有完全共轭的π电子体系的全碳单环或稠合环，其具有6-14个碳原子，优选具有6-12个碳原子，最优选具有6个碳原子。芳基可以是非取代的或被一个或多个取代基所取代，所述取代基的实例包括但不限于烷基、烷基氧基、芳基、芳烷基、氨基、卤素、羟基、磺酰基、亚磺酰基、磷酰基和杂脂环基。非取代的芳基的非限制性实例包括但不限于苯基、萘基和蒽基。
术语“杂芳基”是指5-12个环原子的单环或稠合环，具有5、6、7、8、9、10、11或12个环原子，其中含有1、2、3或4个选自N、O、S的环原子，其余环原子为C，且具有完全共轭的π-电子体系。杂芳基可以是非取代的或取代的，所述的取代基包括但不限于烷基、烷基氧基、芳基、芳烷基、氨基、卤素、羟基、氰基、硝基、羰基和杂脂环基。非取代的杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三嗪基。
本发明使用的术语“多晶型物”或“多晶型(现象)”是指本发明的化合物具有多种晶格形态。本发明的一些化合物可能有一个以上的晶体形式，本发明涵盖所有的多晶型态或其混合物。
本发明化合物的中间体化合物及其多晶形物也在本发明的范围内。
除非另有指定，本发明化合物所含有的烯烃双键包括E和Z异构体。
应理解，本发明化合物可能含有不对称中心。这些不对称中心可以独立的为R或S构型。一些本发明化合物也可显示出顺-反异构现象，这对于本领域技术人员而言是显而易见的。应理解，本发明化合物包括它们的单独的几何异构体和立体异构体以及它们的混合物，包括外消旋混合物。通过实施或修改已知方法，例如层析技术和重结晶技术可以从它们的混合物中分离这些异构体，或者可以由它们的中间体的合适的异构体分别制备它们。
本文所用术语“药学上可接受的盐”既包括加酸盐，也包括加碱盐。
“药学上可接受的加酸盐”是指那些保留了化合物的游离碱的生物效力和特性、在生物学上或其它方面并非不合需要、跟无机酸，例如但是不限于，氢氯酸、氢溴酸、硫酸、硝酸、磷酸等，或有机酸，例如但不限于，乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、癸酸、己酸、碳酸、肉桂酸、柠檬酸等形成的盐。“药学上可接受的加碱盐”是指那些保留了化合物的游离酸的生物效力和特性、在生物学上或其它方面并非不合需要的盐。这些盐通过游离酸跟无机碱或有机碱反应制备。通过跟无机碱反应生成的盐包括，但不限于，钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐、和锰盐。
形成盐的有机碱包括，但不限于，伯胺、仲胺、叔胺、环胺等，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、乙醇胺、二环己胺、乙二胺、嘌呤、哌嗪、哌啶、胆碱和咖啡因等。特别优选的有机碱为异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
结晶经常产生本发明化合物的溶剂化物。本文所用术语“溶剂化物”是指由一个或多个本发明化合物分子和一个或多个溶剂分子组合而成的合体。
溶剂可以是水，这种情况下，溶剂化物是水合物。另外还可以是有机溶剂。因此，本发明化合物可作为水合物存在，包括一水合物、二水合物、半水合物、三水合物、四水合物等，以及相应的溶剂化形态。本发明化合物可以是真溶剂化物，但在其它一些情况下，本发明化合物也可能只是偶然保留了水或水跟一些其它溶剂的混合物。本发明化合物可在一种溶剂中反应或在一种溶剂中沉淀或结晶。本发明化合物的溶剂化物也包括在本发明的范围内。
本文所用术语“药物组合物”是指混合有本发明化合物和通常在本领域被接受的用来将具有生物活性的化合物传送给哺乳动物(比如人类)的介质的制剂。这种介质包含所有药学上可接受的载体。
本文所用的跟制剂、组合物或成分相关的术语“可接受的”是指对治疗主体的总体健康没有持续的有害影响。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
“药学上可接受的载体”包括但不限于已经被相关政府行政部门批准的可以被用于人类和驯养动物的佐剂、载体、赋形剂、助剂、脱臭剂、稀释剂、保鲜剂、染料/着色剂、风味增强剂、表面活性剂和润湿剂、分散剂、悬浮剂、稳定剂、等渗剂、溶剂、或乳化剂。
本文所用术语“主体”、“患者”、“对象”或“个体”是指患有疾病、紊乱或病症等的个体，包括哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物 纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物为人。
本文所用术语“治疗”是指对哺乳动物特别是人类的相关疾病或病症的治疗，包括
(i)预防哺乳动物，特别是之前已经暴漏在某个疾病或病症下但尚未被诊断患有该疾病或病症的哺乳动物，产生相应的疾病或病症；
(ii)抑制疾病或病症，即，控制其发展；
(iii)缓解疾病或病症，即，使疾病或病症消退；
(iv)缓解疾病或病症引起的症状。
本文所用术语“疾病”和“病症”可以互相替代，也可以是不同意思，因为某些特定疾病或病症还没有已知的致病因子(所以发病原因尚不清楚)，所以还不能被认作疾病而只能被看做不想要的状况或综合症，所述综合症或多或少有一些具体症状已经被临床研究人员证实。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
本发明化合物的制备
下述非限制性实施例仅仅是说明性的，不以任何方式限制本申请。
除非另有说明，否则温度是摄氏温度。试剂购自国药集团化学试剂北京有限公司，阿法埃莎(Alfa Aesar)，或北京百灵威科技有限公司等商业供应商，并且这些试剂可直接使用无需进一步纯化，除非另有说明。
除非另有说明，否则下列反应在室温、无水溶剂中、氮气或氩气的正压下或使用干燥管进行；反应瓶上装有橡胶隔膜，以便通过注射器加入底物和试剂；玻璃器皿烘干和/或加热干燥。
除非另有说明，否则柱色谱纯化使用青岛海洋化工厂的200-300目硅胶；制备薄层色谱使用烟台市化学工业研究所生产的薄层色谱硅胶预制板(HSGF254)；MS的测定用Thermo LCQ Fleet型(ESI)液相色谱-质谱联用仪；旋光测定使用SGW-3自动旋光仪,上海申光仪器仪表有限公司。
核磁数据( 1H NMR)使用Varian设备于400MHz运行。核磁数据使用的溶剂有CDCl 3、CD 3OD、D 2O、DMSO-d 6等，以四甲基硅烷(0.00ppm)为基准或以残留溶剂为基准(CDCl 3:7.26ppm；CD3OD:3.31ppm；D2O:4.79ppm；d 6-DMSO:2.50ppm)。当标明峰形多样性时，以下简写表示不同峰形：s(单峰)、d(双重峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(宽峰)、dd(双双重峰)、dt(双三重峰)。 如果给出了耦合常数，则以Hertz(Hz)为单位。
实施例1
((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-1-(N-(叔丁基)苯基磺酰亚胺基)吡咯烷-2-基)甲氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000008
步骤A：苯并呋喃-3-基甲醇
Figure PCTCN2021072666-appb-000009
N 2保护下，将含有苯并呋喃-3-基甲醛(15.0g)的甲醇(200mL)溶液冷却至0℃，并向体系中分批加入硼氢化钠(5.9g)，自然恢复至室温后，搅拌2小时，监测反应完全后，旋转蒸发去除溶剂，残留物在乙酸乙酯和1mol/L的盐酸水溶液中分液，有机相用无水硫酸钠干燥后，过滤后蒸干溶剂得到产物(14.8g)。
1H NMR(400MHz,CDCl 3)δ7.64-7.66(m,2H),7.58(s,1H),7.46-7.48(m,1H),7.23-7.32(m,2H),4.81(s,2H)。
步骤B：3-氯甲基苯并呋喃
Figure PCTCN2021072666-appb-000010
将含有苯并呋喃-3-基甲醇(10.0g)的二氯甲烷(100mL)溶液冷却至0℃，并向体系中分批加入五氯化磷(18.2g)，加毕自然恢复至室温，搅拌1小时后加水淬灭反应，有机相依次用饱和碳酸氢钠水溶液和饱和食盐水洗，有机相经无水硫酸钠干燥，过滤后蒸干溶剂得到产物(12.1g)。
1H NMR(400MHz,CDCl 3)δ7.65-7.70(m,2H),7.49(d,J＝8.4Hz,1H),7.30-7.35(m,2H),4.75(s,2H)。
步骤C：苯并呋喃-3-基甲基硼酸频哪醇酯
Figure PCTCN2021072666-appb-000011
将含有3-氯甲基苯并呋喃(12.0g)，碘化亚铜(1.3g)，联二硼酸频哪醇酯(18.9)和三苯基膦(1.78g)的N,N-二甲基甲酰胺(80mL)悬浊液冷却至0℃，并向体系内分批加入叔丁醇锂(8.68g)，加毕反应液自然恢复至室温并搅拌2小时；加水淬灭反应后，反应液用二氯甲烷萃取并用饱和食盐水洗后，有机相经无 水硫酸钠干燥，过滤后蒸干溶剂，残留物经硅胶柱层析(10-20％乙酸乙酯混合溶液洗脱)纯化得到产物(14.1g)。
1H NMR(400MHz,CDCl 3)δ7.50-7.55(m,2H),7.43(d,J＝8.4Hz,1H),7.20-7.25(m,2H),2.21(s,2H),1.26(s,12H)。
步骤D：苯并呋喃-3-基甲基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000012
将苯并呋喃-3-基甲基硼酸频哪醇酯(14.0g)和(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇(18.4g)加入无水乙醚(200mL)中，该悬浊液在室温下搅拌过夜，检测反应完毕后，用水洗三次，有机相用无水硫酸钠干燥，过滤后蒸干溶剂，残留物经硅胶柱层析(50％二氯甲烷/石油醚)纯化得到产物(10.5g)。
1H NMR(400MHz,CDCl 3)δ7.44-7.56(m,2H),7.43(d,J＝8.4Hz,1H),7.20-7.26(m,2H),4.31(dd,J＝8.4Hz,1.6Hz,1H),2.30-2.36(m,1H),2.26(s,2H),2.17-2.21(m,1H),2.06(t,J＝6.0Hz,1H),1.86-1.91(m,2H),1.40(s,3H),1.27(s,3H),1.11(d,J＝11.2Hz,1H),0.87(s,3H)。
步骤E：2-(苯并呋喃-3-基)-1-(S)-氯乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000013
将干燥的二氯甲烷(4.11g)溶于无水四氢呋喃(30mL)中，充分置换氮气后，将溶液冷却至-100℃，将2.5摩尔/升的丁基锂正己烷溶液(9.6mL)沿反应瓶内壁缓慢滴入体系内，滴加时间不少于10分钟，得到的乳白色悬浊液继续在-100℃下搅拌半小时，将苯并呋喃-3-基甲基硼酸(+)-蒎烷二醇酯(5.0g)的无水四氢呋喃(30mL)溶液沿反应瓶内壁缓慢加入体系内，10分钟后向反应体系内滴加1摩尔/升的氯化锌四氢呋喃溶液(8.8mL)，逐渐恢复至室温，搅拌过夜。加水淬灭反应，反应液在乙酸乙酯(100mL)和饱和氯化铵水溶液(50mL)中分液，有机相经无水硫酸钠干燥后，过滤并蒸干，得到粗产品直接用于下一步反应。(6.0g)。
1H NMR(400MHz,CDCl 3)δ7.58-7.60(m,1H),7.48-7.55(m,2H),7.25-7.30(m,2H),4.30-4.33(m,1H),3.72-3.76(m,1H),3.29(dd,J＝15.2Hz,8.0Hz,1H),3.18(dd,J＝15.2Hz,8.0Hz,1H),2.28-2.35(m,1H),2.06-2.17(m,2H),1.86-1.91(m,2H),1.27(s,3H),1.22(s,3H),1.12-1.17(m,1H),0.84(s,3H)。
步骤F：2-((苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐
Figure PCTCN2021072666-appb-000014
将2-((S)-2-(苯并呋喃-3-基)-1-氯乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(6.0g)溶于无水正己烷中，充分置换氮气后，将上述溶液冷却至-78℃，将1摩尔/升双三甲基硅基氨基锂四氢呋喃溶液(16mL)缓慢滴入体系内，缓慢恢复至室温，搅拌过夜。得到的悬浊液经过硅藻土过滤并用正己烷淋洗，所得母液冷却至0℃，向此溶液中缓慢滴加4摩尔/升氯化氢的1,4-二氧六环溶液(16mL)，滴加完毕后恢复至室温搅拌2小时。反应液经旋转蒸发去除溶剂后加入正己烷充分搅拌后过滤,所得固体用正己烷淋洗得产品(2.91g)。
1H NMR(400MHz,CDCl 3)δ8.32(brs,3H),7.81(s,1H),7.67(d,J＝7.6Hz,1H),7.43(d,J＝8.0Hz,1H),7.22-7.28(m,2H),4.27(d,J＝8.0Hz,1H),3.30-3.36(m,3H),2.19-2.22(m,1H),2.08-2.15(m,1H),1.95-2.05(m,1H),1.80-1.88(m,2H),1.27(s,3H),1.25(s,3H),1.03-1.06(m,1H),0.70(s,3H)。
步骤G：(R)-2-(((氯羰基)氧基)甲基)吡咯烷-1-甲酸叔丁酯
Figure PCTCN2021072666-appb-000015
将(R)-2-(羟甲基)吡咯烷-1-甲酸叔丁酯(314mg)置于三口瓶中，加入二氯甲烷(10mL)和二异丙基乙基胺(402mg)，氮气保护并冷却至0℃，向反应液中滴加二(三氯甲基)碳酸酯(232mg)的二氯甲烷溶液，完毕后0℃下搅拌2小时，直接用于下一步。
步骤H：((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-N-叔丁氧羰基-吡咯烷-2-基)甲氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000016
将2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2，3-二醇酯盐酸盐(470mg)和二异丙基乙基胺(273mg)加入干燥的二氯甲烷中，氮气保护并冷却至0℃，向反应液中滴加(R)-2-(((氯羰基)氧基)甲基)吡咯烷-1-甲酸叔丁酯的二氯甲烷溶液，完毕后恢复至室温搅拌2小时，用水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，有机相经无水硫酸钠干燥后，过滤蒸干溶剂所得残留物经过硅胶柱层析(1：1乙酸乙酯/石油醚)纯化得到产品(350mg)。
1H NMR(400MHz,CDCl 3)δ7.56(d,J＝7.2Hz,1H),7.42-7.45(m,2H),7.27(t,J＝8.0Hz,1H),7.21(t,J＝7.6Hz,1H),4.93(s,1H),4.28(d,J＝8.0Hz,1H), 3.82-4.17(m,3H),3.48-3.55(m,1H),3.24-3.40(m,2H),3.11(dd,J＝14.8Hz,6.0Hz,1H),2.96(dd,J＝14.8Hz,7.2Hz,1H),2.28-2.33(m,1H),2.07-2.14(m,1H),1.97(t,J＝5.6Hz,1H),1.76-1.92(m,6H),1.45(s,9H),1.25(s,3H),1.20(s,3H),0.85(d,J＝6.8Hz,1H),0.80(s,3H)。
步骤J：((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-吡咯烷-2-基)甲氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯三氟乙酸盐
Figure PCTCN2021072666-appb-000017
将((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-N-叔丁氧羰基-吡咯烷-2-基)甲氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(191mg)加入二氯甲烷(5mL)中，随后加入三氟乙酸(1mL)，室温搅拌3小时，减压蒸干溶剂得到产品(190mg)。
该中间体经质谱确认，[M+H +]＝467。
步骤K：N-(叔丁基)苯亚磺酰胺
Figure PCTCN2021072666-appb-000018
将叔丁基胺(414mg)加入干燥的二氯甲烷中，氮气保护并冷却至0℃，向反应液中加入三乙胺(1.14g)，随后逐滴加入苯基磺酰氯(63mg)，完毕后0℃下向上述反应液中逐滴缓慢加入三苯基膦(1.48g)的二氯甲烷溶液，1小时滴加完毕。恢复至室温搅拌过夜，蒸干溶剂所得残留物经过硅胶柱层析(1：4乙酸乙酯/石油醚)纯化得到产品(280mg)。
1H NMR(400MHz,CDCl 3),7.66-7.69(m,2H),7.43-7.48(m,3H),3.86(s,1H),1.39(s,9H)。
步骤L：N-(叔丁基)苯胺基亚磺酰氯
Figure PCTCN2021072666-appb-000019
将N-(叔丁基)苯亚磺酰胺(280mg)加入干燥的二氯甲烷中，氮气保护并冷却至0℃，向反应液中滴加次氯酸叔丁酯(185mg)，完毕后恢复至室温搅拌1小时，用水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，有机相经无水硫酸钠干燥后，过滤蒸干溶剂得到产品(140mg)。
步骤M：((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-1-(N-(叔丁基)苯基磺酰亚胺基)吡咯烷-2-基)甲氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000020
将((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-吡咯烷-2-基)甲氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯三氟乙酸盐(190mg)和二异丙基乙基胺(132mg)加入干燥的二氯甲烷中，氮气保护并冷却至0℃，向反应液中滴加N-(叔丁基)苯胺基亚磺酰氯(106mg)的二氯甲烷溶液，完毕后恢复至室温搅拌2小时，用水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，有机相经无水硫酸钠干燥后，过滤蒸干溶剂所得残留物经过硅胶制备板(1：4乙酸乙酯/石油醚)纯化得到产品(90mg)。
1H NMR(400MHz,CDCl 3)δ7.87-7.97(m,2H),7.41-7.58(m,6H),7.26(t,J＝7.6Hz,1H),7.20(t,J＝8.0Hz,1H),4.86-4.96(m,1H),3.78-4.29(m,4H),2.92-3.70(m,5H),2.27-2.48(m,1H),1.56-2.21(m,8H),1.37(s,3H),1.33(s,3H),1.24(s,3H),1.22(s,3H),1.19(s,3H),1.12(d,J＝7.2Hz,1H),0.92(s,0.5Hz),0.79(s,2.5H).
步骤N：((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-1-(N-(叔丁基)苯基磺酰亚胺基)吡咯烷-2-基)甲氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000021
将((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-1-(N-(叔丁基)苯基磺酰亚胺基)吡咯烷-2-基)甲氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(90mg)溶于甲醇中，向此溶液中加入异丁基硼酸(45mg)，1摩尔/升盐酸(3mL)和正己烷，室温搅拌过夜，分液去除上层正己烷，并将甲醇相用正己烷洗三次后30℃浓缩至干，加入饱和食盐水(15mL)，用二氯甲烷萃取三次后，有机相经无水硫酸钠干燥，过滤蒸干溶剂所得残留物经过硅胶制备板(1：40甲醇/二氯甲烷)纯化得到两个基于硫原子的同分异构体分别为异构体1(30mg)和异构体2(20mg)。
异构体1
1H NMR(400MHz,CD 3OD)δ7.89(d,J＝7.2Hz,2H),7.49-7.60(m,5H),7.40(d,J＝8.0Hz,1H),7.17-7.26(m,2H),4.20(dd,J＝10.8Hz,4.0Hz,1H),4.11(dd,J＝10.0Hz,6.8Hz,1H),3.80-3.86(m,1H),3.28-3.32(m,1H),3.12-3.26(m,2H),2.93(dd,J＝14.4Hz,6.8Hz,1H),2.85(dd,J＝14.4Hz,8.0Hz,1H),1.50-1.70(m, 3H),1.36(s,9H),1.08-1.16(m,1H)。
异构体2
1H NMR(400MHz,CD 3OD)δ7.82-7.90(m,2H),7.44-7.58(m,5H),7.41(d,J＝8.0Hz,1H),7.25(t,J＝7.6Hz,1H),7.20(t,J＝7.6Hz,1H),4.20(dd,J＝10.4Hz,2.8Hz,1H),4.04(dd,J＝10.4Hz,7.2Hz,1H),3.91-3.98(m,1H),3.22-3.30(m,2H),3.10-3.15(m,1H),2.91(dd,J＝14.4Hz,7.2Hz,1H),2.83(dd,J＝14.4Hz,7.6Hz,1H),1.61-1.86(m,4H),1.32(s,9H)。
实施例2
((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-1-(N,S-二甲基磺酰亚胺基)吡咯烷基-2-基)甲氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000022
步骤A：N-亚磺酰基三苯甲胺
Figure PCTCN2021072666-appb-000023
将三苯甲胺(10g)和三乙胺(7.8g)加入干燥的乙醚中，氮气保护并冷却至0℃，向反应液中滴加二氯亚砜(4.6g)，完毕后0℃搅拌2小时，硅藻土过滤并用乙醚淋洗，常温下减压蒸干溶剂得到白色固体产品(11g)。
步骤B：(±)-N-三苯甲基甲烷亚磺酰胺
Figure PCTCN2021072666-appb-000024
将N-亚磺酰基三苯甲胺(6g)溶于无水四氢呋喃中，氮气保护并冷却至0℃，向反应液中滴加3摩尔/升的甲基溴化镁四氢呋喃溶液(5.2mL)，完毕后恢复至室温搅拌1小时，用饱和氯化铵淬灭反应，并用乙酸乙酯萃取，有机相用饱和食盐水洗，有机相经无水硫酸钠干燥后，过滤蒸干溶剂所得残留物用石油醚打浆，抽滤得到固体产品(4.5g)。
1H NMR(400MHz,CDCl 3)δ7.24-7.33(m,15H),4.83(s,1H),2.57(s,3H)。
步骤C：(R)-2-(((叔丁基苯甲基甲硅烷基)氧)甲基)吡咯烷
Figure PCTCN2021072666-appb-000025
将D-脯氨醇(1g)和咪唑(1.3g)加入二氯甲烷中，冷却至0℃，向反应液中滴加叔丁基二苯基氯硅烷(5.7g)，完毕后恢复至室温搅拌1小时，抽滤得到滤液，滤液加入饱和氯化铵水溶液，并用二氯甲烷萃取，有机相经无水硫酸钠干燥后，过滤蒸干溶剂所得残留物经过硅胶柱层析(1：7甲醇/二氯甲烷)纯化得到产品(3.1g)。
1H NMR(400MHz,CDCl 3)δ7.64-7.69(m,4H),7.35-7.44(m,6H),3.85(dd,J＝11.2Hz,4.8Hz,1H),3.74(dd,J＝11.2Hz,5.6Hz,1H),3.58-3.65(m,1H),3.23(t,J＝7.2Hz,2H),1.85-1.99(m,3H),1.67-1.75(m,1H),1.06(s,9H)。
步骤D：(2R)-2-(((叔丁基二苯基甲硅烷基)氧基)甲基)-1-(S-甲基磺酰亚胺基)吡咯烷
Figure PCTCN2021072666-appb-000026
将(±)-N-三苯甲基甲烷亚磺酰胺(2g)加入干燥的二氯甲烷中，氮气保护并冷却至0℃，向反应液中滴加次氯酸叔丁酯(676mg)，0℃下搅拌1小时，随后将该反应液逐滴加入至(R)-2-(((叔丁基苯甲基甲硅烷基)氧)甲基)吡咯烷(1.4g)和三乙胺(1.2g)的二氯甲烷溶液中，氮气保护下室温搅拌过夜，加入对甲苯磺酸一水化合物(10.6g)，室温搅拌30分钟，加入1摩尔/升氢氧化钠水溶液调节pH至碱性，并用二氯甲烷萃取，有机相用饱和食盐水洗，有机相经无水硫酸钠干燥后，过滤蒸干溶剂所得残留物经过硅胶柱层析(纯乙酸乙酯)纯化得到产品(1.6g)。
1H NMR(400MHz,CDCl 3)δ7.62-7.68(m,4H),7.34-7.43(m,6H),3.82(dd,J＝10.4Hz,4.0Hz,0.5H),3.69-3.79(m,1H),3.64(dd,J＝10.4Hz,4.0Hz,0.5H),3.51-3.59(m,1H),3.22-3.42(m,2H),2.78(s,3H),2.17-2.21(m,1H),1.78-2.13(m,4H),1.05(s,9H)。
步骤E：(2R)-2-(((叔丁基二苯基甲硅烷基)氧基)甲基)-1-(N,S-二甲基磺酰亚胺基)吡咯烷
Figure PCTCN2021072666-appb-000027
将(2R)-2-(((叔丁基二苯基甲硅烷基)氧基)甲基)-1-(S-甲基磺酰亚胺基)吡咯烷(1.2g)加入干燥的四氢呋喃中，冷却至0℃，向反应液中分批加入氢化钠(230mg)，0℃搅拌30分钟，滴加碘甲烷(809mg)，完毕后恢复至室温搅拌过夜，用水淬灭反应，并用乙酸乙酯萃取，有机相用饱和食盐水洗，有机相经无水硫酸钠干燥后，过滤蒸干溶剂得到产品(1.2g)。
1H NMR(400MHz,CDCl 3)δ7.62-7.67(m,4H),7.35-7.44(m,6H),3.77-3.82 (m,1H),3.67-3.72(m,1H),3.53-3.62(m,1H),3.16-3.30(m,2H),2.76(s,1.7H),2.75(s,1.3s),2.64(s,1.3s),2.51(s,1.7H),2.04-2.13(m,1H),1.78-1.98(m,3H),1.05(s,9H)。
步骤F：((2R)-1-(N,S-二甲基磺酰亚胺基)吡咯烷-2-基)甲醇
Figure PCTCN2021072666-appb-000028
将(2R)-2-(((叔丁基二苯基甲硅烷基)氧基)甲基)-1-(N,S-二甲基磺酰亚胺基)吡咯烷(1.2g)溶于四氢呋喃中，向此溶液中加入四丁基氟化铵一水化合物(1.2g)，40℃搅拌2小时，蒸干溶剂所得残留物经过硅胶柱层析(甲醇：乙酸乙酯3/40)纯化得到产品(400mg)。
1H NMR(400MHz,CDCl 3)δ3.57-3.70(m,2H),3.51-3.54(m,2H),3.24-3.31(m,2H),2.85(s,0.6H),2.80(s,2.4H),2.67(s,0.6H),2.65(s,2.4H),1.97-2.06(m,1H),1.66-1.95(m,3H)。
步骤G：((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-1-(N,S-二甲基磺酰亚胺基)吡咯烷基-2-基)甲氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000029
将2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(150mg)和三乙胺(162mg)加入干燥的二氯甲烷中，氮气保护并冷却至-60℃，向反应液中滴加二(三氯甲基)碳酸酯(47mg)的二氯甲烷溶液，完毕后-60℃下搅拌1小时，-60℃下将((2R)-1-(N,S-二甲基磺酰亚胺基)吡咯烷-2-基)甲醇(93mg)的二氯甲烷溶液滴加至上述溶液中，-60℃下搅拌1小时，用水淬灭反应，并用二氯甲烷萃取，饱和食盐水洗，有机相经无水硫酸钠干燥后，过滤蒸干溶剂所得残留物经过硅胶制备板(1：30甲醇/二氯甲烷)纯化得到产品(25mg)。
1H NMR(400MHz,CDCl 3)δ7.56(d,J＝6.8Hz,1H),7.45(s,1H),7.43(d,J＝8.0Hz,1H),7.26(t,J＝7.2Hz,1H),7.21(t,J＝7.2Hz,1H),4.96(d,J＝5.6Hz,1H),4.27-4.30(m,1H),3.96-4.14(m,2H),3.87-3.94(m,0.6H),3.72-3.80(m,0.4H),3.49-3.55(m,1H),3.18-3.28(m,2H),3.10(dd,J＝14.8Hz,5.2Hz,1H),2.96(dd,J＝14.8Hz,7.2Hz,1H),2.83(s,1.8H),2.80(s,1.2H),2.67(s,1.8H),2.65(s,1.2H),2.06-2.48(m,3H),1.59-2.01(m,6H),1.24(s,3H),1.20(s,3H),1.05(d,J＝10.8Hz,1H),0.79(s,3H)。
步骤H：((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-1-(N,S-二甲基磺酰亚胺基)吡咯烷 基-2-基)甲氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000030
将((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-1-(N,S-二甲基磺酰亚胺基)吡咯烷基-2-基)甲氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(25mg)溶于甲醇中，向此溶液中加入异丁基硼酸(14mg)，1摩尔/升盐酸(0.1mL)和正己烷，室温搅拌过夜，分液去除上层正己烷，并将甲醇相用正己烷洗三次后30℃浓缩至干用二氯甲烷稀释并用2摩尔/升氢氧化钠水溶液(5mL)将产品洗至水相，水相用二氯甲烷洗三次后用3摩尔/升盐酸酸化至pH酸性，用二氯甲烷萃取三次后，有机相经无水硫酸钠干燥，过滤并在30℃浓缩去除溶剂得到产品(10mg)。
1H NMR(400MHz,CD 3OD)δ7.59(d,J＝8.0Hz,1H),7.54(s,1H),7.42(d,J＝7.6Hz,1H),7.26(t,J＝7.2Hz,1H),7.21(t,J＝7.2Hz,1H),4.17-4.30(m,2H),3.96-4.07(m,1H),3.62(s,1H),3.58(s,2H),3.33-3.50(m,3H),2.83-2.97(m,2H),2.79(s,2H),2.76(s,1H),1.94-2.20(m,4H)。
实施例3
(R)-(2-(苯并呋喃-3-基)-1-(2-(3-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基)硼酸
Figure PCTCN2021072666-appb-000031
步骤A：2-(3-二甲基亚磺酰亚胺基苯基)乙酸
Figure PCTCN2021072666-appb-000032
将3-溴苯乙酸(431mg)溶于1,4-二氧六环中，依次加入三(二亚苄基丙酮)二钯(184mg)，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(230mg)，碳酸铯(1.96g)，体系充分置换氮气，升温至100℃反应过夜，经监测原料转化完全，加入水稀释，二氯甲烷萃取，合并有机相，依次用水和饱和食盐水洗，有机相经无水硫酸钠干燥，过滤后蒸干溶剂，残留物经硅胶制备板(1：10甲醇/二氯甲烷)纯化得到产品(67mg)。
1H NMR(400MHz,CDCl 3)δ7.15(t,J＝8.0Hz,1H),6.96-6.98(m,2H),6.89(d,J＝7.6Hz,1H),3.54(s,2H),3.13(s,6H)。
步骤B：(R)-2-(苯并呋喃-3-基)-1-(2-(3-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2，3-二醇酯
Figure PCTCN2021072666-appb-000033
将2-(3-二甲基亚磺酰亚胺基苯基)乙酸(67mg)，2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(111mg)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(146mg)，N,N-二异丙基乙胺(114mg)和4-二甲基氨基吡啶(36mg)加入干燥的二氯甲烷中，完毕后室温搅拌过夜，用水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，有机相经无水硫酸钠干燥后，过滤蒸干溶剂所得残留物经过硅胶制备板(20：1甲醇/二氯甲烷)纯化得到产品(30mg)。
1H NMR(400MHz,CDCl 3)δ7.44(d,J＝8.0Hz,1H),7.38(d,J＝8.0Hz,1H),7.22-7.26(m,2H),7.17(d,J＝7.2Hz,1H),7.13(t,J＝8.0Hz,1H),6.97(d,J＝8.0Hz,1H),6.83(s,1H),6.72(d,J＝7.2Hz,1H),6.21(s,1H),4.24(d,J＝8.0Hz,1H),3.61(d,J＝16.8Hz,1H),3.54(d,J＝16.8Hz,1H),3.08(s,6H),2.92-2.99(m,2H),2.73-2.80(m,1H),2.30-2.35(m,1H),2.11-2.16(m,1H),1.99(t,J＝5.6Hz,1H),1.80-1.89(m,2H),1.40(d,J＝10.4Hz,1H),1.37(s,3H),1.26(s,3H),0.85(s,3H)。
步骤C：(R)-(2-(苯并呋喃-3-基)-1-(2-(3-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基)硼酸
Figure PCTCN2021072666-appb-000034
将2(R)-2-(苯并呋喃-3-基)-1-(2-(3-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2，3-二醇酯(30mg)溶于甲醇(1mL)中，向此溶液中加入异丁基硼酸(28mg)，1摩尔/升盐酸(0.2mL)和正己烷(1mL)，室温搅拌过夜，分液去除上层正己烷，并将甲醇相用正己烷洗三次后30℃浓缩至干得粗产物，加入乙醚打浆，过滤收集固体，固体干燥得到产品(15mg)。
1H NMR(400MHz,CD 3OD)δ7.57(s,1H),7.56(d,J＝8.4Hz,1H),7.42-7.47(m,2H),7.24-7.33(m,4H),7.21(t,J＝7.6Hz,1H),3.74-3.77(m,8H),3.01(dd,J＝9.6Hz,5.2Hz,1H),2.89(dd,J＝14.8Hz,4.8Hz,1H),2.71(dd,J＝14.8Hz,9.6Hz,1H)。
实施例4
(R)-(1-(3-(6-((二甲基(氧代)-λ 6-亚硫烷基)氨基)吡啶-2-基)脲基)-2-苯基乙基)硼酸
Figure PCTCN2021072666-appb-000035
步骤A：((6-溴吡啶-2-基)亚氨基)二甲基-λ 6-亚磺酰亚胺
Figure PCTCN2021072666-appb-000036
N 2保护下，将含有2,6-二溴吡啶(6.00g)，二甲基亚磺酰亚胺(1.63g)，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(1.50g)，三(二亚苄基丙酮)二钯(0.793g)和碳酸铯(8.59g)的1,4-二氧六环(100mL)悬浊液加热至回流过夜。冷却至室温后，过滤并用二氯甲烷淋洗，滤液去除溶剂后经过硅胶柱层析(100％AcOEt)纯化得到产物(4.0g)。
1H NMR(400MHz,CDCl 3)δ7.31-7.35(m,1H),6.93(dd,J＝7.6Hz,0.8Hz,1H),6.69(dd,J＝7.6Hz,0.8Hz,1H),3.36(s,6H)。
步骤B：((6-氨基吡啶-2-基)亚氨基)二甲基-λ 6-亚磺酰亚胺
Figure PCTCN2021072666-appb-000037
将含有((6-溴吡啶-2-基)亚氨基)二甲基-λ 6-亚磺酰亚胺(4.0g)，氧化亚铜(0.230g)，N,N’-二甲基乙二胺(0.142g)，无水碳酸钾(4.43g)，25％氨水(20mL)和乙二醇(20mL)的混合物加热至60℃搅拌过夜。冷却至室温后，经过硅藻土过滤，并用二氯甲烷淋洗，分液后水相用二氯甲烷萃取，有机相经无水硫酸钠干燥后过滤，蒸干去除溶剂得到产物(1.4g)。
1H NMR(400MHz,CDCl 3)δ7.27-7.31(m,1H),6.19(d,J＝7.6Hz,1H),6.04(d,J＝7.6Hz,1H),4.26(brs,2H),3.35(s,6H)。
步骤C：苄基硼酸频哪醇酯
Figure PCTCN2021072666-appb-000038
参照实施例1中步骤C的方法，以氯化苄，碘化亚铜，联二硼酸频哪醇酯，三苯基膦和叔丁醇锂为原料反应得到产物(2.5g)。
1H NMR(400MHz,CDCl 3)δ7.23-7.27(m,2H),7.17-7.19(m,2H),7.13(t,J＝7.6Hz,1H),2.29(s,2H),1.25(s,12H)。
步骤D：苄基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000039
参照实施例1中步骤D的方法，以苄基硼酸频哪醇酯和(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇为主要原料反应得到产物(2.0g)。
1H NMR(400MHz,CDCl 3)δ7.22-7.27(m,2H),7.18-7.20(m,2H),7.13(t,J＝7.6Hz,1H),4.27(dd,J＝8.4Hz,2.0Hz,1H),2.32(s,2H),2.17-2.30(m,2H),2.04(t,J＝6.0Hz,1H),1.80-1.90(m,2H),1.37(s,3H),1.25(s,3H),1.06(d,J＝10.4Hz,1H),0.87(s,3H)。
步骤E：1-(S)-氯-2-苯基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000040
参照实施例1中步骤E的方法以苄基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯，二氯甲烷，丁基锂和氯化锌四氢呋喃溶液为主要原料反应得到淡黄色油状粗产品(2.3g)直接用于下一步反应。
1H NMR(400MHz,CDCl 3)δ7.22-7.31(m,3H),7.12-7.16(m,1H),4.77(d,J＝8.8Hz,1H),3.59-3.63(m,1H),3.18-3.23(m,1H),3.08-3.12(m,1H),2.32-2.37(m,1H),2.15-2.22(m,2H),2.05(t,J＝5.6Hz,1H),1.82-1.91(m,2H),1.35(s,3H),1.27(s,3H),1.06(d,J＝10.8Hz,1H),0.85(s,3H)。
步骤F：2-苯基-1-(R)-氨基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐
Figure PCTCN2021072666-appb-000041
参照实施例1中步骤F的方法，以1-(S)-氯-2-苯基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯，双三甲基硅基氨基锂四氢呋喃溶液和氯化氢的1,4-二氧六环溶液为主要原料反应得到产品(0.70g)。
1H NMR(400MHz,CDCl 3)δ7.97-8.16(brs,3H),7.34-7.43(m,3H),7.17-7.26(m,2H),4.35(d,J＝8.4Hz,1H),2.80-3.06(m,3H),2.17-2.20(m,1H),1.95-2.13(m,2H),1.80-1.88(m,2H),1.27(s,3H),1.20(s,3H),1.03-1.06(m,1H),0.76(s,3H)。
步骤G：(R)-(1-(3-(6-((二甲基(氧代)-λ 6-亚硫烷基)氨基)吡啶-2-基)脲基)-2-苯基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000042
将2-苯基-1-(R)-氨基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(150mg)和三乙胺(162mg)加入干燥的二氯甲烷中，氮气保护并冷却至-60℃，向反应液中滴加二(三氯甲基)碳酸酯(48mg)的二氯甲烷溶液，完毕后-60℃下搅拌1小时，-60℃下将((6-氨基吡啶-2-基)亚氨基)二甲基-λ 6-亚磺酰亚胺(81mg)的二氯甲烷溶液滴加至上述溶液中，-60℃下搅拌1小时，用水淬灭反应，并用二氯甲烷萃取，饱和食盐水洗，有机相经无水硫酸钠干燥后，过滤蒸干溶剂所得残留物经过硅胶制备板(1：30甲醇/二氯甲烷)纯化得到产品(20mg)。
1H NMR(400MHz,CDCl 3)δ8.97(s,1H),7.48(s,1H),7.43(t,J＝8.0Hz,1H),7.28(d,J＝7.2Hz,2H),7.21(t,J＝7.6Hz,2H),7.11(t,J＝7.2Hz,1H),6.36(d,J＝8.4Hz,1H),6.28(d,J＝8.0Hz,1H),4.18(d,J＝7.2Hz,1H),3.14-3.21(m,1H),3.12(s,3H),2.94-3.05(m,5H),2.18-2.22(m,1H),1.85-1.94(m,2H),1.71-1.81(m,2H),1.31(s,3H),1.20(s,3H),1.04(d,J＝9.2Hz,1H),0.80(s,3H)。
步骤H：(R)-(1-(3-(6-((二甲基(氧代)-λ 6-亚硫烷基)氨基)吡啶-2-基)脲基)-2-苯基乙基)硼酸
Figure PCTCN2021072666-appb-000043
将(R)-(1-(3-(6-((二甲基(氧代)-λ 6-亚硫烷基)氨基)吡啶-2-基)脲基)-2-苯基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(20mg)溶于甲醇(1mL)中，向此溶液中加入异丁基硼酸(12mg)，1摩尔/升盐酸(0.1mL)和正己烷(1mL)，室温搅拌过夜，分液去除上层正己烷，并将甲醇相用正己烷洗三次后30℃浓缩至干用二氯甲烷稀释并用2摩尔/升氢氧化钠水溶液(5mL)将产品洗至水相，水相用二氯甲烷洗三次后用3摩尔/升的盐酸酸化至pH酸性，用二氯甲烷萃取三次后，有机相经无水硫酸钠干燥，过滤并在30℃浓缩去除溶剂得到产品(10mg)。
1H NMR(400MHz,CD 3OD)δ7.81(t,J＝8.0Hz,1H),7.15-7.27(m,5H),6.76(d,J＝7.6Hz,1H),6.46(d,J＝8.4Hz,1H),3.44(s,3H),3.43(s,3H),3.28-3.31(m,1H),2.84-2.94(m,2H)。
实施例5
((1R)-1-(((((2R)-1-(N,S-二甲基磺酰亚胺基)吡咯烷-2-基)甲氧基)羰基)氨基)-2-苯基乙基)硼酸
Figure PCTCN2021072666-appb-000044
步骤A：((1R)-1-(((((2R)-1-(N,S-二甲基磺酰亚胺基)吡咯烷-2-基)甲氧基)羰基)氨基)-2-苯基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000045
将2-苯基-1-(R)-氨基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(150mg)和三乙胺(162mg)加入干燥的二氯甲烷中，氮气保护并冷却至-60℃，向反应液中滴加二(三氯甲基)碳酸酯(48mg)的二氯甲烷溶液，完毕后-60℃下搅拌1小时，-60℃下将((2R)-1-(N,S-二甲基磺酰亚胺基)吡咯烷-2-基)甲醇(93mg)的二氯甲烷溶液滴加至上述溶液中，-60℃下搅拌1小时，用水淬灭反应，并用二氯甲烷萃取，饱和食盐水洗，有机相经无水硫酸钠干燥后，过滤蒸干溶剂所得残留物经过硅胶制备板(1：35甲醇/二氯甲烷)纯化得到产品(105mg)。
1H NMR(400MHz,CDCl 3)δ7.24-7.28(m,2H),7.16-7.21(m,3H),4.81(d,J＝5.2Hz,1H),4.32(d,J＝8.8Hz,1H),4.04-4.14(m,2H),3.86-3.94(m,0.4H),3.73-3.80(m,0.6H),3.38-3.44(m,1H),3.14-3.32(m,2H),3.01(dd,J＝14.0Hz,4.8Hz,1H),2.77-2.88(m,4H),2.67(s,1.2H),2.66(s,1.8H),2.29-2.34(m,1H),2.13-2.18(m,1H),1.81-2.01(m,7H),1.31(s,3H),1.26(s,3H),1.11(d,J＝11.2Hz,1H),0.82(s,3H)。
步骤B：((1R)-1-(((((2R)-1-(N,S-二甲基磺酰亚胺基)吡咯烷-2-基)甲氧基)羰基)氨基)-2-苯基乙基)硼酸
Figure PCTCN2021072666-appb-000046
将((1R)-1-(((((2R)-1-(N,S-二甲基磺酰亚胺基)吡咯烷-2-基)甲氧基)羰基)氨基)-2-苯基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(105mg)溶于甲醇中，向此溶液中加入异丁基硼酸(62mg)，1摩尔/升盐酸(0.1mL)和正己烷，室温搅拌过夜，分液去除上层正己烷，并将甲醇相用正己烷洗三次后30℃浓缩至干用二氯甲烷稀释并用2M氢氧化钠水溶液(5mL)将产品洗至水相，水相用二氯甲烷洗三次后用3摩尔/升盐酸酸化至pH酸性，用二氯甲烷萃取三次后，有机相经无水硫酸钠干燥，过滤并在30℃浓缩去除溶剂得到产品(40mg)。
1H NMR(400MHz,CD 3OD)δ7.16-7.26(m,5H),3.94-4.22(m,3H),3.33-3.43(m,5H),3.20-3.25(m,1H),2.73-2.90(m,5H),1.94-2.18(m,4H)。
实施例6
((1R)-2-(苯并呋喃-3-基)-1-(2-((2R)-1-(N-(叔丁基)苯基磺酰亚胺基)吡咯烷-2-基)乙酰胺基)乙基)硼酸
Figure PCTCN2021072666-appb-000047
步骤A：((R)-2-(苯并呋喃-3-基)-1-(2-((R)-1-(叔丁氧羰基)吡咯烷-2-基)乙酰胺基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000048
将(R)-吡咯烷-2-乙酸(366mg)、2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(600mg)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(912mg)、4-二甲基氨基吡啶(20mg)和二异丙基乙基胺(406mg)加入干燥的二氯甲烷(20mL)中，完毕后室温搅拌过夜，用水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶制备板(1:40甲醇/二氯甲烷)纯化得到产品(180mg)。
1H NMR(400MHz,CDCl 3)δ8.28-8.46(brs,1H),7.56(d,J＝8.0Hz,1H),7.48(s,1H),7.44(d,J＝8.4Hz,1H),7.27(t,J＝7.2Hz,1H),7.20(t,J＝7.6Hz,1H),4.16-4.26(m,1H),3.94-4.03(m,1H),3.22-3.37(m,2H),3.06-3.17(m,1H),2.94-3.04(m,1H),2.63-2.88(m,2H),2.39-2.52(m,1H),2.27-2.38(m,1H),2.04-2.15(m,1H),1.90-2.04(m,2H),1.73-1.89(m,5H),1.40(d,J＝10.8Hz,1H),1.29-1.41(m,12H),1.25(s,3H),0.85(s,3H)。
步骤B：((R)-2-(苯并呋喃-3-基)-1-(2-((R)-吡咯烷-2-基)乙酰胺基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯三氟乙酸盐
Figure PCTCN2021072666-appb-000049
将((R)-2-(苯并呋喃-3-基)-1-(2-((R)-1-(叔丁氧羰基)吡咯烷-2-基)乙酰胺基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(180mg)加入二氯甲烷(5mL)中，随后加入三氟乙酸(1mL)，室温搅拌3小时，减压浓缩蒸干溶剂得到产品(175mg)。
步骤C：((1R)-2-(苯并呋喃-3-基)-1-(2-((2R)-1-(N-(叔丁基)苯基磺酰亚胺基)吡咯烷-2-基)乙酰胺基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000050
氮气保护下，将((R)-2-(苯并呋喃-3-基)-1-(2-((R)-吡咯烷-2-基)乙酰胺基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯三氟乙酸盐(63mg)和三乙胺(33mg)加入干燥的二氯甲烷(5mL)中，冷却至0℃，向反应液中滴加N-(叔丁基)苯胺基亚磺酰氯(37mg)的二氯甲烷(2mL)溶液，完毕后升至室温搅拌2小时，用水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶制备版(1:2乙酸乙酯/石油醚)纯化得到产品(12mg)。
1H NMR(400MHz,CDCl 3)δ8.10-8.19(brs,1H),7.79(d,J＝7.2Hz,2H),7.58(d,J＝6.8Hz,1H),7.38-7.50(m,5H),7.27(td,J＝7.2Hz,1.2Hz,1H),7.22(td,J＝7.6Hz,1.2Hz,1H),4.20(dd,J＝8.8Hz,2.0Hz,1H),3.86-3.94(m,1H),3.12-3.22(m,2H),2.96-3.09(m,2H),2.79-2.91(m,2H),2.57(dd,J＝16.0Hz,6.8Hz,1H),2.40-2.48(m,1H),2.16-2.35(m,2H),1.85-2.08(m,4H),1.74-1.85(m,2H),1.58-1.64(m,1H),1.32(s,3H),1.24(s,3H),1.22(s,9H),0.83(s,3H)。
步骤D：((1R)-2-(苯并呋喃-3-基)-1-(2-((2R)-1-(N-(叔丁基)苯基磺酰亚胺基)吡咯烷-2-基)乙酰胺基)乙基)硼酸
Figure PCTCN2021072666-appb-000051
将((1R)-2-(苯并呋喃-3-基)-1-(2-((2R)-1-(N-(叔丁基)苯基磺酰亚胺基)吡咯烷-2-基)乙酰胺基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(12mg)溶于甲醇(5mL)中，向此溶液中加入异丁基硼酸(10mg)、1mol/L盐酸(1mL)和正己烷(5mL)，室温搅拌过夜，分液去除上层正己烷，甲醇相用正己烷洗涤，减压浓缩，加入饱和食盐水(5mL)，用二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗产物经乙醚打浆纯化得到产品(3mg)。
1H NMR(400MHz,CD 3OD)δ8.07-8.22(m,2H),7.94(t,J＝7.2Hz,1H),7.78-7.85(m,2H),7.58-7.63(m,2H),7.43(d,J＝8.0Hz,1H),7.20-7.29(m,2H),4.42-4.52(m,1H),3.45-3.58(m,1H),3.30-3.42(m,1H),3.05-3.15(m,1H),2.72-2.98(m,4H),1.93-2.09(m,2H),1.77-1.91(m,2H),1.43(s,9H)。
实施例7
((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-1-(N-甲基丙烷-2-基磺酰亚胺基)吡咯烷-2-基)甲氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000052
步骤A：N-三苯甲基丙烷-2-亚磺酰胺
Figure PCTCN2021072666-appb-000053
氮气保护下，将N-亚磺酰基三苯甲胺(9.2g)溶于无水四氢呋喃(100mL)中，冷却至0℃，向反应液中滴加2mol/L的异丙基氯化镁的四氢呋喃溶液(15mL)，完毕后升至室温搅拌1小时，用饱和氯化铵水溶液淬灭反应，并用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用石油醚打浆，抽滤得到固体产品(8.1g)。
1H NMR(400MHz,CDCl 3)δ7.24-7.32(m,15H),4.67(s,1H),2.71-2.78(m,1H),1.26(d,J＝7.2Hz,3H),1.24(d,J＝7.2Hz,3H)。
步骤B：(2R)-2-(((叔丁基二苯基甲硅烷基)氧基)甲基)-1-(丙基-2-基磺酰亚胺基)吡咯烷
Figure PCTCN2021072666-appb-000054
氮气保护下，将N-三苯甲基丙烷-2-亚磺酰胺(8g)加入干燥的二氯甲烷(50mL)中，冷却至0℃，向反应液中滴加次氯酸叔丁酯(2.48g)，0℃下搅拌1小时，随后将该反应液逐滴加入至(R)-2-(((叔丁基苯甲基甲硅烷基)氧)甲基)吡咯烷(3.12g)和三乙胺(4.6g)的二氯甲烷(50mL)溶液中，氮气保护下室温搅拌过夜，加入对甲苯磺酸一水合物(19.8g)，室温搅拌30分钟，加入1mol/L氢氧化钠水溶液调节pH至9-10，并用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶柱层析(纯乙酸乙酯)纯化得到产品(2.1g)。 1H NMR(400MHz,CDCl 3)δ7.62-7.68(m,4H),7.34-7.44(m,6H),3.94-4.02(m,1H),3.75(dd,J＝10.0Hz,4.0Hz,0.5H),3.37-3.64(m,2.5H),3.11-3.29(m,2H),2.07-2.56(brs,1H),1.79-2.05(m,4H),1.25-1.34(m,6H),1.05(s,9H)。步骤C：(2R)-2-(((叔丁基二苯基甲硅烷基)氧基)甲基)-1-(N-甲基丙烷-2-基磺酰亚胺基)吡咯烷
Figure PCTCN2021072666-appb-000055
将(2R)-2-(((叔丁基二苯基甲硅烷基)氧基)甲基)-1-(丙基-2-基磺酰亚胺基)吡 咯烷(1.0g)加入干燥的四氢呋喃(20mL)中，冷却至0℃，向反应液中分批加入氢化钠(180mg)，0℃下搅拌30分钟，滴加碘甲烷(480mg)，完毕后升至室温搅拌过夜，用水淬灭反应，并用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到产品(1.0g)。
1H NMR(400MHz,CDCl 3)δ7.61-7.66(m,4H),7.34-7.43(m,6H),4.01-4.07(m,0.5H),3.75-3.84(m,1H),3.68-3.71(m,0.5H),3.53-3.59(m,1H),3.35-3.41(m,0.5H),3.16-3.30(m,2H),3.05-3.12(m,0.5H),2.62(s,1.5H),2.60(s,1.5H),1.80-2.11(m,4H),1.20-1.37(m,6H),1.05(s,4.5H),1.04(s,4.5H)。
步骤D：((2R)-1-(N-甲基丙烷-2-基磺酰亚胺基)吡咯烷-2-基)甲醇
Figure PCTCN2021072666-appb-000056
将(2R)-2-(((叔丁基二苯基甲硅烷基)氧基)甲基)-1-(N-甲基丙烷-2-基磺酰亚胺基)吡咯烷(1.0g)溶于四氢呋喃(20mL)中，向此溶液中加入四丁基氟化铵三水化合物(900mg)，升至40℃搅拌2小时，蒸干溶剂，所得残留物经过硅胶柱层析(甲醇:乙酸乙酯1/40)纯化得到产品(450mg)。
1H NMR(400MHz,CDCl 3)δ3.97-4.42(brs,1H),3.86-3.93(m,1H),3.34-3.60(m,4H),3.20-3.31(m,1H),2.72(s,1.5H),2.70(s,1.5H),2.04-2.14(m,1H),1.78-1.98(m,2H),1.60-1.69(m,1H),1.39(d,J＝6.8Hz,3H),1.29(d,J＝6.8Hz,3H)。
步骤E：((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-1-(N-甲基丙烷-2-基磺酰亚胺基)吡咯烷-2-基)甲氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000057
氮气保护下，将2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(100mg)和三乙胺(60mg)加入干燥的二氯甲烷(10mL)中，冷却至-60℃，向反应液中滴加二三氯甲基碳酸酯(31mg)的二氯甲烷(5mL)溶液，完毕后-60℃下搅拌1小时，-60℃下将((2R)-1-(N-甲基丙烷-2-基磺酰亚胺基)吡咯烷-2-基)甲醇(60mg)的二氯甲烷(3mL)溶液滴加至上述溶液中，-60℃下搅拌1小时，用水淬灭反应，并用二氯甲烷萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶制备版(1:50甲醇/二氯甲烷)纯化得到产品(68mg)。
1H NMR(400MHz,CDCl 3)δ7.57(d,J＝7.2Hz,1H),7.43-7.45(m,2H),7.27(t,J＝7.6Hz,1H),7.21(t,J＝7.2Hz,1H),4.94(d,J＝5.6Hz,1H),4.28(d,J＝7.2Hz,1H),4.02-4.18(m,3H),3.50-3.54(m,1H),3.35-3.41(m,1H),3.08-3.32(m,3H),2.96(dd,J＝14.8Hz,6.8Hz,1H),2.65-2.67(m,3H),2.27-2.34(m,1H),2.07-2.14(m,1H),1.78-2.05(m,7H),1.23-1.41(m,9H),1.19(s,3H),1.04(d,J＝10.8Hz,1H),0.79(s,3H)。
步骤F：((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-1-(N-甲基丙烷-2-基磺酰亚胺基)吡咯烷-2-基)甲氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000058
将((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-1-(N-甲基丙烷-2-基磺酰亚胺基)吡咯烷-2-基)甲氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(68mg)溶于甲醇(5mL)中，向此溶液中加入异丁基硼酸(35mg)、1mol/L盐酸(0.5mL)和正己烷(5mL)，室温搅拌过夜，分液去除上层正己烷，甲醇相用正己烷洗涤，减压浓缩，残留物用二氯甲烷稀释并用2mol/L氢氧化钠水溶液(5mL)萃取，萃取液用二氯甲烷洗涤，用3mol/L盐酸酸化至pH值3-4，用二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到产品(45mg)。
1H NMR(400MHz,CD 3OD)δ7.59(d,J＝7.6Hz,1H),7.53(s,1H),7.41(d,J＝7.6Hz,1H),7.19-7.27(m,2H),4.32-4.38(m,0.5H),3.95-4.19(m,3.5H),3.32-3.48(m,3H),2.75-2.97(m,5H),1.95-2.22(m,4H),1.46-1.51(m,3H),1.39-1.43(m,3H)。
实施例8
((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-1-(N-甲基环己烷磺酰亚胺基)吡咯烷-2-基)甲氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000059
步骤A：N-三苯甲基环己烷亚磺酰胺
Figure PCTCN2021072666-appb-000060
氮气保护下，将N-亚磺酰基三苯甲胺(15g)溶于无水四氢呋喃(200mL)中，冷却至0℃，向反应液中滴加1mol/L的环己基溴化镁的四氢呋喃溶液(50mL)，完毕后升至40℃搅拌12小时，用饱和氯化铵水溶液淬灭反应，并用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用甲基叔丁基醚打浆，抽滤得到固体产品(5.2g)。
1H NMR(400MHz,CDCl 3)δ7.22-7.32(m,15H),4.70(s,1H),2.45-2.53(m,1H),1.22-1.90(m,10H)。
步骤B：(2R)-2-(((叔丁基二苯基甲硅烷基)氧基)甲基)-1-(环己烷磺酰亚胺基)吡咯烷
Figure PCTCN2021072666-appb-000061
氮气保护下，将N-三苯甲基环己烷亚磺酰胺(2g)加入干燥的二氯甲烷(50mL)中，冷却至0℃，向反应液中滴加次氯酸叔丁酯(554mg)，0℃下搅拌1小时，随后将该反应液逐滴加入至(R)-2-(((叔丁基苯甲基甲硅烷基)氧)甲基)吡咯烷(692mg)和三乙胺(1g)的二氯甲烷(10mL)溶液中，升至40℃搅拌过夜，加入对甲苯磺酸一水化合物(4.0g)，室温搅拌30分钟，加入1mol/L氢氧化钠水溶液调节pH至9-10，并用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶柱层析(石油醚/乙酸乙酯2/1)纯化得到产品(1.1g)。
1H NMR(400MHz,CDCl 3)δ7.63-7.71(m,4H),7.36-7.48(m,6H),4.30-4.39(brs,0.5H),3.95-4.06(m,1H),3.76-3.79(m,0.5H),3.37-3.65(m,2.7H),3.22-3.31(m,1H),2.87-3.01(m,1.3H),1.15-2.28(m,14H),1.07(s,9H)。
步骤C：(2R)-2-(((叔丁基二苯基甲硅烷基)氧基)甲基)-1-(N-甲基环己烷磺酰亚胺基)吡咯烷
Figure PCTCN2021072666-appb-000062
将(2R)-2-(((叔丁基二苯基甲硅烷基)氧基)甲基)-1-(环己烷磺酰亚胺基)吡咯烷(1.0g)加入干燥的四氢呋喃(30mL)中，冷却至0℃，向反应液中分批加入60％氢化钠(173mg)，0℃下搅拌30分钟，滴加碘甲烷(460mg)，完毕后升至室温搅拌过夜，用水淬灭反应，并用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到产品(0.98g)。
1H NMR(400MHz,CDCl 3)δ7.61-7.65(m,4H),7.34-7.43(m,6H),4.01-4.06(m,0.5H),3.75-3.84(m,1H),3.66-3.69(m,0.5H),3.53-3.58(m,1H),3.33-3.39(m,0.5H),3.15-3.26(m,1.5H),2.80-3.04(m,1H),2.61(s,1.5H),2.59(s,1.5H),1.10-2.28(m,14H),1.05(s,4.5H),1.04(s,4.5H)。
步骤D：((2R)-1-(N-甲基环己烷磺酰亚胺基)吡咯烷-2-基)甲醇
Figure PCTCN2021072666-appb-000063
将(2R)-2-(((叔丁基二苯基甲硅烷基)氧基)甲基)-1-(N-甲基环己烷磺酰亚胺基)吡咯烷(1.0g)溶于四氢呋喃(30mL)中，向此溶液中加入四丁基氟化铵三水化合物(900mg)，升至40℃搅拌2小时，蒸干溶剂，所得残留物经过硅胶柱层析(甲醇:乙酸乙酯1/40)纯化得到产品(450mg)。
1H NMR(400MHz,CDCl 3)δ3.98-4.50(brs,1H),3.86-3.94(m,1H),3.44-3.61(m,2.5H),3.35-3.41(m,0.5H),3.21-3.31(m,1H),3.06-3.16(m,1H),2.72(s,1.5H),2.71(s,1.5H),2.17-2.27(m,1H),2.06-2.15(m,1H),1.82-2.02(m,5H),1.49-1.68(m,4H),1.14-1.32(m,3H)。
步骤E：((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-1-(N-甲基环己烷磺酰亚胺基)吡咯烷-2-基)甲氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000064
氮气保护下，将2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(120mg)和三乙胺(120mg)加入干燥的二氯甲烷(10mL)中，冷却至-60℃，向反应液中滴加二三氯甲基碳酸酯(38mg)的二氯甲烷(3mL)溶液，完毕后-60℃下搅拌1小时，-60℃下将((2R)-1-(N-甲基环己烷磺酰亚胺基)吡咯烷-2-基)甲醇(83mg)的二氯甲烷(3mL)溶液滴加至上述溶液中，-60℃下搅拌1小时，用水淬灭反应，并用二氯甲烷萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶制备版(1:50甲醇/二氯甲烷)纯化得到产品(80mg)。
1H NMR(400MHz,CDCl 3)δ7.57(d,J＝7.2Hz,1H),7.42-7.46(m,2H),7.27(t,J＝7.2Hz,1H),7.21(t,J＝7.2Hz,1H),4.95(d,J＝5.6Hz,1H),4.27(d,J＝8.4Hz,1H),3.86-4.18(m,3H),3.48-3.56(m,1H),2.85-3.38(m,5H),2.66(s,2H),2.65(s,1H),1.76-2.34(m,14H),1.44-1.66(m,2H),1.02-1.34(m,10H),0.79(s,3H)。
步骤F：((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-1-(N-甲基环己烷磺酰亚胺基)吡咯烷-2-基)甲氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000065
将((1R)-2-(苯并呋喃-3-基)-1-(((((2R)-1-(N-甲基环己烷磺酰亚胺基)吡咯烷-2-基)甲氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(80mg)溶于甲醇(5mL)中，向此溶液中加入异丁基硼酸(40mg)、1mol/L盐酸(0.5mL)和正己烷(5mL)，室温搅拌过夜，分液去除上层正己烷，甲醇相用正己烷洗涤，减压浓缩，残留物用二氯甲烷稀释并用2mol/L氢氧化钠水溶液(5mL)萃取，萃取液用二氯甲烷洗涤，用3mol/L盐酸酸化至pH为3-4，用二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到产品(45mg)。
1H NMR(400MHz,CD 3OD)δ7.59(d,J＝7.6Hz,1H),7.53(s,1H),7.41(d,J＝8.0Hz,1H),7.19-7.28(m,2H),3.80-4.39(m,5H),3.32-3.52(m,2H),2.82-2.98(m,2H),2.81(s,2H),2.76(s,1H),1.86-2.24(m,8H),1.53-1.78(m,2H),1.11-1.48(m,4H)。
实施例9
(R)-2-(苯并呋喃-3-基)-1-(2-(2-二甲基亚磺酰亚胺基)乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000066
步骤A：2-(2-二甲基亚磺酰亚胺基)乙酸甲酯
Figure PCTCN2021072666-appb-000067
将2-溴苯乙酸甲酯(1g)溶于1,4-二氧六环(20mL)中，依次加入三(二亚苄基丙酮)二钯(200mg)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(380mg)、碳酸铯(2.13g)和亚氨基二甲基亚砜(490mg)，氮气鼓泡，110℃微波加热2小时，冷却至室温后加入水中并用二氯甲烷萃取，有机相经无水硫酸钠干燥后蒸干溶剂，残留物经硅胶制备板(1:30甲醇/二氯甲烷)纯化得产品(800mg)。
1H NMR(400MHz,CDCl 3)δ7.21(d,J＝8.0Hz,1H),7.12-7.18(m,2H),6.94(td,J＝7.2Hz,1.2Hz,1H),3.65(s,3H),3.62(s,2H),3.09(s,6H)。
步骤B：2-(2-二甲基亚磺酰亚胺基)乙酸
Figure PCTCN2021072666-appb-000068
将2-(2-二甲基亚磺酰亚胺基)乙酸甲酯(800mg)溶于甲醇(5mL)和水(2mL)的混合溶剂中，加入氢氧化钠(160mg)，升至70℃搅拌4小时，降至室温，用1mol/L稀盐酸调节pH至5-6，直接蒸干溶剂，残留物真空干燥，用1:10甲醇/二氯甲烷打浆，过滤，滤液减压浓缩，得到产品(756mg)。
1H NMR(400MHz,CDCl 3)δ7.14-7.25(m,3H),6.97(t,J＝7.6Hz,1H),3.65(s,2H),3.17(s,6H)。
步骤C：(R)-2-(苯并呋喃-3-基)-1-(2-(2-二甲基亚磺酰亚胺基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000069
将2-(2-二甲基亚磺酰亚胺基)乙酸(756mg)、2-(苯并呋喃-3-基)-1-(R)-(3-乙酰基苯磺酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(1.75g)溶于N,N-二甲基甲酰胺(5mL)中，依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.519g)和4-二甲氨基吡啶(620mg)，室温搅拌过夜。加入水，用二氯甲烷萃取，萃取液用水洗涤，减压浓缩，残留物经硅胶制备板(1:30甲醇/二氯甲烷)纯化得产品(640mg)。
1H NMR(400MHz,CDCl 3)δ7.46(d,J＝7.2Hz,1H),7.40(d,J＝8.0Hz,1H),7.23-7.27(m,1H),7.21(s,1H),7.12-7.18(m,4H),6.88-6.92(m,1H),4.22(dd,J＝8.8Hz,2.0Hz,1H),3.60(s,2H),2.92-2.96(m,4H),2.87-2.90(m,4H),2.73(dd,J＝15.2Hz,11.2Hz,1H),2.28-2.36(m,1H),2.10-2.17(m,1H),1.96-1.99(m,1H),1.80-1.89(m,2H),1.44(d,J＝10.0Hz,1H),1.35(s,3H),1.26(s,3H),0.85(s,3H)。
步骤D：(R)-2-(苯并呋喃-3-基)-1-(2-(2-二甲基亚磺酰亚胺基)乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000070
将(R)-2-(苯并呋喃-3-基)-1-(2-(2-二甲基亚磺酰亚胺基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(434mg)溶于甲醇(5mL)和正己烷(5mL)的混合溶剂中，加入异丁基硼酸(485mg)，1mol/L稀盐酸(0.25mL)，室温搅拌过夜。正己烷洗涤，收集甲醇相，减压浓缩，残留物经硅胶制备板(1:4甲醇/二氯甲烷)纯化得产品(120mg)。
1H NMR(400MHz,CD 3OD)δ7.55(d,J＝8.0Hz,1H),7.53(s,1H),7.42(d,J＝8.0Hz,1H),7.25(t,J＝7.6Hz,1H),7.13-7.21(m,4H),6.89-6.93(m,1H),3.66-3.75(m,2H),3.14(s,3H),3.11(s,3H),2.85-2.96(m,2H),2.69(dd,J＝14.8Hz,9.6Hz,1H)。
实施例10
(R)-(2-(苯并呋喃-3-基)-1-(2-(4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基)硼酸
Figure PCTCN2021072666-appb-000071
步骤A：2-(3-二甲基亚磺酰亚胺基苯基)乙酸乙酯
Figure PCTCN2021072666-appb-000072
氮气保护下，将4-溴苯乙酸乙酯(460mg)溶于1,4-二氧六环(10mL)中，依次加入三(二亚苄基丙酮)二钯(185mg)、碳酸铯(2.00g)和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(230mg)，升温至105℃搅拌过夜。降至室温，加入水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶制备板(1:10甲醇/二氯甲烷)纯化得到产品(210mg)。
1H NMR(400MHz,CDCl 3)δ7.1-7.12(m,2H),6.98-7.00(m,2H),4.10(q,J＝7.20Hz,2H),3.51(s,2H),3.10(s,6H),1.21(d,J＝7.20Hz,3H)。
步骤B：2-(3-二甲基亚磺酰亚胺基苯基)乙酸
Figure PCTCN2021072666-appb-000073
将2-(3-二甲基亚磺酰亚胺基苯基)乙酸乙酯(210mg)溶于甲醇(2mL)中，加入1mol/L的NaOH水溶液(1mL)，室温下搅拌过夜。反应液经1mol/L盐酸酸化至pH值3-4，反应液直接浓缩至干，残留物用二氯甲烷淋洗，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗产品直接用于下一步反应。
步骤C：(R)-(2-(苯并呋喃-3-基)-1-(2-(4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000074
将2-(4-二甲基亚磺酰亚胺基苯基)乙酸(100mg)、2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(190mg)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(250mg)、N,N-二异丙基乙胺(130mg)和4-二甲基氨基吡啶(60mg)加入干燥的二氯甲烷(20mL)中，室温搅拌过夜。用水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶制备板(20:1甲醇/二氯甲烷)纯化得到产品(105mg)。
1H NMR(400MHz,CDCl 3)δ7.45(d,J＝7.6Hz,1H),7.38(d,J＝8.0Hz,1H),7.16-7.27(m,3H),6.96-7.01(m,3H),6.12(brs,1H),4.26(d,J＝7.2Hz,1H),3.60(d,J＝16.8Hz,1H),3.20(s,1H),3.07(s,6H),2.91-2.97(m,2H),2.74-2.80(m,1H),2.30-2.35(m,1H),2.07-2.14(m,1H),1.99-2.02(m,1H),1.82-1.91(m,2H),1.59-1.63(m,1H),1.33-1.42(m,2H),1.20-1.29(m,5H),0.85(s,3H)。
步骤D：(R)-(2-(苯并呋喃-3-基)-1-(2-(4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基)硼酸
Figure PCTCN2021072666-appb-000075
将2(R)-2-(苯并呋喃-3-基)-1-(2-(4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(105mg)溶于甲醇(2mL)中，向此溶液中加入异丁基硼酸(100mg)、1mol/L盐酸(0.2mL)和正己烷(2mL)，室温搅拌过夜，分液去除上层正己烷，甲醇相用正己烷洗涤，减压浓缩，得粗产物，加入乙醚打浆，过滤收集固体，固体干燥得到产品(10mg)。
1H NMR(400MHz,CD 3OD)δ7.55(d,J＝4.8Hz,2H),7.41-7.44(m,3H),7.31-7.38(m,2H),7.19-7.26(m,2H),3.78-3.80(m,2H),3.77(s,6H),2.99-3.07(m,1H),2.84-2.92(m,1H),2.68-2.74(m,1H)。
实施例11
(R)-(2-(苯并呋喃-3-基)-1-(2-(3-氯-4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000076
步骤A：2-(4-溴-3-氯苯基)乙腈
Figure PCTCN2021072666-appb-000077
将1-溴-4-(溴甲基)-2-氯苯(2.84g)溶于乙腈(100mL)中，依次加入三甲基硅氰(990mg)和三水和四丁基氟化铵(3.15g)，30℃搅拌过夜，加入水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品(2.9g)。
1H NMR(400MHz,CDCl 3)δ7.61(d,J＝8.0Hz,1H),7.43(d,J＝2.0Hz,1H),7.09(dd,J＝8.0Hz,2.0Hz,1H),3.69(s,2H)。
步骤B：2-(3-氯-4-二甲基亚磺酰亚胺基苯基)乙腈
Figure PCTCN2021072666-appb-000078
氮气保护下，将2-(4-溴-3-氯苯基)乙腈(750mg)溶于1,4-二氧六环(50mL)中，依次加入二甲基亚磺酰亚胺(329mg)、三(二亚苄基丙酮)二钯(146mg)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(278mg)和碳酸铯(2.1g)，升温至110℃搅拌过夜。降至室温加入水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶制备板(1:60甲醇/二氯甲烷)纯化得到产品(150mg)。
1H NMR(400MHz,CDCl 3)δ7.34(d,J＝2.4Hz,1H),7.27(d,J＝8.0Hz,1H),7.07(dd,J＝8.0Hz,2.4Hz,1H),3.65(s,2H),3.16(s,6H)。
步骤C：2-(3-氯-4-二甲基亚磺酰亚胺基苯基)乙酸
Figure PCTCN2021072666-appb-000079
将2-(3-氯-4-二甲基亚磺酰亚胺基苯基)乙腈(150mg)溶于乙醇(5mL)中，8mol/L氢氧化钠水溶液(1mL)，升温至80℃搅拌2小时。降至室温，加入水稀释，用1mol/L盐酸调pH至4-5，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，得到产品(130mg)。
1H NMR(400MHz,CDCl 3)δ7.29(d,J＝2.4Hz,1H),7.22(d,J＝8.0Hz,1H),7.03(dd,J＝8.0Hz,2.0Hz,1H),3.55(s,2H),3.16(s,6H)。
步骤D：(R)-2-(苯并呋喃-3-基)-1-(2-(3-氯-4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000080
将2-(3-氯-4-二甲基亚磺酰亚胺基苯基)乙酸(131mg)、2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(226mg)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(228mg)和4-二甲基氨基吡啶(74mg)加入干燥的二氯甲烷(5mL)中，完毕后室温搅拌过夜，用水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶制备板(20:1甲醇/二氯甲烷)纯化得到产品(160mg)。
1H NMR(400MHz,CDCl 3)δ7.47(d,J＝7.6Hz,1H),7.39(d,J＝8.4Hz,1H),7.28(s,1H),7.15-7.25(m,4H),6.88(dd,J＝8.0Hz,2.0Hz,1H),6.19-6.23(brs,1H),4.26(dd,J＝8.8Hz,1.6Hz,1H),3.47-3.56(m,2H),3.14(s,6H),3.03-3.07(m,1H),2.93-2.99(m,1H),2.80-2.85(m,1H),2.29-2.36(m,1H),2.11-2.17(m,1H),1.98-2.01(m,1H),1.80-1.89(m,2H),1.35-1.38(m,4H),1.26(s,3H),0.84(s,3H)。
步骤E：(R)-(2-(苯并呋喃-3-基)-1-(2-(3-氯-4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000081
将(R)-2-(苯并呋喃-3-基)-1-(2-(3-氯-4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(160mg)溶于甲醇(5mL)中，向此溶液中加入异丁基硼酸(137mg)、1mol/L盐酸(0.2mL)和正己烷(5mL)，室温搅拌过夜，分液去除上层正己烷，甲醇相用正己烷洗涤，减压浓缩，残留物经过硅胶制备板(1:10甲醇/二氯甲烷)纯化得到产品(50mg)。
1H NMR(400MHz,CD 3OD),7.53-7.55(m,2H),7.42(d,J＝7.6Hz,1H),7.33(d,J＝2.4Hz,1H),7.26(td,J＝7.6Hz,1.2Hz,1H),7.18-7.23(m,2H),7.05(dd,J＝8.4Hz,2.4Hz,1H),3.62(s,2H),3.20(s,6H),2.97(dd,J＝10.0Hz,5.2Hz,1H),2.85-2.90(m,1H),2.68(dd,J＝15.2Hz,10.0Hz,1H)。
实施例12
(R)-(2-(苯并呋喃-3-基)-1-(2-(3-氟-4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000082
步骤A：2-(4-溴-3-氟苯基)乙腈
Figure PCTCN2021072666-appb-000083
将1-溴-4-(溴甲基)-2-氟苯(2.84g)溶于乙腈(100mL)中，依次加入三甲基硅氰(990mg)和三水和四丁基氟化铵(3.15g)，30℃搅拌过夜，加入水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品(3.03g)直接用于下一部分反应。
1H NMR(400MHz,CDCl 3)δ7.56(t,J＝8.0Hz,1H),7.12(dd,J＝8.8Hz,2.0Hz,1H),7.02(d,J＝8.0Hz,1H),3.72(s,2H)。
步骤B：2-(3-氟-4-二甲基亚磺酰亚胺基苯基)乙腈
Figure PCTCN2021072666-appb-000084
氮气保护下，将2-(4-溴-3-氟苯基)乙腈(750mg)溶于1,4-二氧六环(50mL)中，依次加入二甲基亚磺酰亚胺(329mg)、三(二亚苄基丙酮)二钯(146mg)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(278mg)和碳酸铯(2.1g)，升温至110℃搅拌过夜。降至室温，加入水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶制备板(1:60甲醇/二氯甲烷)纯化得到产品(150mg)。
1H NMR(400MHz,CDCl 3)δ7.22(t,J＝8.0Hz,1H),7.03(dd,J＝10.8Hz,2.0Hz,1H),6.95(d,J＝8.0Hz,1H),3.67(s,2H),3.18(s,6H)。
步骤C：2-(3-氟-4-二甲基亚磺酰亚胺基苯基)乙酸
Figure PCTCN2021072666-appb-000085
将2-(3-氟-4-二甲基亚磺酰亚胺基苯基)乙腈(150mg)溶于乙醇(5mL)中，3mol/L氢氧化钠水溶液(1mL)，升温至80℃搅拌2小时。降至室温，加入水稀释，用1mol/L盐酸调pH至4-5，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，得到产品(130mg)。
1H NMR(400MHz,CDCl 3)δ7.16(t,J＝8.4Hz,1H),7.01(dd,J＝11.2Hz,1.6Hz,1H),6.91(d,J＝8.0Hz,1H),3.57(s,2H),3.18(s,6H)。
步骤D：(R)-2-(苯并呋喃-3-基)-1-(2-(3-氟-4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000086
将2-(3-氟-4-二甲基亚磺酰亚胺基苯基)乙酸(131mg)、2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(226mg)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(228mg)和4-二甲基氨基吡啶(74mg)加入干燥的二氯甲烷(10mL)中，完毕后室温搅拌过夜，用水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶制备板(20:1甲醇/二氯甲烷)纯化得到产品(160mg)。
1H NMR(400MHz,CDCl 3)δ7.46(d,J＝7.2Hz,1H),7.38(d,J＝8.0Hz,1H),7.28(s,1H),7.22-7.24(m,1H),7.15-7.19(m,1H),6.86(d,J＝11.6Hz,1H),6.75(d,J＝8.0Hz,1H),6.39(brs,1H),4.25(d,J＝7.2Hz,1H),3.50(d,J＝4.0Hz,2H),3.13(s,6H),3.03-3.07(m,1H),2.93-2.98(m,1H),2.80-2.85(m,1H),2.28-2.34(m,1H),2.09-2.15(m,1H),1.97-1.99(m,1H),1.79-1.89(m,2H),1.34-1.36(m,4H),1.26(s,3H),0.83(s,3H)。
步骤E：(R)-(2-(苯并呋喃-3-基)-1-(2-(3-氟-4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000087
将(R)-2-(苯并呋喃-3-基)-1-(2-(3-氟-4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(160mg)溶于甲醇(5mL)中，向此溶液中加入异丁基硼酸(137mg)1mol/L盐酸(0.2mL)和正己烷(5mL)，室温搅拌过夜，分液去除上层正己烷，甲醇相用正己烷洗涤，减压浓缩，残留物经过硅胶制备板(1:10甲醇/二氯甲烷)纯化得到产品(50mg)。
1H NMR(400MHz,CD 3OD)δ7.56-7.59(m,2H),7.42-7.46(m,2H),7.18-7.30(m,4H),3.84(s,2H),3.79(s,6H),3.07-3.11(m,1H),2.90-2.94(m,1H),2.79-2.89(m,1H)。
实施例13
(R)-(2-(苯并呋喃-3-基)-1-(2-(3-甲氧基-4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000088
步骤A：(4-溴-3-甲氧基苯基)甲醇
Figure PCTCN2021072666-appb-000089
将(3-甲氧基苯基)甲醇(13.8g)溶于四氢呋喃(150mL)中，加入N-溴代丁二酰亚胺(17.8g)，室温搅拌过夜，加入水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品(20.1g)。
1H NMR(400MHz,CDCl 3)δ7.38(d,J＝8.4Hz,1H),7.03(d,J＝2.8Hz,1H),6.78(dd,J＝8.8Hz,3.2Hz,1H),4.66(s,2H),3.77(s,3H)。
步骤B：1-溴-4-(溴甲基)-2-甲氧基苯
Figure PCTCN2021072666-appb-000090
将(4-溴-3-甲氧基苯基)甲醇(2.17g)溶于四氢呋喃(100mL)中，加入三溴化磷(813mg)，室温搅拌过夜，加入水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品(2.98g)。
1H NMR(400MHz,CDCl 3)δ7.43(d,J＝8.4Hz,1H),6.97(d,J＝3.2Hz,1H),6.72(dd,J＝8.4Hz,3.2Hz,1H),4.54(s,2H),3.78(s,3H)。
步骤C：2-(4-溴-3-甲氧基苯基)乙腈
Figure PCTCN2021072666-appb-000091
参照实施例10中步骤A的方法以1-溴-4-(溴甲基)-2-甲氧基苯(1.5g)为原料得到产品(1.05g)。
1H NMR(400MHz,CDCl 3)δ7.45(d,J＝8.4Hz,1H),7.05(d,J＝3.2Hz,1H),6.75(dd,J＝8.4Hz,3.2Hz,1H),3.80(s,3H),3.78(s,2H)。
步骤D：2-(3-甲氧基-4-二甲基亚磺酰亚胺基苯基)乙腈
Figure PCTCN2021072666-appb-000092
氮气保护下，将2-(4-溴-3-甲氧基苯基)乙腈(520mg)溶于1,4-二氧六环(15mL)中，依次加入二甲基亚磺酰亚胺(319mg)、三(二亚苄基丙酮)二钯(92mg)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(197mg)和碳酸铯(1.5g)，微波反应器升 温至110℃反应2小时。降至室温，加入水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶制备板(1:50甲醇/二氯甲烷)纯化得到产品(210mg)。
1H NMR(400MHz,CDCl 3)δ7.17(d,J＝8.8Hz,1H),6.79(d,J＝2.8Hz,1H),6.75(dd,J＝8.4Hz,3.2Hz,1H),3.75(s,3H),3.60(s,2H),3.15(s,6H)。
步骤E：2-(3-甲氧基-4-二甲基亚磺酰亚胺基苯基)乙酸
Figure PCTCN2021072666-appb-000093
参照实施例10中步骤C的方法以2-(3-甲氧基-4-二甲基亚磺酰亚胺基苯基)乙腈(210mg)为原料得到产品(170mg)。
1H NMR(400MHz,CDCl 3)δ9.55-13.01(brs,1H),7.16(d,J＝8.4Hz,1H),6.79(d,J＝3.2Hz,1H),6.73(dd,J＝8.4Hz,3.2Hz,1H),3.75(s,3H),3.64(s,2H),3.18(s,6H)。
步骤F：(R)-2-(苯并呋喃-3-基)-1-(2-(3-甲氧基-4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000094
参照实施例10步骤D的方法以2-(3-甲氧基-4-二甲基亚磺酰亚胺基苯基)乙酸(170mg)和2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(230mg)为原料得到产品(180mg)。
1H NMR(400MHz,CDCl 3)δ7.47(d,J＝8.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.35-7.39(brs,1H),7.21-7.26(m,2H),7.16(t,J＝7.6Hz,1H),7.06(d,J＝8.4Hz,1H),6.69-6.73(m,2H),4.21-4.24(m,1H),3.72(s,3H),3.57(s,2H),2.95-3.01(m,1H),2.87-2.91(m,4H),2.82(s,3H),2.71-2.77(m,1H),2.29-2.35(m,1H),2.10-2.15(m,1H),1.97(t,J＝5.6Hz,1H),1.79-1.88(m,2H),1.43(d,J＝10.0Hz,1H),1.35(s,3H),1.26(s,3H),0.85(s,3H)。
步骤G：(R)-(2-(苯并呋喃-3-基)-1-(2-(3-甲氧基-4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000095
参照实施例10中步骤E的方法以(R)-2-(苯并呋喃-3-基)-1-(2-(3-甲氧基-4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(180mg)为原料得到产品(32mg)。
1H NMR(400MHz,CD 3OD)δ7.53-7.56(m,2H),7.41(d,J＝7.6Hz,1H),7.25(td,J＝8.0Hz,1.2Hz,1H),7.19(td,J＝7.6Hz,1.2Hz,1H),7.09(d,J＝8.8Hz,1H),6.81(d,J＝2.8Hz,1H),6.75(dd,J＝8.8Hz,2.8Hz,1H),3.72(s,3H),3.70(s,2H),3.09(s,3H),3.07(s,3H),2.95(dd,J＝9.6Hz,4.8Hz,1H),2.84-2.90(m,1H),2.70(dd,J＝14.8Hz,9.6Hz,1H)。
实施例14
(R)-(2-(苯并呋喃-3-基)-1-(2-(2-氯-4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000096
步骤A：2-(4-溴-2-氯苯基)乙酸甲酯
Figure PCTCN2021072666-appb-000097
将2-(4-溴-2-氯苯基)乙酸(420mg)溶于甲醇(10mL)中，加入氯化亚砜(0.2mL)，加热至60℃搅拌过夜，蒸干溶剂，得到粗产品(430mg)。
1H NMR(400MHz,CDCl 3)δ7.54(d,J＝2.0Hz,1H),7.35(dd,J＝8.0Hz,2.0Hz,1H),7.15(d,J＝8.0Hz,1H),3.72(s,2H),3.70(s,3H)。
步骤B：2-(2-氯-4-二甲基亚磺酰亚胺基苯基)乙酸甲酯
Figure PCTCN2021072666-appb-000098
参照实施例10中步骤B的方法以2-(2-氯-4-二甲基亚磺酰亚胺基苯基)乙酸甲酯(430mg)和亚氨基二甲基-λ 6-砜(190mg)为原料得到产品(250mg)。
1H NMR(400MHz,CDCl 3)δ7.10-7.12(m,2H),6.92(dd,J＝8.0Hz,2.0Hz,1H),3.69(s,3H),3.68(s,2H),3.14(s,6H)。
步骤C：2-(2-氯-4-二甲基亚磺酰亚胺基苯基)乙酸
Figure PCTCN2021072666-appb-000099
将2-(2-氯-4-二甲基亚磺酰亚胺基苯基)乙酸甲酯(250mg)溶于1,4-二氧六环(10mL)，加入1mol/L的氢氧化锂水溶液(5mL)，室温搅拌2小时，用1mol/L盐酸调pH至4-5，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸 钠干燥，过滤，滤液减压浓缩，得到产品(220mg)。
1H NMR(400MHz,DMSO-d 6)δ12.10-12.54(brs,1H),7.14(d,J＝8.0Hz,1H),6.91(d,J＝2.4Hz,1H),6.80(dd,J＝8.0Hz,2.4Hz,1H),3.55(s,2H),3.20(s,6H)。
步骤D：(R)-2-(苯并呋喃-3-基)-1-(2-(2-氯-4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000100
参照实施例10中步骤D的方法以2-(2-氯-4-二甲基亚磺酰亚胺基苯基)乙酸(220mg)和2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(210mg)为原料得到产品(307mg)。
1H NMR(400MHz,CDCl 3)δ7.48(d,J＝7.2Hz,1H),7.37(d,J＝8.0Hz,1H),7.22-7.27(m,2H),7.18(td,J＝7.6Hz,0.8Hz,1H),7.08(d,J＝2.4Hz,1H),7.04(d,J＝8.4Hz,1H),6.88(dd,J＝8.0Hz,2.4Hz,1H),6.22(s,1H),4.25(dd,J＝9.6Hz,1.6Hz,1H),3.71(d,J＝16.8Hz,1H),3.64(d,J＝16.8Hz,1H),3.13(s,6H),2.94-3.02(m,2H),2.75-2.81(m,1H),2.29-2.35(m,1H),2.11-2.16(m,1H),1.98-2.01(m,1H),1.80-1.89(m,2H),1.36-1.39(m,4H),1.26(s,3H),0.84(s,3H)。
步骤G：(R)-(2-(苯并呋喃-3-基)-1-(2-(3-甲氧基-4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000101
参照实施例10中步骤E的方法以(R)-2-(苯并呋喃-3-基)-1-(2-(2-氯-4-二甲基亚磺酰亚胺基苯基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(280mg)为原料得到产品(30mg)。
1H NMR(400MHz,CD 3OD)δ7.56(d,J＝7.2Hz,1H),7.54(s,1H),7.41(d,J＝8.0Hz,1H),7.25(td,J＝8.0Hz,1.2Hz,1H),7.17-7.22(m,2H),7.08(d,J＝2.4Hz,1H),6.95(dd,J＝8.0Hz,2.0Hz,1H),3.75-3.83(m,2H),3.20(s,6H),2.97(dd,J＝9.2Hz,5.6Hz,1H),2.88(dd,J＝14.8Hz,6.0Hz,1H),2.71(dd,J＝14.8Hz,9.2Hz,1H)。
实施例15
(R)-(2-(苯并呋喃-3-基)-1-(2-(3-(二甲基亚磺酰亚胺基)-5-甲氧基苯基)乙酰胺基)乙基)硼酸
Figure PCTCN2021072666-appb-000102
步骤A：2-(3-溴-5-甲氧基苯基)乙腈
Figure PCTCN2021072666-appb-000103
将1-溴-3-(溴甲基)-5-甲氧基苯(1.0g)溶于干燥的乙腈(10mL)中，依次加入三甲基氰硅烷(380mg)和四丁基氟化铵三水合物(0.98g)，加热至35℃搅拌过夜，加入水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶柱层析(1:10乙酸乙酯/石油醚)纯化得到产品(450mg)。
1H NMR(400MHz,CDCl 3)δ7.04(s,1H),7.00(s,1H),6.79(s,1H),3.79(s,3H),3.68(s,2H)。
步骤B：2-(3-二甲基亚磺酰亚胺基-5-甲氧基苯基)乙腈
Figure PCTCN2021072666-appb-000104
氮气保护下，将2-(3-溴-5-甲氧基苯基)乙腈(400mg)溶于1,4-二氧六环(10mL)中，依次加入亚氨基二甲基-λ 6-砜(280mg)、三(二亚苄基丙酮)二钯(91mg)、碳酸铯(1.30g)和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(174mg)，升温至105℃搅拌过夜。降至室温，加入水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶制备板(1:10甲醇/二氯甲烷)纯化得到产品(200mg)。
1H NMR(400MHz,CDCl 3)δ6.60(s,1H),6.56(t,J＝2.0Hz,1H),6.50(s,1H),3.76(s,3H),3.62(s,2H),3.13(s,6H)。
步骤C：2-(3-二甲基亚磺酰亚胺基-5-甲氧基苯基)乙酸
Figure PCTCN2021072666-appb-000105
将2-(3-二甲基亚磺酰亚胺基-5-甲氧基苯基)乙腈(200mg)溶于甲醇(2mL)中，加入1mol/L的NaOH水溶液(1mL)，室温下搅拌过夜。反应液经1mol/L盐酸酸化至pH值3-4，反应液直接浓缩至干，残留物用二氯甲烷洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗产品直接用于下一步反应。
1H NMR(400MHz,CDCl 3)δ6.61(s,1H),6.54(t,J＝2.0Hz,1H),6.48(s,1H),3.52(s,2H),3.46(s,3H),3.13(s,6H)。
步骤D：(R)-(2-(苯并呋喃-3-基)-1-(2-(3-二甲基亚磺酰亚胺基-5-甲氧基苯基)乙酰胺基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000106
将2-(3-二甲基亚磺酰亚胺基-5-甲氧基苯基)乙酸(120mg)、2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(210mg)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(310mg)、N,N-二异丙基乙胺(183mg)和4-二甲基氨基吡啶(82mg)加入干燥的二氯甲烷(20mL)中，室温搅拌过夜。用水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶制备板(20:1甲醇/二氯甲烷)纯化得到产品(128mg)。
1H NMR(400MHz,CDCl 3)δ7.44(d,J＝8.0Hz,1H),7.39(d,J＝8.0Hz,1H),7.19-7.24(m,2H),7.15-7.18(m,2H),6.53(t,J＝2.0Hz,1H),6.45(s,1H),6.31(s,1H),6.22(brs,1H),4.25(d,J＝6.8Hz,1H),3.71(s,3H),3.60(d,J＝16.8Hz,1H),3.09(s,6H),2.94-2.99(m,2H),2.73-2.80(m,1H),2.30-2.33(m,1H),2.13-2.16(m,1H),2.00(t,J＝5.6Hz,1H),1.81-1.85(m,2H),1.41(t,J＝5.2Hz,1H),1.38(s,3H),1.27(s,3H),0.86(s,3H)。
步骤E：(R)-(2-(苯并呋喃-3-基)-1-(2-(3-(二甲基亚磺酰亚胺基)-5-甲氧基苯基)乙酰胺基)乙基)硼酸
Figure PCTCN2021072666-appb-000107
将(R)-(2-(苯并呋喃-3-基)-1-(2-(3-二甲基亚磺酰亚胺基-5-甲氧基苯基)乙酰胺基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(128mg)溶于甲醇(3mL)中，向此溶液中加入异丁基硼酸(120mg)、1mol/L盐酸(0.2mL)和正己烷(3mL)，室温搅拌过夜，分液去除上层正己烷，甲醇相用正己烷洗涤，减压浓缩，得粗产物，加入乙醚打浆，过滤收集固体，固体干燥得到产品(25mg)。
1H NMR(400MHz,CD 3OD)δ7.53-7.57(m,3H),7.40-7.43(m,1H),7.20-7.28(m,2H),6.66-6.69(m,2H),3.78(s,6H),3.71(s,2H),3.47-3.49(m,2H),3.46(s,3H),3.11(s,1H),2.80-2.90(m,1H),2.69-2.73(m,1H)。
实施例16
(R)-(2-(苯并呋喃-3-基)-1-(4-(2-二甲基亚磺酰亚胺基吡啶)乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000108
步骤A：4-(2-二甲基亚磺酰亚胺基吡啶)乙酸乙酯
Figure PCTCN2021072666-appb-000109
氮气保护下，将4-(2-氯吡啶)乙酸乙酯(600mg)溶于1,4-二氧六环(20mL)中，依次加入亚氨基二甲基-λ 6-砜(336mg)、三(二亚苄基丙酮)二钯(137mg)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(260mg)和碳酸铯(1.9g)，升温至110℃搅拌过夜。降至室温，加入水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶制备板(1:40甲醇/二氯甲烷)纯化得到产品(150mg)。
1H NMR(400MHz,CDCl 3)δ8.12(s,1H),6.62-6.80(m,2H),4.14(q,J＝7.2Hz,2H),3.51(s,2H),3.34(s,6H),1.24(t,J＝7.2Hz,3H)。
步骤B：4-(2-二甲基亚磺酰亚胺基吡啶)乙酸
Figure PCTCN2021072666-appb-000110
将4-(2-二甲基亚磺酰亚胺基吡啶)乙酸乙酯(150mg)溶于乙醇(5mL)中，8mol/L氢氧化钠水溶液(1mL)，升温至80℃搅拌2小时。降至室温，加入水稀释，用1mol/L盐酸调pH为至4-5，减压浓缩，残留物经柱层析分离(1:5甲醇/二氯甲烷)得到产品(100mg)。
1H NMR(400MHz,DMSO-d 6)δ12.42-13.14(brs,1H),8.13(d,J＝6.4Hz,1H),7.31(s,1H),7.11(d,J＝6.4Hz,1H),3.81(s,2H),3.57(s,6H)。
步骤C：(R)-2-(苯并呋喃-3-基)-1-(4-(2-二甲基亚磺酰亚胺基吡啶)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000111
将4-(2-二甲基亚磺酰亚胺基吡啶)乙酸(100mg)、2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(160mg)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(334mg)、4-二甲基氨基吡啶(54mg)和二异丙基乙基胺(114mg)加入干燥的二氯甲烷(15mL)中，完毕后室温搅 拌过夜，用水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶制备板(30:1甲醇/二氯甲烷)纯化得到产品(73mg)。
1H NMR(400MHz,CDCl 3)δ8.04-8.10(m,1H),7.48(d,J＝7.2Hz,1H),7.42(d,J＝8.0Hz,1H),7.31(s,1H),7.26(t,J＝7.6Hz,1H),7.20(t,J＝8.0Hz,1H),6.55-6.61(m,2H),5.98(s,1H),4.28(dd,J＝8.4Hz,2.0Hz,1H),3.50(d,J＝16.0Hz,1H),3.46(d,J＝16.0Hz,1H),3.34(s,6H),3.08-3.16(m,1H),2.98(dd,J＝14.8Hz,4.0Hz,1H),2.84(dd,J＝15.2Hz,10.4Hz,1H),2.28-2.37(m,1H),2.11-2.18(m,1H),2.00(t,J＝5.6Hz,1H),1.80-1.90(m,2H),1.35(s,3H),1.26-1.30(m,4H),0.84(s,3H)。
步骤D：(R)-(2-(苯并呋喃-3-基)-1-(4-(2-二甲基亚磺酰亚胺基吡啶)乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000112
将(R)-2-(苯并呋喃-3-基)-1-(4-(2-二甲基亚磺酰亚胺基吡啶)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(73mg)溶于甲醇(5mL)中，向此溶液中加入异丁基硼酸(43mg)、1mol/L盐酸(0.2mL)和正己烷(5mL)，室温搅拌过夜，分液去除上层正己烷，甲醇相用正己烷洗涤，减压浓缩，得粗产物，经过乙醚打浆纯化得到产品(25mg)。
1H NMR(400MHz,CD 3OD)δ8.06(d,J＝6.8Hz,1H),7.56-7.59(m,2H),7.48(s,1H),7.43(d,J＝7.6Hz,1H),7.19-7.29(m,2H),7.12(dd,J＝6.4Hz,1.2Hz,1H),3.85-3.89(m,2H),3.53-3.56(m,6H),3.11(dd,J＝9.2Hz,5.6Hz,1H),2.89-2.95(m,1H),2.77(dd,J＝14.8Hz,10.0Hz,1H)。
实施例17
(R)-(2-(苯并呋喃-3-基)-1-(2-(5-(二甲基亚磺酰亚胺基)吡啶-2-基)乙酰胺基)乙基)硼酸
Figure PCTCN2021072666-appb-000113
步骤A：2-(5-二甲基亚磺酰亚胺基-吡啶-2-基)乙酸甲酯
Figure PCTCN2021072666-appb-000114
氮气保护下，将2-(5-溴-吡啶-2-基)乙酸甲酯(0.5g)溶于1,4-二氧六环(20mL)中，依次加入亚氨基二甲基-λ 6-砜(150mg)、三(二亚苄基丙酮)二钯(50mg)、碳酸铯(0.70g)和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(88mg)，升温至105℃搅拌过夜。降至室温，加入水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐 水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶制备板(1:10甲醇/二氯甲烷)纯化得到产品(300mg)。
1H NMR(400MHz,CDCl 3)δ8.40(d,J＝2.8Hz,1H),7.98(d,J＝8.8Hz,1H),7.49(dd,J＝8.8Hz,2.8Hz,1H),3.97(s,3H),3.48(s,2H),3.23(s,6H)。
步骤B：2-(5-二甲基亚磺酰亚胺基-吡啶-2-基)乙酸
Figure PCTCN2021072666-appb-000115
将2-(5-二甲基亚磺酰亚胺基-吡啶-2-基)乙酸甲酯(300mg)溶于甲醇(5mL)中，加入1mol/L的NaOH水溶液(3mL)，室温下搅拌过夜。反应液经1mol/L盐酸酸化至pH值5-6，反应液直接浓缩至干，残留物用硅胶制备板(1:10甲醇/二氯甲烷)纯化得到产品(180mg)。
1H NMR(400MHz,CDCl 3)δ8.27(d,J＝1.6Hz,1H),8.08-8.10(m,1H),7.76(d,J＝8.8Hz,1H),4.05(s,2H),3.38(s,6H)。
步骤C：(R)-(2-(苯并呋喃-3-基)-1-(2-(5-(二甲基亚磺酰亚胺基)吡啶-2-基)乙酰胺基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000116
将2-(5-二甲基亚磺酰亚胺基-吡啶-2-基)乙酸(180mg)、2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(300mg)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(455mg)、N,N-二异丙基乙胺(248mg)和4-二甲基氨基吡啶(123mg)加入干燥的二氯甲烷(15mL)中，室温搅拌过夜。用水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶制备板(20:1甲醇/二氯甲烷)纯化得到产品(150mg)。
1H NMR(400MHz,CDCl 3)δ8.38(brs,1H),8.05(s,1H),7.53(d,J＝7.6Hz,1H),7.44(d,J＝8.0Hz,1H),7.30-7.40(m,1H),7.18-7.28(m,2H),7.16-7.20(m,1H),7.02(d,J＝8.0Hz,1H),4.25(d,J＝8.4Hz,1H),3.61-3.77(m,1H),3.15(s,6H),2.98-3.10(m,2H),2.78-2.84(m,1H),2.30-2.35(m,1H),2.08-2.17(m,2H),2.00(t,J＝5.6Hz,1H),1.82-1.91(m,2H),1.40(d,J＝10.4Hz,1H),1.37(s,3H),1.27(s,3H),0.85(s,3H)。
步骤D：(R)-(2-(苯并呋喃-3-基)-1-(2-(5-(二甲基亚磺酰亚胺基)吡啶-2-基)乙酰胺基)乙基)硼酸
Figure PCTCN2021072666-appb-000117
将(R)-(2-(苯并呋喃-3-基)-1-(2-(5-(二甲基亚磺酰亚胺基)吡啶-2-基)乙酰胺基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(145mg)溶于甲醇(2mL)中，向此溶液中加入异丁基硼酸(130mg)、1mol/L盐酸(0.2mL)和正己烷(2mL)，室温搅拌过夜，分液去除上层正己烷，甲醇相用正己烷洗涤，减压浓缩，得粗产物，加入乙醚打浆，过滤收集固体，固体干燥得到产品(10mg)。
1H NMR(400MHz,CD 3OD)δ7.68(d,J＝8.4Hz,2H),7.43-7.48(m,2H),7.22-7.34(m,4H),3.76(s,2H),3.58-3.73(m,1H),3.29(s,6H),2.83-2.92(m,1H),2.68-2.71(m,1H)。
实施例18
(R)-(2-(苯并呋喃-3-基)-1-(3-(二甲基亚磺酰亚胺基苯基)丙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000118
步骤A：3-(二甲基亚磺酰亚胺基苯基)丙酸甲酯
Figure PCTCN2021072666-appb-000119
氮气保护下，将3-溴-3-苯基丙酸甲酯(600mg)溶于1,4-二氧六环(15mL)中，依次加入二甲基亚磺酰亚胺(276mg)、三(二亚苄基丙酮)二钯(112mg)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(200mg)和碳酸铯(1.6g)，升温至110℃搅拌过夜。降至室温，加入水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶制备板(1:60甲醇/二氯甲烷)纯化得到产品(500mg)。
1H NMR(400MHz,CDCl 3)δ7.14(t,J＝7.6Hz,1H),6.89-6.92(m,2H),6.81(d,J＝7.6Hz,1H),3.66(s,3H),3.14(s,6H),2.88(t,J＝8.0Hz,2H),2.61(t,J＝8.0Hz,2H)。
步骤B：3-(二甲基亚磺酰亚胺基苯基)丙酸
Figure PCTCN2021072666-appb-000120
将3-(二甲基亚磺酰亚胺基苯基)丙酸甲酯(500mg)溶于乙醇(10mL)中，加入8mol/L氢氧化钠水溶液(1mL)，升温至80℃搅拌2小时。降至室温，加入水稀释，用1mol/L盐酸调pH至3-4，减压浓缩，残留物经柱层析分离(1:5甲醇/二氯甲烷)得到产品(300mg)。
步骤C：(R)-2-(苯并呋喃-3-基)-1-(3-(二甲基亚磺酰亚胺基苯基)丙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000121
将3-(二甲基亚磺酰亚胺基苯基)丙酸(150mg)、2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(233mg)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(471mg)、4-二甲基氨基吡啶(76mg)和二异丙基乙基胺(160mg)加入干燥的二氯甲烷(10mL)中，完毕后室温搅拌过夜，用水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶制备板(1:40甲醇/二氯甲烷)纯化得到产品(60mg)。
1H NMR(400MHz,CDCl 3)δ7.51(d,J＝7.6Hz,1H),7.44(d,J＝8.4Hz,1H),7.26-7.30(m,2H),7.21(t,J＝7.6Hz,1H),7.10(t,J＝8.0Hz,1H),6.91(d,J＝7.6Hz,1H),6.84(s,1H),6.74(d,J＝8.0Hz,1H),6.19(s,1H),4.26(d,J＝7.2Hz,1H),3.11(s,6H),3.01-3.06(m,1H),2.92-2.97(m,1H),2.86(t,J＝7.6Hz,2H),2.76(dd,J＝15.2Hz,11.2Hz,1H),2.52-2.56(m,2H),2.31-2.38(m,1H),2.12-2.18(m,1H),2.01(t,J＝5.6Hz,1H),1.81-1.90(m,2H),1.42(d,J＝10.8Hz,1H),1.38(s,3H),1.27(s,3H),0.86(s,3H)。
步骤D：(R)-(2-(苯并呋喃-3-基)-1-(3-(二甲基亚磺酰亚胺基苯基)丙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000122
将(R)-2-(苯并呋喃-3-基)-1-(3-(二甲基亚磺酰亚胺基苯基)丙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(60mg)溶于甲醇(5mL)中，向此溶液中加入异丁基硼酸(47mg)、1mol/L盐酸(0.2mL)和正己烷(5mL)，室温搅拌过夜，分液去除上层正己烷，甲醇相用正己烷洗涤，减压浓缩，得粗产物，经过乙醚打浆纯化得到产品(32mg)。
1H NMR(400MHz,CD 3OD)δ8.51(d,J＝8.0Hz,1H),7.40-7.42(m,2H),7.14-7.26(m,3H),6.89-6.93(m,2H),6.85(d,J＝7.6Hz,1H),3.17(s,6H),2.79-2.92(m,4H),2.64-2.70(m,2H),2.54(dd,J＝15.2Hz,10.4Hz,1H)。
实施例19
(R)-(2-(苯并呋喃-3-基)-1-(4-(二甲基亚磺酰亚胺基苯基)丙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000123
步骤A：4-(二甲基亚磺酰亚胺基苯基)丙酸甲酯
Figure PCTCN2021072666-appb-000124
氮气保护下，将4-溴苯基丙酸甲酯(600mg)溶于1,4-二氧六环(50mL)中，依次加入二甲基亚磺酰亚胺(276mg)、三(二亚苄基丙酮)二钯(112mg)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(200mg)和碳酸铯(1.6g)，升温至110℃搅拌过夜。降至室温，加入水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶制备板(1:60甲醇/二氯甲烷)纯化得到产品(480mg)。
1H NMR(400MHz,CDCl 3)δ7.02-7.07(m,2H),6.96-6.99(m,2H),3.65(s,3H),3.12(s,6H),2.87(t,J＝7.6Hz,2H),2.58(t,J＝7.6Hz,2H)。
步骤B：4-(二甲基亚磺酰亚胺基苯基)丙酸
Figure PCTCN2021072666-appb-000125
将4-(二甲基亚磺酰亚胺基苯基)丙酸甲酯(410mg)溶于乙醇(10mL)中，加入8mol/L氢氧化钠水溶液(1mL)，升温至80℃搅拌2小时。降至室温，加入水稀释，用1mol/L盐酸调pH至3-4，减压浓缩，残留物经柱层析分离(1:5甲醇/二氯甲烷)得到产品(300mg)。
步骤C：(R)-2-(苯并呋喃-3-基)-1-(4-(二甲基亚磺酰亚胺基苯基)丙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000126
将4-(二甲基亚磺酰亚胺基苯基)丙酸(150mg)、2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(233mg)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(471mg)、4-二甲基氨基吡啶(76mg)和二异丙基乙基胺(160mg)加入干燥的二氯甲烷(10mL)中，完毕后室温搅拌过夜，用水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶制备板(1:40甲醇/二氯甲烷)纯化得到产品(120mg)。
1H NMR(400MHz,CDCl 3)δ7.51(d,J＝7.6Hz,1H),7.44(d,J＝8.0Hz,1H), 7.25-7.30(m,2H),7.20(t,J＝7.6Hz,1H),6.94-6.99(m,4H),4.26(dd,J＝8.8Hz,1.6Hz,1H),3.09(s,6H),3.02-3.08(m,1H),2.93-2.98(m,1H),2.84(t,J＝7.6Hz,2H),2.74-2.80(m,1H),2.46-2.55(m,2H),2.31-2.37(m,1H),2.12-2.18(m,1H),2.01(t,J＝5.6Hz,1H),1.81-1.90(m,2H),1.42(d,J＝10.0Hz,1H),1.38(s,3H),1.27(s,3H),0.86(s,3H)。
步骤D：(R)-(2-(苯并呋喃-3-基)-1-(4-(二甲基亚磺酰亚胺基苯基)丙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000127
将(R)-2-(苯并呋喃-3-基)-1-(4-(二甲基亚磺酰亚胺基苯基)丙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(120mg)溶于甲醇(5mL)中，向此溶液中加入异丁基硼酸(65mg)、1mol/L盐酸(0.5mL)和正己烷(5mL)，室温搅拌过夜，分液去除上层正己烷，甲醇相用正己烷洗涤，减压浓缩，得粗产物，经过乙醚打浆纯化得到产品(40mg)。
1H NMR(400MHz,CD 3OD)δ7.49(d,J＝8.0Hz,1H),7.40(d,J＝8.4Hz,1H),7.37(s,1H),7.17-7.26(m,2H),7.08-7.11(m,2H),6.97-7.01(m,2H),3.14(s,6H),2.79-2.92(m,4H),2.57-2.71(m,2H),2.52(dd,J＝14.8Hz,10.4Hz,1H)。
实施例20
(R)-(2-(苯并呋喃-3-基)-1-((((2-(N,S-二甲基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基硼酸
Figure PCTCN2021072666-appb-000128
步骤A：2-(甲硫基)苯甲酸
Figure PCTCN2021072666-appb-000129
0℃下，将2-巯基苯甲酸(8g)溶于甲醇(100mL)中，缓慢添加8mol/L的氢氧化钠水溶液(19.5mL)，于0℃保温10分钟后，添加碘甲烷(1.8g)，升至室温搅拌5小时，添加1mol/L稀盐酸调节pH至3-4，蒸干溶剂后，残留物分散于甲醇(50mL)中，过滤固体，固体用甲醇充分冲洗，蒸干甲醇后得到产品(4.1g)。
1H NMR(400MHz,CDCl 3)δ8.16(d,J＝8.0Hz,1H),7.54(t,J＝7.6Hz,1H),7.32(d,J＝8.0Hz,1H),7.21(t,J＝8.0Hz,1H),2.49(s,3H)。
步骤B：2-(甲硫基)苯甲酸甲酯
Figure PCTCN2021072666-appb-000130
0℃下，将2-(甲硫基)苯甲酸(4g)加入甲醇(150mL)中，缓慢添加氯化亚砜(8.5g)，室温搅拌10分钟后，加热回流过夜。蒸干溶剂后得到产品(4.7g)。 1H NMR(400MHz,CDCl 3)δ7.99(dd,J＝8.0Hz,1.2Hz,1H),7.46(td,J＝7.6Hz,1.2Hz,1H),7.26(d,J＝8.0Hz,1H),7.14(t,J＝7.6Hz,1H),3.90(s,3H),2.45(s,3H)。
步骤C：(2-(甲硫基)苯基)甲醇
Figure PCTCN2021072666-appb-000131
氮气保护下，将2-(甲硫基)苯甲酸甲酯(4.7g)溶于四氢呋喃(150mL)中，冰浴冷却下缓慢添加1mol/L二异丁基氢化铝的甲苯溶液(78mL),室温搅拌过夜。缓慢添加饱和硫酸钠水溶液淬灭反应，过滤固体，用二氯甲烷充分冲洗，分液收集有机相，蒸干溶剂得到产品(3.5g)。
1H NMR(400MHz,CDCl 3)δ7.36(d,J＝7.6Hz,1H),7.24-7.28(m,2H),7.14-7.19(m,1H),4.74(s,2H),2.47(s,3H),2.22-2.29(brs,1H)。
步骤D：2-((2-(甲硫基)苄基)氧基)四氢-2H-吡喃
Figure PCTCN2021072666-appb-000132
将(2-(甲硫基)苯基)甲醇(1.95g)溶于3,4-二氢吡喃(50mL)中，加入对甲苯磺酸吡啶盐(0.975g)，室温搅拌过夜。加入碳酸氢钠水溶液并用乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤后，蒸干有机相得到产品(2.7g)。
1H NMR(400MHz,CDCl 3)δ7.40(d,J＝7.2Hz,1H),7.21-7.28(m,2H),7.12-7.16(m,1H),4.82(d,J＝12.4Hz,1H),4.79(t,J＝3.6Hz,1H),4.57(d,J＝12.4Hz,1H),3.91-3.96(m,1H),3.52-3.57(m,1H),2.44(s,3H),1.81-1.93(m,1H),1.62-1.78(m,2H),1.48-1.62(m,3H)。
步骤E：亚氨基(甲基)(2-((((四氢-2H-吡喃-2-基)氧基)甲基)苯基)-λ 6-砜
Figure PCTCN2021072666-appb-000133
将2-((2-(甲硫基)苄基)氧基)四氢-2H-吡喃(2.7g)溶于甲醇(200mL)中，依次加入二醋酸碘苯(10.9g)和氨基甲酸铵(4.4g)，室温搅拌过夜。减压浓缩去除溶剂，残留物经过硅胶柱层析(5％甲醇/二氯甲烷)纯化得到产物(1.1g)。 1H NMR(400MHz,CDCl 3)δ8.11(td,J＝8.0Hz,1.2Hz,1H),7.56-7.68(m,2H),7.44-7.49(m,1H),5.02-5.21(m,2H),4.74-4.77(m,1H),3.84-3.90(m,1H),3.50-3.57(m,1H),3.26(s,3H),1.68-1.88(m,2H),1.46-1.65(m,4H)。
步骤F：甲基(甲基亚氨基)(2-((((四氢-2H-吡喃-2-基)氧基)甲基)苯基)-λ 6-砜
Figure PCTCN2021072666-appb-000134
将亚氨基(甲基)(2-((((四氢-2H-吡喃-2-基)氧基)甲基)苯基)-λ 6-砜(170mg)溶于四氢呋喃(10mL)中，冰浴冷却下添加氢化钠(51mg)，10分钟后添加碘甲烷(135mg)，室温搅拌过夜。过滤，加入水并用二氯甲烷萃取，萃取液减压浓缩去除溶剂后得到产物(180mg)。
1H NMR(400MHz,CDCl 3)δ7.95-7.99(m,1H),7.64-7.68(m,1H),7.53-7.58(m,1H),7.42-7.47(m,1H),4.94-5.09(m,2H),4.70-4.75(m,1H),3.82-3.89(m,1H),3.48-3.55(m,1H),3.16(s,3H),2.61-2.62(m,3H),1.68-1.84(m,2H),1.45-1.64(m,4H)。
步骤G：2-(N,S-二甲基磺酰亚胺基)苄醇
Figure PCTCN2021072666-appb-000135
将甲基(甲基亚氨基)(2-((((四氢-2H-吡喃-2-基)氧基)甲基)苯基)-λ 6-砜(180mg)溶于甲醇(10mL)中，添加对甲苯磺酸(12mg)，加热至45℃搅拌过夜。加入水并用二氯甲烷萃取，萃取液减压浓缩，残留物经硅胶制备板(1:30甲醇/二氯甲烷)纯化得产品(100mg)。
1H NMR(400MHz,CDCl 3)δ7.93(d,J＝7.6Hz,1H),7.49-7.57(m,2H),7.44(td,J＝7.6Hz,2.0Hz,1H),4.76-4.83(m,2H),3.13(s,3H),2.69(s,3H)。
步骤H：2-(苯并呋喃-3-基)-1-(R)-(3-乙酰基苯磺酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000136
将2-(苯并呋喃-3-基)-1-(R)-氨基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(104mg)溶于二氯甲烷(10mL)中，冷却至-60℃，添加干燥的三乙胺(112mg)，保温15分钟后逐滴添加三光气(33mg)的二氯甲烷(5mL)溶液，-60℃保温30分钟后，逐滴添加2-(N,S-二甲基磺酰亚胺基)苄醇(55mg)的二氯甲烷(5mL)溶液，-60℃保温1小时。升至室温，搅拌过夜。加入饱和食盐水并用二氯甲烷萃取，经硅胶制备板(1:30甲醇/二氯甲烷)纯化得产品(90mg)。 1H NMR(400MHz,CDCl 3)δ7.98(d,J＝8.4Hz,1H),7.55-7.62(m,2H),7.45-7.52(m,2H),7.43(d,J＝8.0Hz,1H),7.40(s,1H),7.23-7.28(m,1H),7.13-7.18(m,1H),5.46-5.62(m,2H),5.10(d,J＝4.8Hz,1H),4.26(d,J＝8.4Hz,1H),3.48-3.52(m,1H),3.17(s,3H),3.10(dd,J＝14.8Hz,5.2Hz,1H),2.95(dd,J＝14.8Hz,6.8Hz,1H),2.66(s,3H),2.24-2.31(m,1H),2.04-2.11(m,1H),1.94(t,J＝5.6Hz,1H),1.82-1.87(m,1H),1.73-1.79(m,1H),1.23(s,3H),1.15(s,1.5H),1.14(s,1.5H),1.04(d,J＝11.2Hz,1H),0.78(s,3H)。
步骤I：(R)-(2-(苯并呋喃-3-基)-1-((((2-(N,S-二甲基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基硼酸
Figure PCTCN2021072666-appb-000137
将2-(苯并呋喃-3-基)-1-(R)-(3-乙酰基苯磺酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(90mg)溶于甲醇(5mL)和正己烷(5mL)的混合溶剂中，加入异丁基硼酸(98mg)，1mol/L稀盐酸(0.2mL)，室温搅拌过夜。将甲醇相分出，并用正己烷洗涤，收集甲醇相，减压浓缩，残留物经硅胶制备板(1:10甲醇/二氯甲烷)纯化得产品(29mg)。
1H NMR(400MHz,CD 3OD)δ7.93-7.96(m,1H),7.65-7.69(m,2H),7.52-7.59(m,2H),7.48(s,1H),7.40(d,J＝8.4Hz,1H),7.21-7.26(m,1H),7.16(t,J＝7.6Hz,1H),5.40-5.54(m,2H),3.31-3.34(m,1H),3.17(s,3H),2.90-2.98(m,1H),2.84(dd,J＝14.8Hz,8.0Hz,1H),2.59(s,3H)。
实施例21
(R)-2-(苯并呋喃-3-基)-1-N-(3-(S-甲基磺酰亚氨基)苯基甲氧基氧代)氨基乙基硼酸
Figure PCTCN2021072666-appb-000138
步骤A：3-甲硫基苯甲醇
Figure PCTCN2021072666-appb-000139
氮气保护下，将3-甲硫基苯甲酸甲酯(1.82g)溶于无水四氢呋喃(50mL)中，冷却至0℃，滴加1mol/L的二一丁基氢化铝的甲苯溶液(30mL)，滴加完毕后，反应液升至室温，搅拌2小时。加水淬灭反应，然后加入1mol/L的氢氧化钠水溶液(100mL)，用乙酸乙酯萃取，有机相分别用1mol/L盐酸和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到无色油状产品(1.50g)，直接用于下一步反应。
1H NMR(400MHz,CDCl 3)δ7.22-7.28(m,2H),7.16(d,J＝7.2Hz,1H),7.10(d,J＝7.2Hz,1H),4.65(s,2H),2.47(s,3H)。
步骤B：2-((3-甲硫基)苄基)氧基)四氢-2H-吡喃
Figure PCTCN2021072666-appb-000140
将3-甲硫基苯甲醇(1.50g)溶于3,4-二氢-2H-吡喃(20mL)中，加入吡啶对甲苯磺酸盐(100mg)，室温下搅拌过夜。反应液直接浓缩至干，残留物用硅胶柱层析(1:5乙酸乙酯/石油醚)纯化得到产品(2.2g)。
1H NMR(400MHz,CDCl 3)δ7.23-7.29(m,2H),7.13(d,J＝7.6Hz,1H),7.11(d,J＝7.6Hz,1H),4.62(s,2H),4.78-4.83(m,1H),3.75-3.96(m,1H),3.66-3.69(m,1H),2.44(s,3H),1.85-1.99(m,2H),1.67-1.78(m,3H),1.55-1.63(m,1H)。
步骤C：亚氨基(3-((((四氢-2H-吡喃-2-基)氧基)甲基)苯基)-λ 6-甲基砜
Figure PCTCN2021072666-appb-000141
将2-((3-甲硫基)苄基)氧基)四氢-2H-吡喃(1.5g)、二乙酸碘苯(3.1g)和氨基甲酸铵(1.6g)加入甲醇(100mL)中，室温搅拌2小时，蒸干溶剂后残留物经硅胶柱层析(1:10甲醇/二氯甲烷)纯化得到产品(1.3g)。
1H NMR(400MHz,CDCl 3)δ8.07(d,J＝8.0Hz,1H),7.98-8.03(m,1H),7.48(t,J＝8.0Hz,1H),7.30(t,J＝8.0Hz,1H),4.77-4.86(m,1H),4.45-4.71(m,2H),3.70-3.90(m,1H),3.55(t,J＝5.6Hz,1H),3.46(s,3H),3.08-3.13(m,1H),1.84-1.98(m,2H),1.66-1.79(m,3H),1.55-1.63(m,1H)。
步骤D：亚氨基(3-羟甲基苯基)-λ 6-甲基砜
Figure PCTCN2021072666-appb-000142
将亚氨基(3-((((四氢-2H-吡喃-2-基)氧基)甲基)苯基)-λ 6-甲基砜(1.0g)和对甲苯磺酸(100mg)溶于甲醇(10mL)中，加热回流过夜后蒸干去除溶剂，残留物溶于二氯甲烷中，并用饱和NaHCO 3水溶液和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析(1:10甲醇/二氯甲烷)纯化得到产品(510mg)。
1H NMR(400MHz,CDCl 3)δ8.01(s,1H),7.89(d,J＝8.0Hz,1H),7.60(d,J＝8.0Hz,1H),7.52(t,J＝8.0Hz,1H),4.77(s,2H),3.11(s,3H)。
步骤E：(R)-2-(苯并呋喃-3-基)-1-N-(3-(S-甲基磺酰亚氨基)苯基甲氧基氧代)氨基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000143
将2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(300mg)溶于二氯甲烷(5mL)中，冷却至-78℃，向反应液中加入三光气(100mg)，并在此温度下搅拌30分钟，然后加入亚氨基(3-羟甲基苯基)-λ 6-甲基砜(200mg)的二氯甲烷(2mL)溶液。升至室温搅拌过夜。加水淬灭反应，有机相分离，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶制备版(1:20甲醇/二氯甲烷)纯化得到产品(208mg)。
1H NMR(400MHz,CDCl 3)δ7.98(s,1H),7.94(d,J＝8.0Hz,1H),7.50-7.59(m,3H),7.41-7.44(m,2H),7.16-7.20(m,1H),5.10-5.21(m,3H),4.28(d,J＝8.0Hz,1H),3.54-3.59(m,1H),3.14-3.17(m,1H),3.11(s,3H),2.95-2.99(m,1H),2.67-2.74(m,1H),2.27-2.33(m,1H),2.05-2.15(m,1H),1.95-2.01(m,2H),1.79-1.87(m,2H),1.55(s,3H),1.17(s,3H),1.03(d,J＝10.8Hz,1H),0.79(s,3H)。
步骤F：(R)-2-(苯并呋喃-3-基)-1-N-(3-(S-甲基磺酰亚氨基)苯基甲氧基氧代)氨基乙基硼酸
Figure PCTCN2021072666-appb-000144
将(R)-2-(苯并呋喃-3-基)-1-N-(3-(S-甲基磺酰亚氨基)苯基甲氧基氧代)氨基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(200mg)溶于甲醇(5mL)中，向反应液中加入异丁基硼酸(215mg)、1mol/L盐酸(0.2mL)和正己烷(5mL)，室温搅拌过夜，分液去除上层正己烷，甲醇相用正己烷洗涤，减压浓缩，得粗产物，加入乙醚打浆，过滤收集固体，固体干燥得到产品(25mg)。
1H NMR(400MHz,CD 3OD)δ8.11-8.5(m,2H),7.90(d,J＝8.0Hz,1H),7.79-7.83(m,1H),7.57(d,J＝8.0Hz,1H),7.50(s,1H),7.41(d,J＝8.0Hz,1H),7.17-7.27(m,2H),5.21(s,2H),3.90(s,3H),3.28-3.25(m,3H),2.92-2.98(m,1H),2.83-2.88(m,1H)。
实施例22
(R)-(2-(苯并呋喃-3-基)-1-(4-(2-甲氧基-(二甲基亚磺酰亚胺基苯基))乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000145
步骤A：4-(2-甲氧基-(二甲基亚磺酰亚胺基苯基))乙腈
Figure PCTCN2021072666-appb-000146
氮气保护下，将4-溴-2-甲氧基苯乙腈(620mg)溶于1,4-二氧六环(50mL)中，依次加入二甲基亚磺酰亚胺(308mg)、三(二亚苄基丙酮)二钯(125mg)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(238mg)和碳酸铯(1.7g)，升温至110℃搅拌过夜。降至室温，加入水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶制备板(1:100甲醇/二氯甲烷)纯化得到产品(300mg)。
步骤B：4-(2-甲氧基-(二甲基亚磺酰亚胺基苯基))乙酸
Figure PCTCN2021072666-appb-000147
将4-(2-甲氧基-(二甲基亚磺酰亚胺基苯基))乙腈(200mg)溶于乙醇(10mL)中，加入8mol/L氢氧化钠水溶液(1mL)，升温至80℃搅拌2小时。降至室温，加入水稀释，用1mol/L盐酸调pH至5-6，二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到产品(150mg)。
1H NMR(400MHz,DMSO-d 6)δ11.68-12.28(brs,1H),6.91(d,J＝7.6Hz,1H),6.42-6.47(m,2H),3.66(s,3H),3.35(s,2H),3.17(s,6H)。
步骤C：(R)-2-(苯并呋喃-3-基)-1-(4-(2-甲氧基-(二甲基亚磺酰亚胺基苯基))乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000148
将4-(2-甲氧基-(二甲基亚磺酰亚胺基苯基))乙酸(150mg)、2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(219mg)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(332mg)、4-二甲基氨基吡啶(71mg)和二异丙基乙基胺(150mg)加入干燥的二氯甲烷(20mL)中，完毕后室温搅拌过夜，用水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶制备板(1:40甲醇/二氯甲烷)纯化得到产品(80mg)。
1H NMR(400MHz,CDCl 3)δ7.51(d,J＝7.6Hz,1H),7.43(d,J＝8.0Hz,1H),7.28(td,J＝8.4Hz,1.2Hz,1H),7.19-7.24(m,2H),6.98(d,J＝8.4Hz,1H),6.65(dd,J＝8.0Hz,2.0Hz,1H),6.57-6.61(brs,1H),6.54(d,J＝1.6Hz,1H),4.27(dd,J＝8.8Hz,2.0Hz,1H),3.54-3.63(m,5H),3.17(s,6H),2.92-2.98(m,2H),2.76(dd,J＝15.6Hz,12.0Hz,1H),2.32-2.40(m,1H),2.12-2.19(m,1H),2.03(t,J＝5.6Hz,1H),1.83-1.92(m,2H),1.47(d,J＝10.8Hz,1H),1.40(s,3H),1.29(s,3H),0.88(s,3H)。
步骤D：(R)-(2-(苯并呋喃-3-基)-1-(4-(2-甲氧基-(二甲基亚磺酰亚胺基苯基))乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000149
将(R)-2-(苯并呋喃-3-基)-1-(4-(2-甲氧基-(二甲基亚磺酰亚胺基苯基))乙酰胺 基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(20mg)溶于甲醇(5mL)中，向此溶液中加入异丁基硼酸(55mg)、1mol/L盐酸(0.5mL)和正己烷(5mL)，室温搅拌过夜，分液去除上层正己烷，甲醇相用正己烷洗涤，减压浓缩，得粗产物，经过乙醚打浆纯化得到产品(9mg)。
1H NMR(400MHz,CD 3OD)δ7.55(d,J＝8.0Hz,1H),7.52(s,1H),7.42(d,J＝8.0Hz,1H),7.25(t,J＝7.6Hz,1H),7.20(t,J＝7.6Hz,1H),7.05-7.08(m,1H),6.64-6.69(m,2H),3.73(s,3H),3.54-3.66(m,2H),3.25(s,6H),2.84-2.96(m,2H),2.69(dd,J＝14.8Hz,9.6Hz,1H)。
实施例23
(R)-(2-(苯并呋喃-3-基)-1-(4-(3-氯-(二甲基亚磺酰亚胺基苯基))丙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000150
步骤A：4-(3-氯-(二甲基亚磺酰亚胺基苯基))丙酸甲酯
Figure PCTCN2021072666-appb-000151
氮气保护下，将4-(3-氯-(二甲基亚磺酰亚胺基苯基))丙酸甲酯(1.0g)溶于1,4-二氧六环(50mL)中，依次加入二甲基亚磺酰亚胺(340mg)、三(二亚苄基丙酮)二钯(165mg)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(313mg)和碳酸铯(2.3g)，升温至110℃搅拌过夜。降至室温，加入水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶制备板(1:100甲醇/二氯甲烷)纯化得到产品(900mg)。
1H NMR(400MHz,CDCl 3)δ7.06-7.08(m,2H),6.88(dd,J＝8.0Hz,2.0Hz,1H),3.66(s,3H),3.13(s,6H),2.97(t,J＝8.0Hz,2H),2.60(t,J＝8.0Hz,2H)。
步骤B：4-(3-氯-(二甲基亚磺酰亚胺基苯基))丙酸
Figure PCTCN2021072666-appb-000152
将4-(3-氯-(二甲基亚磺酰亚胺基苯基))丙酸甲酯(333mg)溶于乙醇(10mL)中，加入8mol/L氢氧化钠水溶液(1mL)，升温至80℃搅拌2小时。降至室温，加入水稀释，用1mol/L盐酸调pH至5-6，二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到产品(305mg)。
1H NMR(400MHz,DMSO-d 6)δ11.90-12.44(brs,1H),7.11(d,J＝7.6Hz,1H),6.89(d,J＝2.0Hz,1H),7.78(dd,J＝8.4Hz,2.4Hz,1H),3.18(s,6H),2.78(t,J＝7.6Hz,2H),2.45(t,J＝7.6Hz,2H)。
步骤C：(R)-2-(苯并呋喃-3-基)-1-(4-(3-氯-(二甲基亚磺酰亚胺基苯基))丙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000153
将4-(3-氯-(二甲基亚磺酰亚胺基苯基))丙酸(100mg)、2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(136mg)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(205mg)、4-二甲基氨基吡啶(44mg)和二异丙基乙基胺(93mg)加入干燥的二氯甲烷(15mL)中，完毕后室温搅拌过夜，用水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶制备板(1:40甲醇/二氯甲烷)纯化得到产品(80mg)。
1H NMR(400MHz,CDCl 3)δ7.50(d,J＝7.2Hz,1H),7.44(d,J＝8.4Hz,1H),7.26-7.31(m,2H),7.21(t,J＝8.0Hz,1H),7.04-7.07(m,2H),6.87(dd,J＝8.0Hz,2.0Hz,1H),6.24(s,1H),4.27(dd,J＝8.4Hz,2.0Hz,1H),3.04-3.14(m,7H),2.92-2.99(m,3H),2.75-2.82(m,1H),2.52(t,J＝7.2Hz,2H),2.31-2.38(m,1H),2.12-2.20(m,1H),2.01(t,J＝5.6Hz,1H),1.82-1.92(m,2H),1.42(d,J＝10.8Hz,1H),1.38(s,3H),1.27(s,3H),0.86(s,3H)。
步骤D：(R)-(2-(苯并呋喃-3-基)-1-(4-(3-氯-(二甲基亚磺酰亚胺基苯基))丙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000154
将(R)-2-(苯并呋喃-3-基)-1-(4-(3-氯-(二甲基亚磺酰亚胺基苯基))丙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(80mg)溶于甲醇(5mL)中，向此溶液中加入异丁基硼酸(55mg)、1mol/L盐酸(0.5mL)和正己烷(5mL)，室温搅拌过夜，分液去除上层正己烷，甲醇相用正己烷洗涤，减压浓缩，得粗产物，经过乙醚打浆纯化得到产品(40mg)。
1H NMR(400MHz,CD 3OD)δ7.49(d,J＝6.8Hz,1H),7.39-7.41(m,2H),7.17-7.27(m,2H),7.15(d,J＝8.0Hz,1H),7.07(d,J＝2.4Hz,1H),6.94(dd,J＝8.0Hz,2.4Hz,1H),3.17(s,6H),2.98-3.07(m,2H),2.80-2.91(m,2H),2.67(t,J＝7.2Hz,2H),2.56(dd,J＝14.8Hz,10.0Hz,1H)。
实施例24
(1R)-2-(苯并呋喃-3-基)-1-(2-(3-(N,S-二甲基亚磺酰亚胺基)苯基)乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000155
步骤A：3-(甲硫基)苯甲酸甲酯
Figure PCTCN2021072666-appb-000156
将3-巯基苯甲酸(5.0g)溶于无水N,N-二甲基甲酰胺(80mL)中，冷却至0℃，向反应液中依次加入无水碳酸钾(22.5g)和碘甲烷(18.5g)，恢复至室温后搅拌1小时。反应液经乙酸乙酯(200mL)稀释后通过硅藻土过滤，滤液用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩蒸干溶剂，所得残留物经过硅胶柱层析(5％乙酸乙酯/石油醚混合液)纯化得到产品(5.6g)。
1H NMR(400MHz,CDCl 3)δ7.89(s,1H),7.77(d,J＝7.6Hz,1H),7.40(d,J＝8.0Hz,1H),7.30-7.34(m,1H),3.89(s,3H),2.50(s,3H)。
步骤B：3-(甲硫基)苯甲醇
Figure PCTCN2021072666-appb-000157
将3-(甲硫基)苯甲酸甲酯(1.82g)溶于无水四氢呋喃(50mL)中，氮气保护下，冷却至0℃。向体系内滴加1mol/L二异丙基氢化铝的甲苯溶液(30mL)。恢复至室温后搅拌3小时，向体系内依次缓慢加入乙酸乙酯(150mL)和1mol/L的氢氧化钠水溶液(70mL)。有机相分离，并用无水硫酸钠干燥，过滤，滤液减压浓缩蒸干溶剂得到目标产品(1.51g)。
1H NMR(400MHz,CDCl 3)δ7.47-7.50(m,1H),7.24-7.26(m,1H),7.16(d,J＝8.0Hz,1H),7.10(d,J＝8.0Hz,1H),4.65(s,2H),2.47(s,3H)。
步骤C：(3-(氯甲基)苯基)甲基硫醚
Figure PCTCN2021072666-appb-000158
将3-(甲硫基)苯甲醇(1.0g)溶于二氯甲烷(30mL)中，冷却至0℃。向反应体系内分批加入五氯化磷(2.8g)，恢复至室温搅拌1小时，小心加入水(50mL)淬灭反应，用二氯甲烷萃取，分出有机相经无水硫酸钠干燥，过滤后蒸干溶剂，残留物经硅胶柱层析(10％乙酸乙酯/石油醚混合液)纯化得到产品(1.3g)。
1H NMR(400MHz,CDCl 3)δ7.35-7.32(m,1H),7.28-7.30(m,1H),7.13(d,J＝8.0Hz,1H),7.10(d,J＝8.0Hz,1H),4.67(s,2H),2.49(s,3H)。
步骤D：2-(3-(甲硫基)苯基)乙腈
Figure PCTCN2021072666-appb-000159
将(3-(氯甲基)苯基)甲基硫醚(1.0g)、三甲基腈硅烷(0.7g)和三水合四丁 基氟化铵(1.86g)加入乙腈(10mL)中，加热至40℃搅拌过夜，恢复至室温后加水淬灭反应，并用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩蒸干溶剂，所得残留物经过硅胶柱层析(10％乙酸乙酯/石油醚混合液)纯化得到产品(1.1g)。
1H NMR(400MHz,CDCl 3)δ7.26-7.30(m,1H),7.18-7.20(m,2H),7.07(d,J＝7.6Hz,1H),3.71(s,2H),2.48(s,3H)。
步骤E：2-(3-(S-甲基磺酰亚胺基)苯基)乙腈
Figure PCTCN2021072666-appb-000160
将2-(3-(甲硫基)苯基)乙腈(1.0g)、二乙酸碘苯(0.8g)和氨基甲酸铵(0.25g)加入甲醇(10mL)中，室温下在空气氛下搅拌过夜。蒸干溶剂，所得残留物经过硅胶柱层析(2％-10％甲醇/二氯甲烷混合液)纯化得到产品(0.95g)。
1H NMR(400MHz,CDCl 3)δ9.23(brs,1H),7.90(s,1H),7.81(d,J＝8.0Hz,1H),7.51-7.57(m,2H),3.74(s,2H),2.59(s,3H)。
步骤F：2-(3-(N,S-二甲基磺酰亚胺基)苯基)乙酸
Figure PCTCN2021072666-appb-000161
将2-(3-(S-甲基磺酰亚胺基)苯基)乙腈(0.9g)和多聚甲醛(0.88g)混于甲酸(50mL)中，加热至105℃反应72小时。蒸干溶剂，所得残留物经过硅胶柱层析(10％甲醇/二氯甲烷混合液)纯化得到产品(0.35g)。
1H NMR(400MHz,CDCl 3)δ8.09(s,1H),7.83-7.92(m,1H),7.54-7.61(m,2H),3.77(s,2H),3.21(s,3H),2.63(s,3H)。
步骤G：(1R)-2-(苯并呋喃-3-基)-1-(2-(3-(N,S-二甲基亚磺酰亚胺基)苯基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000162
将2-(3-(N,S-二甲基磺酰亚胺基)苯基)乙酸(100mg)溶于二氯甲烷(10mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(189mg)、N,N-二异丙基乙胺(89mg)和2-(苯并呋喃-3-基)-1-(R)-氨基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(165mg)，室温搅拌2小时，加入水(20mL)淬灭反应，并用二氯甲烷萃取，有机相用1mol/L盐酸和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经硅胶制备板(1:2乙酸乙酯/石油醚)纯化得到产品(87mg)。
1H NMR(400MHz,CDCl 3)δ7.76-7.79(m,2H),7.48-7.52(m,3H),7.40-7.44(m,1H),7.25-7.33(m,2H),7.16-7.22(m,1H),6.26(s,1H),4.27(dd,J＝8.8Hz,2.0Hz,1H),3.63(s,2H),3.57(s,3H),3.21-3.26(m,1H),3.06-3.10(m,1H),2.97-3.03(m,1H),2.87-2.90(m,1H),2.62(s,3H),2.28-2.35(m,1H),2.09-2.16(m,1H),1.98(t,J＝5.2Hz,1H),1.79-1.87(m,1H),1.31(s,3H),1.26(d,J＝12.4Hz,1H),1.26(s, 3H),0.83(s,3H)。
步骤H：(1R)-2-(苯并呋喃-3-基)-1-(2-(3-(N,S-二甲基亚磺酰亚胺基)苯基)乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000163
将(1R)-2-(苯并呋喃-3-基)-1-(2-(3-(N,S-二甲基亚磺酰亚胺基)苯基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(80mg)溶于甲醇(5mL)中，向此溶液中加入异丁基硼酸(80mg)、1mol/L盐酸(0.05mL)和正己烷(5mL)，室温搅拌过夜，分液去除上层正己烷，将甲醇相用正己烷洗涤，减压浓缩，残留物经二氯甲烷/乙醚体系重结晶得到产品(21mg)。
1H NMR(400MHz,CD 3OD)δ7.91(s,1H),7.87(d,J＝6.8Hz,1H),7.55-7.66(m,4H),7.42(d,J＝8.0Hz,1H),7.25-7.28(m,1H),7.18-7.24(m,1H),3.89(s,2H),3.31(s,3H),3.02-3.06(m,1H),2.90(dd,J＝14.4Hz,4.8Hz,1H),2.73(dd,J＝14.4Hz,10.0Hz,1H),2.58(s,3H)。
实施例25
(R)-2-(苯并呋喃-3-基)-1-(3-(4-二甲基亚磺酰亚胺基-3-氯苯基)丙胺基)乙基硼酸
Figure PCTCN2021072666-appb-000164
步骤A：3-(4-溴-3-氯苯基)丙烯酸
Figure PCTCN2021072666-appb-000165
将4-溴-3-氯苯甲醛(2.2g)和丙二酸环(亚)异丙酯(2.16g)加入三乙胺(10.5mL)中，完毕后降温至0℃，缓慢滴加甲酸(8.5mL)，滴加完毕升温至100℃反应过夜。将反应液倒入冰水中，有大量固体析出，过滤，滤饼用冰水洗，收集固体，真空干燥得产物(1.9g)。
1H NMR(400MHz,DMSO-d 6)δ12.22-12.66(br,1H),7.98(d,J＝2.0Hz,1H),7.77(d,J＝8.4Hz,1H),7.58(dd,J＝8.4Hz,1.6Hz,1H),7.52(d,J＝16.0Hz,1H),6.64(d,J＝16.0Hz,1H)。
步骤B：3-(4-溴-3-氯苯基)丙烯酸甲酯
Figure PCTCN2021072666-appb-000166
将3-(4-溴-3-氯苯基)丙烯酸(1.9g)加入甲醇(20mL)中，降温至0℃，缓慢滴加二氯亚砜(2.6g)，完毕后升温至60℃反应2小时，将反应液减压蒸馏除去溶剂得产品(1.9g)。
1H NMR(400MHz,CDCl 3)δ7.62(d,J＝8.0Hz,1H),7.58(d,J＝2.0Hz,1H),7.55(d,J＝16.0Hz,1H),7.24(dd,J＝8.4Hz,2.0Hz,1H),6.42(d,J＝16.0Hz,1H),3.80(s,3H)。
步骤C：(4-二甲基亚磺酰亚胺基-3-氯苯基)丙烯酸甲酯
Figure PCTCN2021072666-appb-000167
将3-(4-溴-3-氯苯基)丙烯酸甲酯(1.7g)、二甲基亚磺酰亚胺(846mg)、三(二亚苄基丙酮)二钯(283mg)、4,5-双二苯基膦-9,9-二甲氧杂蒽(354mg)和碳酸铯(4.06g)加入1,4-二氧六环(20mL)中，置换氮气后升温至100℃反应过夜。冷却至室温，硅藻土过滤除去不溶物，收集滤液，滤液减压浓缩除去溶剂，所得残留物经过硅胶柱层析分离(3：4乙酸乙酯/石油醚)纯化得到产品(2g)。产品经质谱确认，[M+H] +信号288。
步骤D：(4-二甲基亚磺酰亚胺基-3-氯苯基)丙酸甲酯
Figure PCTCN2021072666-appb-000168
将(4-二甲基亚磺酰亚胺基-3-氯苯基)丙烯酸甲酯(1.7g)和5％铂碳(500mg)加入甲醇(20mL)中，完毕后置换氢气六次，室温搅拌1小时，硅藻土过滤除去不溶物，收集滤液，滤液蒸干得产品(1.7g)。
1H NMR(400MHz,CDCl 3)δ7.19(d,J＝2.0Hz,1H),7.17(d,J＝8.4Hz,1H),6.95(dd,J＝8.0Hz,2.0Hz,1H),3.66(s,3H),3.14(s,6H),2.85(t,J＝7.6Hz,2H),2.58(t,J＝7.6Hz,2H)。
步骤E：(4-二甲基亚磺酰亚胺基-3-氯苯基)丙酸
Figure PCTCN2021072666-appb-000169
将(4-二甲基亚磺酰亚胺基-3-氯苯基)丙酸甲酯(320mg)和氢氧化钠(133mg)加入甲醇(10mL)和水(3mL)中，升温至60℃反应1小时，减压浓缩除去溶剂，加入水调节pH至5，水相用二氯甲烷萃取，收集有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后得产品(220mg)。
1H NMR(400MHz,CDCl 3)δ7.21(s,1H),7.18(d,J＝7.6Hz,1H),6.96(dd,J＝8.0Hz,1.6Hz,1H),3.15(s,6H),2.87(t,J＝7.6Hz,2H),2.64(t,J＝7.6Hz,2H)。
步骤F：(R)-2-(苯并呋喃-3-基)-1-(3-(4-二甲基亚磺酰亚胺基-3-氯苯基)丙胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000170
将(4-二甲基亚磺酰亚胺基-3-氯苯基)丙酸(220mg)溶于干燥的二氯甲烷(15mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(394mg)、N,N-二异丙基乙胺(150mg)和2-(苯并呋喃-3-基)-1-(R)-氨基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(450mg)，室温搅拌2小时，加入水(20mL)，并用二氯甲烷萃取，有机相用1mol/L盐酸和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经硅胶制备板(30％乙酸乙酯/二氯甲烷)纯化得到产品(100mg)。
1H NMR(400MHz,CDCl 3)δ7.50(d,J＝7.6Hz,1H),7.42(d,J＝8.0Hz,1H),7.32(s,1H),7.25(td,J＝7.6Hz,1.2Hz,1H),7.16-7.21(m,1H),7.13(d,J＝2.0Hz,1H),7.09(d,J＝8.4Hz,1H),7.84(dd,J＝8.0Hz,2.4Hz,1H),6.66-6.74(br,1H),4.24(dd,J＝8.4Hz,1.6Hz,1H),3.02-3.11(m,7H),2.91-2.98(m,1H),2.76-2.83(m,3H),2.43-2.48(m,2H),2.27-2.37(m,1H),2.10-2.17(m,1H),1.97-2.01(m,1H),1.78-1.90(m,2H),1.40(d,J＝10.4Hz,1H),1.36(s,3H),1.25(s,3H),0.84(s,3H)。
步骤G：(R)-2-(苯并呋喃-3-基)-1-(3-(4-二甲基亚磺酰亚胺基-3-氯苯基)丙胺基)乙基硼酸
Figure PCTCN2021072666-appb-000171
将(R)-2-(苯并呋喃-3-基)-1-(3-(4-二甲基亚磺酰亚胺基-3-氯苯基)丙胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(100mg)溶于甲醇(10mL)中，向此溶液中加入异丁基硼酸(88mg)、1mol/L盐酸(0.3mL)和正己烷(10mL)，室温搅拌过夜，分液去除上层正己烷，将甲醇相用正己烷洗涤，减压浓缩，残留物经硅胶制备板(1:6甲醇/二氯甲烷)纯化得到产品(22mg)。
1H NMR(400MHz,CD 3OD)δ7.49(d,J＝7.6Hz,1H),7.39-7.42(m,2H),7.17-7.28(m,4H),7.02(dd,J＝8.0Hz,2.0Hz,1H),3.16(s,6H),2.80-2.92(m,4H),2.58-2.72(m,2H),2.53(dd,J＝14.8Hz,10.4Hz,1H)。
实施例26
(R)-(2-(苯并呋喃-3-基)-1-(2-(4-(N,S-二甲基磺酰亚胺基)苯基)乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000172
步骤A：2-(4-(甲硫基)苯基)乙酸甲酯
Figure PCTCN2021072666-appb-000173
室温下，将2-(4-(甲硫基)苯基)乙酸(4g)溶解于甲醇(40mL)中，加入氯化亚砜(1mL)回流过夜，蒸干溶剂得到产品(4.1g)。
1H NMR(400MHz,CDCl 3)δ7.16-7.22(m,4H),3.67(s,3H),3.57(s,2H),2.45(s,3H)。
步骤B：2-(4-(S-甲基磺酰亚胺基)苯基)乙酸甲酯
Figure PCTCN2021072666-appb-000174
室温下，将2-(4-(甲硫基)苯基)乙酸甲酯(3.92g)、二乙酸碘苯(19.3g)和氨基甲酸铵(7.8g)加入甲醇(100mL)中，敞口搅拌过夜，减压浓缩，残留物经硅胶柱(1:20甲醇/二氯甲烷)纯化得到产品(3.1g)。
1H NMR(400MHz,CDCl 3)δ7.98(d,J＝8.4Hz,2H),7.48(d,J＝8.0Hz,2H),3.70-3.75(m,5H),3.12(s,3H)。
步骤C：2-(4-(N,S-二甲基磺酰亚胺基)苯基)乙酸
Figure PCTCN2021072666-appb-000175
室温下，将2-(4-(S-甲基磺酰亚胺基)苯基)乙酸甲酯(1g)和甲醛水溶液(2mL)加入到甲酸(10mL)中，加热至105℃搅拌过夜，蒸干溶剂得到产品(900mg)。
1H NMR(400MHz,DMSO-d 6)δ7.73(d,J＝8.0Hz,2H),7.48(d,J＝8.4Hz,2H),3.68(s,2H),3.07(s,3H),2.42(s,3H)。
步骤D：(R)-2-(苯并呋喃-3-基)-1-(2-(4-(N,S-二甲基磺酰亚胺基)苯基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000176
参照实施例10中步骤D的方法以2-(4-(N,S-二甲基磺酰亚胺基)苯基)乙酸(228mg)和2-(苯并呋喃-3-基)-1-(R)-氨基乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3- 二醇酯盐酸盐(376mg)为原料得到产品(100mg)。
1H NMR(400MHz,CDCl 3)δ7.77(d,J＝8.0Hz,2H),7.49(d,J＝7.2Hz,1H),7.42(d,J＝7.6Hz,1H),7.36(d,J＝8.4Hz,2H),7.27(t,J＝7.2Hz,1H),7.25(s,1H),7.19(t,J＝7.6Hz,1H),6.03(s,1H),4.29(dd,J＝8.8Hz,2.0Hz,1H),3.61(s,2H),3.20-3.27(m,1H),2.97-3.07(m,4H),2.88(dd,J＝14.8Hz,10.0Hz,1H),2.60(s,3H),2.29-2.37(m,1H),2.10-2.19(m,1H),1.99(t,J＝5.2Hz,1H),1.79-1.92(m,2H),1.32(s,3H),1.27(d,J＝12.4Hz,1H),1.26(s,3H),0.83(s,3H)。
步骤E：(R)-2-(苯并呋喃-3-基)-1-(2-(4-(N,S-二甲基磺酰亚胺基)苯基)乙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000177
参照实施例10步骤E的方法以(R)-2-(苯并呋喃-3-基)-1-(2-(4-(N,S-二甲基磺酰亚胺基)苯基)乙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(100mg)为原料得到产品(30mg)。
1H NMR(400MHz,CD 3OD)δ7.87(d,J＝8.4Hz,2H),7.54-7.60(m,4H),7.43(d,J＝8.0Hz,1H),7.24-7.29(m,1H),7.19-7.24(m,1H),3.85(s,2H),3.24(s,3H),3.02(dd,J＝10.0Hz,5.2Hz,1H),2.89(dd,J＝14.8Hz,5.2Hz,1H),2.72(dd,J＝14.8Hz,10.0Hz,1H),2.58(s,3H)。
实施例27
((1R)-2-(苯并呋喃-3-基)-1-((((3-(N,S-二甲基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000178
步骤A：3-(S-甲基磺酰亚胺基)苯甲酸甲酯
Figure PCTCN2021072666-appb-000179
将3-(甲硫基)苯甲酸甲酯(1.0g)、二乙酸碘苯(5.3g)和氨基甲酸铵(1.72g)加入甲醇(20mL)中，室温下在空气氛下搅拌过夜。蒸干溶剂，所得残留物经过硅胶柱层析(2％-10％甲醇/二氯甲烷混合液)纯化得到产品(1.1g)。
1H NMR(400MHz,CDCl 3)δ8.65(t,J＝1.6Hz,1H),8.27(d,J＝8.0Hz,1H),8.20(dd,J＝8.0Hz,1.6Hz,1H),7.64(t,J＝8.0Hz,1H),5.04(brs,1H),3.95(s,3H),3.13(s,3H)。
步骤B：3-(N,S-二甲基磺酰亚胺基)苯甲酸甲酯
Figure PCTCN2021072666-appb-000180
将3-(S-甲基磺酰亚胺基)苯甲酸甲酯(500mg)和多聚甲醛(210mg)混于甲酸(10mL)中，加热至105℃反应72小时。蒸干溶剂，所得残留物经过硅胶柱层析(10％甲醇/二氯甲烷混合液)纯化得到产品(0.31g)。
1H NMR(400MHz,CDCl 3)δ8.53(t,J＝1.6Hz,1H),8.26(dd,J＝8.0Hz,1.6Hz,1H),8.08(d,J＝8.0Hz,1H),7.66(t,J＝8.0Hz,1H),3.95(s,3H),3.09(s,3H),2.64(s,3H)。
步骤C：(3-(羟甲基)苯基)(甲基)(甲基亚氨基)-λ 6-砜
Figure PCTCN2021072666-appb-000181
将3-(N,S-二甲基磺酰亚胺基)苯甲酸甲酯(300mg)溶于无水四氢呋喃(10mL)中，氮气保护下冷却至0℃。向体系内滴加1mol/L二异丙基氢化铝的甲苯溶液(4.0mL)。恢复至室温后搅拌至反应完全，向体系内依次缓慢加入乙酸乙酯(50mL)和1mol/L的氢氧化钠水溶液(30mL)。有机相分离，并用无水硫酸钠干燥，过滤，滤液减压浓缩蒸干溶剂得到目标产品(105mg)。
1H NMR(400MHz,CDCl 3)δ7.90(s,1H),7.79(d,J＝7.6Hz,1H),7.62(d,J＝7.6Hz,1H),7.55(t,J＝7.6Hz,1H),4.79(s,2H),3.08(s,3H),2.62(s,3H),1.83(brs,1H)。
步骤D：((1R)-2-(苯并呋喃-3-基)-1-((((3-(N,S-二甲基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000182
氮气保护下，将2-(苯并呋喃-3-基)-1-(R)-氨基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(200mg)溶于二氯甲烷(10mL)中，冷却至-60℃，加入三光气(63mg)的二氯甲烷(1mL)溶液，缓慢滴加三乙胺(214mg)的二氯甲烷(1mL)溶液，保持低温搅拌30分钟，加入(3-(羟甲基)苯基)(甲基)(甲基亚氨基)-λ 6-砜(105mg)，恢复至室温，搅拌1小时。用水淬灭反应，并用二氯甲烷萃取，有机相用1mol/L盐酸和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经硅胶制备板(1:3乙酸乙酯/石油醚)纯化得到产品(25mg)。
1H NMR(400MHz,CDCl 3)δ7.88(s,1H),7.52-7.60(m,4H),7.42-7.44(m,2H),7.23-7.27(m,1H),7.18(t,J＝7.6Hz,1H),5.12-5.22(m,3H),4.28(dd,J＝7.6Hz,1.6Hz,1H),3.57(q,J＝6.0Hz,1H),3.12-3.17(m,1H),3.08(s,3H),2.95-3.01(m,1H),2.64(s,3H),2.27-2.33(m,1H),2.08-2.14(m,1H),1.96(t,J＝6.0Hz,1H),1.78-1.95(m,2H),1.24(s,3H),1.18(s,3H),1.02(d,J＝11.2Hz,1H),0.79(s,3H)。
步骤E：((1R)-2-(苯并呋喃-3-基)-1-((((3-(N,S-二甲基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000183
将((1R)-2-(苯并呋喃-3-基)-1-((((3-(N,S-二甲基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(25mg)溶于甲醇(5mL)中，向此溶液中加入异丁基硼酸(37mg)、1mol/L盐酸(0.1mL)和正己烷(5mL)，室温搅拌过夜，分液去除上层正己烷，并将甲醇相用正己烷洗涤，30℃减压浓缩得到产品(11mg)。
1H NMR(400MHz,CD 3OD)δ7.88(s,1H),7.83(d,J＝7.6Hz,1H),7.60-7.64(m,2H),7.56(d,J＝7.6Hz,1H),7.49(s,1H),7.40(d,J＝7.6Hz,1H),7.16-7.26(m,2H),5.17(s,2H),3.32-3.34(m,1H),3.15(s,3H),2.92-2.97(m,1H),2.82-2.87(m,1H),2.56(s,3H)。
实施例28
(R)-(2-(苯并呋喃-3-基)-1-(2-(4-((二甲基(氧基)-λ 6-磺胺基)氨基)-3-(二甲基氨基)苯基)乙酰胺基)乙基)硼酸
Figure PCTCN2021072666-appb-000184
步骤A：4-溴-3-(二甲基氨基)苯甲酸甲酯
Figure PCTCN2021072666-appb-000185
将3-氨基-4-溴苯甲酸甲酯(5g)、多聚甲醛(15.6g)、醋酸硼氢化钠(23g)溶于乙酸(100mL)中，室温下搅拌96小时。加入二氯甲烷(800mL)稀释反应液，并用水(100mL)洗涤混合溶液3次，有机相依次用饱和食盐水洗涤、无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱层析(1:5乙酸乙酯/石油醚)纯化得到产品(3.56g)。
1H NMR(400MHz,CDCl 3)δ7.72(d,J＝2.0Hz,1H),7.60(d,J＝8.4Hz,1H),7.51(dd,J＝8.4Hz,2.0Hz,1H),3.89(s,3H),2.82(s,6H)。
步骤B：(4-溴-3-(二甲基氨基)苯基)甲醇
Figure PCTCN2021072666-appb-000186
将4-溴-3-(二甲基氨基)苯甲酸甲酯(1g)溶于四氢呋喃(30mL)和乙醇(1mL) 混合溶剂中，在0℃下缓慢加入4mol/L的硼氢化锂四氢呋喃溶液(3.4mL)，升至室温搅拌过夜。加入甲醇淬灭反应，混合溶液减压浓缩，所得残余物经硅胶柱(1:3乙酸乙酯/石油醚)纯化得到产品(0.9g)。
1H NMR(400MHz,CDCl 3)δ7.51(d,J＝8.0Hz,1H),7.09(d,J＝2.0Hz,1H),6.86(dd,J＝8.0Hz,2.0Hz,1H),4.63(s,2H),2.79(s,6H),1.68-1.79(br,1H)。
步骤C：2-溴-5-(溴甲基)-N,N-二甲基苯胺
Figure PCTCN2021072666-appb-000187
将(4-溴-3-(二甲基氨基)苯基)甲醇(0.72g)溶于二氯甲烷(50mL)中，在0℃下依次缓慢加入三苯基膦(1.05g)和四溴化碳(1.33g)，升至室温搅拌过夜。混合溶液减压浓缩，所得残余物经硅胶柱(1:30乙酸乙酯/石油醚)纯化得到产品(476mg)。
1H NMR(400MHz,CDCl 3)δ7.48(d,J＝8.4Hz,1H),7.06(d,J＝2.0Hz,1H),6.88(dd,J＝8.0Hz,2.4Hz,1H),4.40(s,2H),2.79(s,6H)。
步骤D：2-(4-溴-3-(二甲基氨基)苯基)乙腈
Figure PCTCN2021072666-appb-000188
将2-溴-5-(溴甲基)-N,N-二甲基苯胺(0.72g)溶于乙腈(35mL)中，室温下依次缓慢加入三甲基氰硅烷(0.27mL)和三水合四丁基氟化铵(668mg)，升至室温搅拌过夜。反应液用二氯甲烷(150mL)稀释，用水(50mL)洗涤混合溶液三次，有机相依次用饱和食盐水洗涤、无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶柱(1:20乙酸乙酯/石油醚)纯化得到产品(290mg)。
1H NMR(400MHz,CDCl 3)δ7.52(d,J＝8.4Hz,1H),6.98(d,J＝2.0Hz,1H),6.81(dd,J＝8.4Hz,2.0Hz,1H),3.68(s,2H),2.80(s,6H)。
步骤E：2-(4-((二甲基(氧代)-λ 6-亚磺酰基亚氨基)氨基)-3-(二甲基氨基)苯基)乙腈
Figure PCTCN2021072666-appb-000189
N 2保护下，依次将2-(4-溴-3-(二甲基氨基)苯基)乙腈(100mg)、二甲基亚磺酰胺(80mg)、三(二亚苄基丙酮)二钯(20mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(37mg)和碳酸铯(280mg)加入1,4-二氧六环(10mL)中，升温至110℃搅拌过夜。恢复至室温后经硅藻土过滤，滤液减压浓缩，所得残余物经硅胶柱(1:35甲醇/二氯甲烷)纯化得到产品粗品(83mg)。
1H NMR(400MHz,CDCl 3)δ7.18(d,J＝7.6Hz,1H),6.90(s,1H),6.85(d,J＝7.6Hz,1H),3.65(s,2H),3.21(s,6H),2.84(s,6H)。
步骤F：2-(4-((二甲基(氧代)-λ 6-亚磺酰亚氨基)氨基)-3-(二甲基氨基)苯基)乙酸
Figure PCTCN2021072666-appb-000190
将2-(4-((二甲基(氧代)-λ 6-亚磺酰基亚氨基)氨基)-3-(二甲基氨基)苯基)乙腈(83mg)加入乙醇(10mL)中，缓慢加入8mol/L的氢氧化钠水溶液(0.8mL)，升温至80℃搅拌过夜。1mol/L的盐酸溶液调节pH至3，二氯甲烷(50mL)萃取三次，合并有机相，有机相依次用饱和食盐水洗涤、无水硫酸钠干燥，减压浓缩，得粗产品(100mg)直接用于下一步反应。
步骤G：(R)-(2-(苯并呋喃-3-基)-1-(2-(4-((二甲基(氧基)-λ 6-磺胺基)氨基)-3-(二甲基氨基)苯基)乙酰胺基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000191
将2-(4-((二甲基(氧代)-λ 6-亚磺酰亚氨基)氨基)-3-(二甲基氨基)苯基)乙酸(100mg)、(2-(苯并呋喃-3-基)-1-(R)-氨基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(138mg)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(210mg)、N,N-二异丙基乙胺(0.13mL)依次加入二氯甲烷(15mL)中，室温搅拌0.5小时。加1mol/L的盐酸(30mL)淬灭反应，用二氯甲烷(50mL)洗涤混合溶液，分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经硅胶制备板(1:30甲醇/二氯甲烷)纯化得到产品(20mg)。
1H NMR(400MHz,CDCl 3)δ7.60(s,1H),7.53-7.57(m,3H),7.44(d,J＝7.6Hz,1H),7.21-7.29(m,3H),5.65(d,J＝5.2Hz,1H),4.39(d,J＝7.2Hz,1H),3.12-3.16(m,2H),2.60-2.94(m,15H),2.28-2.38(m,1H),2.15-2.23(m,1H),2.01(t,J＝5.6Hz,1H),1.88-1.95(m,2H),1.35(s,3H),1.23(s,3H),1.02(d,J＝10.8Hz,1H),0.80(s,3H)。
步骤H：(R)-(2-(苯并呋喃-3-基)-1-(2-(4-((二甲基(氧基)-λ 6-磺胺基)氨基)-3-(二甲基氨基)苯基)乙酰胺基)乙基)硼酸
Figure PCTCN2021072666-appb-000192
将(R)-(2-(苯并呋喃-3-基)-1-(2-(4-((二甲基(氧基)-λ 6-磺胺基)氨基)-3-(二甲基氨基)苯基)乙酰胺基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(20mg)溶于 甲醇(8mL)中，向此溶液中加入异丁基硼酸(21mg)、1mol/L盐酸(0.3mL)和正己烷(8mL)，室温搅拌过夜，分液去除上层正己烷，将甲醇相用正己烷(20mL)洗涤，减压浓缩，残留物经正己烷/二氯甲烷重结晶得到产品(4mg)。
1H NMR(400MHz,CD 3OD)δ7.57-7.64(m,4H),7.44(d,J＝7.6Hz,1H),7.19-7.30(m,3H),3.29-3.33(m,8H),3.09(dd,J＝8.8Hz,6.4Hz,1H),2.99(dd,J＝14.8Hz,6.0Hz,1H),2.77-2.86(m,7H)。
实施例29
(R)-2-(苯并呋喃-3-基)-1-(3-(2-(二甲基亚磺酰亚胺基)苯基)丙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000193
步骤A：3-(2-(甲硫基)苯基)丙烯酸乙酯
Figure PCTCN2021072666-appb-000194
氮气保护下，0℃下，将膦酰基乙酸三乙酯(1.77g)溶于无水四氢呋喃(50mL)中，分批加入60％氢化钠(379mg),于室温下搅拌30分钟后，缓慢滴加2-(甲硫基)苯甲醛(800mg)的无水四氢呋喃(10mL)溶液，反应液在室温下搅拌3小时。缓慢加水(100mL)淬灭反应，用二氯甲烷(200mL)萃取水相三次，有机相再用饱和食盐水洗涤，减压浓缩至干。残留物经硅胶制备板(1：1石油醚/二氯甲烷)纯化得产品(1.3g)。
1H NMR(400MHz,CDCl 3)δ8.15(d,J＝16.0Hz,1H),7.51(d,J＝8.0Hz,1H),7.29-7.34(m,2H),7.15-7.19(m,1H),6.36(d,J＝16.0Hz,1H),4.26(q,J＝7.2Hz,2H),2.46(s,3H),1.33(t,J＝7.2Hz,3H)。
步骤B：3-(2-(甲硫基)苯基)丙酸乙酯
Figure PCTCN2021072666-appb-000195
氢气氛围下，将3-(2-(甲硫基)苯基)丙烯酸乙酯(1.3g)和雷尼镍(650mg)混于乙醇(30mL)中，室温下搅拌过夜。反应液经硅藻土过滤，滤液减压浓缩后得到产品(1.28g)。
1H NMR(400MHz,CDCl 3)δ7.18-7.20(m,2H),7.15(d,J＝7.2Hz,1H),7.06-7.10(m,1H),4.12(q,J＝7.2Hz,2H),3.01-3.05(m,2H),2.61-2.65(m,2H),2.45(s,3H),1.23(t,J＝7.2Hz,3H)。
步骤C：3-(2-(S-甲基磺酰亚胺基)苯基)丙酸乙酯
Figure PCTCN2021072666-appb-000196
空气氛围下，将3-(2-(甲硫基)苯基)丙酸乙酯(1.28g)、二醋酸碘苯(5.61g)和氨基甲酸铵(2.26g)溶于乙醇(50mL)中，室温搅拌2小时。缓慢加水(200mL)淬灭反应，用二氯甲烷萃取水相三次，有机相用饱和食盐水洗，减压浓缩至干。残留物经硅胶柱(1：1石油醚/乙酸乙酯)纯化得产品(1.0g)。
1H NMR(400MHz,CDCl 3)δ8.10(d,J＝7.6Hz,1H),7.52(t,J＝7.6Hz,1H),7.36-7.40(m,2H),4.11(t,J＝7.2Hz,2H),3.41(t,J＝7.6Hz,2H),3.17(s,3H),2.67-2.80(m,2H),1.22(t,J＝7.6Hz,3H)。
步骤D：3-(2-(二甲基磺酰亚胺基)苯基)丙酸乙酯
Figure PCTCN2021072666-appb-000197
氮气保护下，将3-(2-(S-甲基磺酰亚胺基)苯基)丙酸乙酯(1.0g)和多聚甲醛(558mg)溶于甲酸(10mL)中，升至105℃搅拌5小时。缓慢加水(100mL)淬灭反应，用二氯甲烷(100mL)萃取水相三次，有机相用饱和食盐水洗，减压浓缩至干，得产品(507mg)。
1H NMR(400MHz,CDCl 3)δ7.97(d,J＝7.6Hz,1H),7.49-7.53(m,1H),7.35-7.40(m,2H),4.11(q,J＝7.2Hz,2H),3.40-3.48(m,1H),3.30-3.38(m,1H),3.13(s,3H),2.63-2.79(m,5H),1.21(t,J＝7.2Hz,3H)。
步骤E：3-(2-(二甲基磺酰亚胺基)苯基)丙酸
Figure PCTCN2021072666-appb-000198
将3-(2-(二甲基磺酰亚胺基)苯基)丙酸乙酯(234mg)和氢氧化钠(42mg)溶于四氢呋喃(12mL)和水(3mL)的混合溶剂中，升至65℃搅拌1小时。恢复至室温后，加入1mol/L的稀盐酸(5mL)，用乙酸乙酯萃取反应液三次，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤后减压浓缩得产品(211mg)。
1H NMR(400MHz,CDCl 3)δ11.68(brs,1H),8.07(d,J＝8.0Hz,1H),7.75(t,J＝7.2Hz,1H),7.58(d,J＝7.6Hz,1H),7.54(t,J＝7.6Hz,1H),3.99(s,3H),3.43-3.54(m,1H),3.10-3.19(m,1H),2.87(t,J＝5.2Hz,2H),2.78(s,3H)。
步骤F：(R)-2-(苯并呋喃-3-基)-1-(3-(2-(二甲基亚磺酰亚胺基)苯基)丙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000199
将3-(2-(二甲基磺酰亚胺基)苯基)丙酸(152mg)和(R)-2-(苯并呋喃-3-基)-1-氨基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(285mg)溶于二氯甲烷(20mL)中，依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(288mg)和4-二甲基氨基吡啶(94mg)，室温搅拌1小时。加水(100mL)淬灭反应。用二氯甲烷萃取水相三次，合并有机相并用饱和食盐水洗，无水硫酸钠干燥 后，减压浓缩至干。残留物经硅胶制备板(21：1二氯甲烷/甲醇)纯化得产品(179mg)。
1H NMR(400MHz,CDCl 3)δ7.84-7.93(m,1H),7.35-7.55(m,6H),7.16-7.28(m,2H),4.20-4.26(m,1H),3.30-3.41(m,1H),3.14-3.25(m,1H),2.99-3.09(m,2.5H),2.92-2.98(m,2.5H),2.84-2.90(m,1H),2.60-2.79(m,2H),2.53(s,1.5H),2.42(s,1.5H),2.28-2.36(m,1H),2.09-2.16(m,1H),1.97-2.01(m,1H),1.78-1.88(m,2H),1.22-1.26(m,7H),0.85(s,3H)。
步骤G：(R)-2-(苯并呋喃-3-基)-1-(3-(2-(二甲基亚磺酰亚胺基)苯基)丙酰胺基)乙基硼酸
Figure PCTCN2021072666-appb-000200
(R)-2-(苯并呋喃-3-基)-1-(3-(2-(二甲基亚磺酰亚胺基)苯基)丙酰胺基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(179mg)溶于甲醇(10mL)和正己烷(10mL)的混合溶剂中，依次加入异丁基硼酸(163mg)和1mol/L的稀盐酸(0.5mL)，室温搅拌过夜。加入甲醇(20mL)萃取反应液，经三次正己烷(20mL)洗涤，收集甲醇相，减压浓缩。残留物经硅胶制备板(1：10甲醇/二氯甲烷)纯化得产品(32mg)。
1H NMR(400MHz,CD 3OD)δ7.92(d,J＝8.0Hz,1H),7.60-7.65(m,1H),7.44-7.55(m,4H),7.41(d,J＝8.8Hz,1H),7.25(t,J＝7.6Hz,1H),7.20(t,J＝7.6Hz,1H),3.38-3.54(m,2H),3.17(s,3H),2.91-2.96(m,1H),2.78-2.89(m,3H),2.59-2.67(m,4H)。
实施例30
((1R)-2-(苯并呋喃-3-基)-1-((((6-(S-甲基磺酰亚胺基)吡啶-2-基)甲氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000201
步骤A：6-(甲硫基)吡啶甲酸
Figure PCTCN2021072666-appb-000202
将6-氯吡啶甲酸甲酯(1.0g)、S-甲基异硫脲硫酸盐(2.14g)和无水碳酸铯(7.43g)混于二甲亚砜(25mL)中，氮气保护下，加热至85℃反应过夜。将反应液恢复至室温后，加水(30mL)淬灭反应，用1mol/L盐酸调pH至5，用乙酸乙酯萃取，合并有机相，依次用水和饱和食盐水洗，有机相经无水硫酸钠干燥，过滤后蒸干溶剂，残留物经过硅胶柱层析(50％乙酸乙酯/石油醚混合液)纯 化得到产物(0.8g)。
1H NMR(400MHz,CDCl 3)δ7.88-7.91(m,1H),7.71(t,J＝8.0Hz,1H),7.43(d,J＝8.0Hz,1H),2.62(s,3H)。
步骤B：(6-(甲硫基)吡啶-2-基)甲醇
Figure PCTCN2021072666-appb-000203
将6-(甲硫基)吡啶甲酸(750mg)溶于无水四氢呋喃(20mL)中，氮气保护下冷却至0℃。向体系内滴加1mol/L二异丙基氢化铝的甲苯溶液(14mL)。恢复至室温后搅拌至反应完全，向体系内依次缓慢加入乙酸乙酯(100mL)和1mol/L的氢氧化钠水溶液(50mL)。有机相分离，并用无水硫酸钠干燥，蒸干溶剂得到目标产品(320mg)。
1H NMR(400MHz,CDCl 3)δ7.43(t,J＝8.0Hz,1H),7.02(d,J＝8.0Hz,1H),6.88(d,J＝8.0Hz,1H),4.65(s,2H),3.92(brs,1H),2.50(s,3H)。
步骤C：(6-(羟甲基)吡啶-2-基)(亚氨基)(甲基)-λ 6-砜
Figure PCTCN2021072666-appb-000204
将(6-(甲硫基)吡啶-2-基)甲醇(160mg)、二乙酸碘苯(1.0g)和氨基甲酸铵(402mg)加入甲醇(20mL)中，室温下在空气氛下搅拌过夜。蒸干溶剂，所得残留物经过硅胶柱层析(2％-10％甲醇/二氯甲烷混合液)纯化得到产品(182mg)。
1H NMR(400MHz,CDCl 3)δ8.00(d,J＝7.6Hz,1H),7.92(t,J＝7.6Hz,1H),7.54(d,J＝7.6Hz,1H),4.84(s,2H),3.24(s,3H),2.98(brs,2H)。
步骤D：((1R)-2-(苯并呋喃-3-基)-1-((((6-(S-甲基磺酰亚胺基)吡啶-2-基)甲氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000205
氮气保护下，将2-(苯并呋喃-3-基)-1-(R)-氨基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(450mg)溶于二氯甲烷(20mL)中，冷却至-60℃，加入三光气(118mg)的二氯甲烷(5mL)溶液，缓慢滴加三乙胺(404mg)的二氯甲烷(5mL)溶液，保持低温搅拌30分钟，加入(6-(羟甲基)吡啶-2-基)(亚氨基)(甲基)-λ 6-砜(180mg)，恢复至室温，搅拌1小时。用水淬灭反应，并用二氯甲烷萃取，有机相用1mol/L盐酸和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经硅胶制备板(1:3乙酸乙酯/石油醚)纯化得到产品(121mg)。
1H NMR(400MHz,CDCl 3)δ8.01(d,J＝7.6Hz,1H),7.89(t,J＝7.6Hz,1H),7.56(d,J＝7.6Hz,1H),7.43-7.49(m,3H),7.28(d,J＝8.0Hz,1H),7.18-7.21(m,1H),5.23-5.34(m,2H),5.19(d,J＝6.0Hz,1H),4.29(d,J＝8.8Hz,1H),3.58(q,J＝6.4Hz,1H),3.24(s,3H),3.12-3.17(m,1H),2.96-3.02(m,1H),2.27-2.34(m,1H),2.08-2.14(m,1H),1.97(t,J＝6.0Hz,1H),1.79-1.89(m,3H),1.25(s,3H),1.19(s, 3H),1.04(d,J＝11.2Hz,1H),0.79(s,3H)。
步骤E：((1R)-2-(苯并呋喃-3-基)-1-((((6-(S-甲基磺酰亚胺基)吡啶-2-基)甲氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000206
将((1R)-2-(苯并呋喃-3-基)-1-((((6-(S-甲基磺酰亚胺基)吡啶-2-基)甲氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(120mg)溶于甲醇(5mL)中，向此溶液中加入异丁基硼酸(115mg)、1mol/L盐酸(0.1mL)和正己烷(5mL)，室温搅拌过夜，分液去除上层正己烷，并将甲醇相用正己烷洗涤后30℃浓缩至得到产品(21mg)。
1H NMR(400MHz,CD 3OD)δ8.01-8.08(m,2H),7.59(d,J＝7.6Hz,1H),7.54(d,J＝7.6Hz,1H),7.53(s,1H),7.41(d,J＝8.0Hz,1H),7.17-7.26(m,2H),5.21(s,2H),4.54-4.56(m,1H),3.36-3.40(m,1H),3.23(s,3H),2.94-2.99(m,1H),2.85-2.91(m,1H)。
实施例31
(R)-2-(苯并呋喃-3-基)-1-((((2-(S-甲基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基硼酸
Figure PCTCN2021072666-appb-000207
步骤A：2-(S-甲基磺酰亚胺基)苄醇
Figure PCTCN2021072666-appb-000208
氮气保护下，将亚氨基(甲基)(2-((((四氢-2H-吡喃-2-基)氧基)甲基)苯基)-λ 6-砜(2.16g)和对甲苯磺酸(207mg)溶于甲醇(30mL)中，45℃搅拌过夜。加水(100mL)淬灭反应，用二氯甲烷(100mL)萃取水相三次，再用饱和食盐水(100mL)洗涤有机相，减压浓缩，经硅胶制备板(1：30甲醇/二氯甲烷)纯化得产品(130mg)。
步骤B：(R)-2-(苯并呋喃-3-基)-1-((((2-(S-甲基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000209
将(R)-2-(苯并呋喃-3-基)-1-氨基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(330mg)溶于无水二氯甲烷中，冷却至-60℃，依次滴加三光气(104mg)的二氯甲烷(5mL)溶液和三乙胺(354mg)的二氯甲烷(5mL)溶液，-60℃下搅拌30分钟后，逐滴添加2-(S-甲基磺酰亚胺基)苄醇(130mg)的二氯甲烷(5mL)溶液，自然升至室温并搅拌过夜。加水淬灭反应，用二氯甲烷(100mL)萃取水相三次，有机相用饱和食盐水洗后经无水硫酸钠干燥，过滤后减压浓缩，经硅胶制备板(2：1石油醚/乙酸乙酯)纯化得产品(20mg)。
1H NMR(400MHz,CDCl 3)δ8.10(d,J＝8.4Hz,1H),7.38-7.60(m,6H),7.14-7.28(m,2H),5.48-5.70(m,2H),5.11(d,J＝6.0Hz,1H),4.24-4.29(m,1H),3.47-3.53(m,1H),3.24(s,3H),3.08-3.16(m,1H),2.92-2.98(m,1H),2.25-2.32(m,1H),2.06-2.11(m,1H),1.72-2.02(m,3H),1.29(s,3H),1.25(s,3H),1.04(d,J＝11.2Hz,1H),0.78(s,3H)。
步骤C：(R)-2-(苯并呋喃-3-基)-1-((((2-(S-甲基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基硼酸
Figure PCTCN2021072666-appb-000210
将(R)-2-(苯并呋喃-3-基)-1-((((2-(S-甲基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(20mg)溶于甲醇(5mL)和正己烷(5mL)的混合溶剂中，依次加入异丁基硼酸(19mg)和1mol/L稀盐酸(0.25mL)，室温搅拌过夜。分液分离出甲醇相，并用正己烷(20mL)洗涤三次减压浓缩至干。残留物经硅胶制备板(1：10甲醇/二氯甲烷)纯化得产品(3mg)。
1H NMR(400MHz,CD 3OD)δ8.05-8.09(m,1H),7.59-7.67(m,2H),7.47-7.56(m,3H),7.39(d,J＝7.6Hz,1H),7.23(t,J＝7.6Hz,1H),7.16(t,J＝7.6Hz,1H),5.46-5.62(m,2H),3.27-3.33(m,1H),3.18(s,3H),2.90-2.97(m,1H),2.81-2.87(m,1H)。
实施例32
((1R)-2-(苯并呋喃-3-基)-1-((((6-(N,S-二甲基磺酰亚胺基)吡啶-2-基)甲氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000211
步骤A：(6-(羟甲基)吡啶-2-基)(甲基亚氨基)(甲基)-λ 6-砜
Figure PCTCN2021072666-appb-000212
将(6-(羟甲基)吡啶-2-基)(亚氨基)(甲基)-λ 6-砜(50mg)和多聚甲醛(35mg)混于甲酸(10mL)中，加热至回流搅拌过夜。蒸干溶剂所得残留物经过硅胶柱层析(2％-10％甲醇/二氯甲烷混合液)纯化得到产品(33mg)。
1H NMR(400MHz,CDCl 3)δ8.00(d,J＝7.2Hz,1H),7.93(t,J＝8.0Hz,1H),7.55(d,J＝8.0Hz,1H),4.80-4.91(m,2H),3.23(s,3H),2.61(s,3H),1.61-2.20(br,1H)。
步骤B：((1R)-2-(苯并呋喃-3-基)-1-((((6-(N,S-甲基磺酰亚胺基)吡啶-2-基)甲氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000213
氮气保护下，将2-(苯并呋喃-3-基)-1-(R)-氨基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(50mg)溶于二氯甲烷(5mL)中，冷却至-60℃，加入三光气(22mg)的二氯甲烷(5mL)溶液，缓慢滴加三乙胺(24mg)的二氯甲烷(5mL)溶液，保持低温搅拌30分钟，加入(6-(羟甲基)吡啶-2-基)(甲基亚氨基)(甲基)-λ 6-砜(30mg)，恢复至室温，搅拌1小时。用水淬灭反应，并用二氯甲烷萃取，有机相用1mol/L盐酸和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经硅胶制备板(1:3乙酸乙酯/石油醚)纯化得到产品(25mg)。
1H NMR(400MHz,CDCl 3)δ8.00(d,J＝7.6Hz,1H),7.90(t,J＝7.6Hz,1H),7.57(d,J＝6.8Hz,1H),7.43-7.46(m,3H),7.28(d,J＝7.6Hz,1H),7.18-7.27(m,1H),5.24-5.34(m,2H),4.29(d,J＝8.0Hz,1H),3.97(d,J＝8.8Hz,1H),3.57-3.59(m,1H),3.24(s,3H),3.14-3.16(m,1H),2.97-3.02(m,1H),2.61(s,3H),2.42-2.47(m,1H),2.28-2.34(m,1H),2.16-2.30(m,1H),1.97-1.99(m,1H),1.79-1.91(m,1H),1.26(s,3H),1.20(s,3H),1.03(d,J＝11.2Hz,1H),0.79(s,3H)。
步骤C：((1R)-2-(苯并呋喃-3-基)-1-((((6-(N,S-二甲基磺酰亚胺基)吡啶-2-基)甲氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000214
将((1R)-2-(苯并呋喃-3-基)-1-((((6-(N,S-甲基磺酰亚胺基)吡啶-2-基)甲氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(20mg)溶于甲醇(3mL)中，向此溶液中加入异丁基硼酸(25mg)、1mol/L盐酸(0.1mL)和正己烷(3mL)，室温搅拌过夜，分液去除上层正己烷，并将甲醇相用正己烷洗涤后30℃浓缩至得到产品(9mg)。
1H NMR(400MHz,CD 3OD)δ8.27(d,J＝4.4Hz,2H),7.77-7.79(m,1H),7.59(d,J＝7.6Hz,1H),7.54(s,1H),7.41(d,J＝8.0Hz,1H),7.17-7.27(m,2H),5.25(s,2H),3.93-3.98(m,1H),3.30-3.33(m,1H),3.23(s,3H),2.85-2.96(m,1H),2.74(s,3H)。
实施例33
((1R)-2-(苯并呋喃-3-基)-1-((((5-氯-2-(N-甲基-乙基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000215
步骤A：5-氯-2-(甲硫基)-苯甲酸甲酯
Figure PCTCN2021072666-appb-000216
将5-氯-2-巯基-苯甲酸甲酯(1.0g)溶于甲醇(20mL)中，冷却至0℃后加入氢氧化钠(580mg)和碘甲烷(1.03g)，恢复至室温搅拌过夜，加水(20mL)淬灭反应，并用二氯甲烷萃取，有机相经无水硫酸钠干燥后蒸干溶剂得到产物(0.7g)。
1H NMR(400MHz,CDCl 3)δ7.96(d,J＝1.6Hz,1H),7.42(dd,J＝8.4Hz,2.4Hz,1H),7.18(d,J＝8.4Hz,1H),3.91(s,3H),2.43(s,3H)。
步骤B：(5-氯-2-(甲硫基)苯基)甲醇
Figure PCTCN2021072666-appb-000217
将5-氯-2-(甲硫基)-苯甲酸甲酯(750mg)溶于无水四氢呋喃(20mL)中， 氮气保护下冷却至0℃。向体系内滴加1mol/L二异丙基氢化铝的甲苯溶液(10mL)。恢复至室温后搅拌至反应完全，向体系内依次缓慢加入乙酸乙酯(80mL)和1mol/L的氢氧化钠水溶液(40mL)。分出有机相，并用无水硫酸钠干燥，蒸干溶剂得到目标产品(205mg)。
1H NMR(400MHz,CDCl 3)δ7.39(d,J＝1.6Hz,1H),7.21-7.24(m,1H),7.16(s,1H),4.69(s,2H),2.45(s,3H),2.20(brs,1H)。
步骤C：(4-氯-2-(羟甲基)苯基)(亚氨基)(甲基)-λ 6-砜
Figure PCTCN2021072666-appb-000218
将(5-氯-2-(甲硫基)苯基)甲醇(170mg)、二乙酸碘苯(870mg)和氨基甲酸铵(352mg)加入甲醇(20mL)中，室温下在空气氛下搅拌过夜。蒸干溶剂所得残留物经过硅胶柱层析(2％-10％甲醇/二氯甲烷混合液)纯化得到产品(111mg)。
1H NMR(400MHz,CDCl 3)δ7.82(d,J＝8.4Hz,1H),7.43(dd,J＝8.4Hz,2.0Hz,1H),7.36(d,J＝2.0Hz,1H),4.61-4.74(m,2H),4.00(brs,1H),2.74(s,3H)。
步骤D：(4-氯-2-(羟甲基)苯基)(甲基亚氨基)(乙基)-λ 6-砜
Figure PCTCN2021072666-appb-000219
将(4-氯-2-(羟甲基)苯基)(亚氨基)(甲基)-λ 6-砜(110mg)和无水碳酸钾(215mg)混于N,N-二甲基甲酰胺(10mL)中，冷却至0℃后加入碘甲烷(230mg)。恢复至室温搅拌过夜。加水(50mL)淬灭反应，并用二氯甲烷萃取，有机相经无水硫酸钠干燥后过滤，蒸干滤液所得残留物经过硅胶柱层析(10％甲醇/二氯甲烷混合液)纯化得到产品(115mg)。
1H NMR(400MHz,CDCl 3)δ7.84(d,J＝8.4Hz,1H),7.52(d,J＝2.0Hz,1H),7.46(dd,J＝8.4Hz,2.0Hz,1H),4.73-4.82(m,2H),4.38(brs,1H),3.23-3.33(m,2H),2.76(s,3H),1.24(t,J＝7.2Hz,3H)。
步骤E：((1R)-2-(苯并呋喃-3-基)-1-((((5-氯-2-(N-甲基-乙基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000220
氮气保护下，将2-(苯并呋喃-3-基)-1-(R)-氨基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(145mg)溶于二氯甲烷(10mL)中，冷却至-60℃，加入 三光气(38mg)的二氯甲烷(1mL)溶液，缓慢滴加三乙胺(130mg)的二氯甲烷(1mL)溶液，保持低温搅拌30分钟，加入(4-氯-2-(羟甲基)苯基)(甲基亚氨基)(乙基)-λ 6-砜(80mg)，恢复至室温，搅拌1小时。用水淬灭反应，并用二氯甲烷萃取，有机相用1mol/L盐酸和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经硅胶制备板(1:3乙酸乙酯/石油醚)纯化得到产品(112mg)。
1H NMR(400MHz,CDCl 3)δ7.84(d,J＝8.4Hz,1H),7.58-7.59(m,1H),7.54(d,J＝8.0Hz,1H),7.41-7.45(m,3H),7.18-7.28(m,2H),5.39-5.55(m,2H),5.16(d,J＝6.4Hz,1H),4.27(d,J＝7.2Hz,1H),3.49-3.54(m,1H),3.45(s,2H),3.27(q,J＝7.6Hz,2H),3.08-3.13(m,1H),2.94-2.99(m,1H),2.65(s,3H),2.26-2.32(m,1H),2.06-2.12(m,1H),1.96(t,J＝6.0Hz,1H),1.76-1.86(m,3H),1.23(s,3H),1.16(s,3H),1.04(d,J＝10.8Hz,1H),0.78(s,3H)。
步骤F：((1R)-2-(苯并呋喃-3-基)-1-((((5-氯-2-(N-甲基-乙基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000221
将((1R)-2-(苯并呋喃-3-基)-1-((((5-氯-2-(N-甲基-乙基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(112mg)溶于甲醇(5mL)中，向此溶液中加入异丁基硼酸(89mg)、1mol/L盐酸(0.3mL)和正己烷(5mL)，室温搅拌过夜，分液去除上层正己烷，并将甲醇相用正己烷洗涤后30℃浓缩至得到产品(41mg)。
1H NMR(400MHz,CD 3OD)δ7.83(dd,J＝8.4Hz,1.6Hz,1H),7.67(s,1H),7.53-7.56(m,2H),7.48(s,1H),7.37(d,J＝8.0Hz,1H),7.13-7.23(m,2H),5.35-5.46(m,2H),3.29-3.33(m,2H),2.95-3.01(m,1H),2.82-2.88(m,1H),2.58(s,3H),2.56-2.57(m,1H),1.12-1.17(m,3H)。
实施例34
((1R)-2-(苯并呋喃-3-基)-1-((((5-环丙基-2-(N,S-二甲基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000222
步骤A：(5-溴-2-(甲硫基)苯基)甲醇
Figure PCTCN2021072666-appb-000223
将5-溴-2-(甲硫基)苯甲酸甲酯(5.0g)溶于无水四氢呋喃(100mL)中，冷却至0℃，向反应液中分批加入氢化铝锂(1.1g)，恢复至室温后搅拌1小时。小心向反应液中滴加乙酸乙酯(100mL)和1mol/L盐酸(150mL)。分出有机相并用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经过硅胶柱层析(10％-50％乙酸乙酯/石油醚混合液)纯化得到产品(4.1g)。
1H NMR(400MHz,CDCl 3)δ7.54(d,J＝2.0Hz,1H),7.38(dd,J＝8.4Hz,2.0Hz,1H),7.09(d,J＝8.0Hz,1H),4.71(s,2H),2.45(s,3H)。
步骤B：2-((5-溴-2-(甲硫基)苄基)氧基)四氢-2H-吡喃
Figure PCTCN2021072666-appb-000224
将(5-溴-2-(甲硫基)苯基)甲醇(4.0g)、3,4-二氢-2H-吡喃(10mL)和对甲苯磺酸一水合物(15mg)溶于四氢呋喃(50mL)中，室温下搅拌过夜，向体系内加入乙酸乙酯(100mL)和1mol/L氢氧化钠水溶液(70mL)。有机相分离，并用无水硫酸钠干燥，蒸干溶剂所得残留物经硅胶柱层析(10％-20％乙酸乙酯/石油醚混合液)纯化得到目标产品(4.6g)。
1H NMR(400MHz,CDCl 3)δ7.56(d,J＝1.6Hz,1H),7.36(dd,J＝8.4Hz,2.0Hz,1H),7.08(d,J＝8.4Hz,1H),4.73-4.79(m,2H),4.49-4.52(m,1H),3.87-3.93(m,1H),3.53-3.58(m,1H),2.43(s,3H),1.84-1.89(m,1H),1.41-1.78(m,5H)。
步骤C：2-((5-环丙基-2-(甲硫基)苄基)氧基)四氢-2H-吡喃
Figure PCTCN2021072666-appb-000225
将2-((5-溴-2-(甲硫基)苄基)氧基)四氢-2H-吡喃(1.0g)、环丙基硼酸(0.54g)、四(三苯基膦)钯(0.36g)和碳酸钾(1.3g)混于甲苯(50mL)中，充分置换氮气后，加热回流过夜。恢复至室温后，反应液经硅藻土过滤，滤液蒸干溶剂所得残留物经硅胶柱层析(10％-20％乙酸乙酯/石油醚混合液)纯化得到产品(0.71g)。
1H NMR(400MHz,CDCl 3)δ7.31(s,1H),7.18(d,J＝8.0Hz,1H),6.96(dd,J＝8.0Hz,2.0Hz,1H),4.73-4.79(m,2H),4.55-4.58(m,1H),3.92-3.97(m,1H),3.54-3.57(m,1H),2.41(s,3H),1.84-1.88(m,2H),1.52-1.74(m,5H),0.90-0.95(m,2H),0.64-0.68(m,2H)。
步骤D：(4-环丙基-2-(((四氢-2H-吡喃-2-基)氧基)甲基)苯基)(亚氨基)(甲基)-λ 6-砜
Figure PCTCN2021072666-appb-000226
将2-((5-环丙基-2-(甲硫基)苄基)氧基)四氢-2H-吡喃(700mg)、二乙酸碘苯(2.43g)和氨基甲酸铵(982mg)加入甲醇(20mL)中，室温下在空气氛下搅拌过夜。蒸干溶剂所得残留物经过硅胶柱层析(2％-10％甲醇/二氯甲烷混合液)纯化得到产品(374mg)。
1H NMR(400MHz,CDCl 3)δ7.97(dd,J＝8.0Hz,6.0Hz,1H),7.30(d,J＝10.8Hz,1H),7.08(dt,J＝8.0Hz,2.4Hz,1H),4.99-5.16(m,2H),4.73-4.76(m,1H),3.86-3.91(m,1H),3.52-3.56(m,1H),3.17-3.18(m,3H),1.91-1.98(m,2H),1.53-1.73(m,5H),1.04-1.09(m,2H),0.75-0.79(m,2H)。
步骤E：(4-环丙基-2-(((四氢-2H-吡喃-2-基)氧基)甲基)苯基)(甲基亚氨基)(甲基)-λ 6-砜
Figure PCTCN2021072666-appb-000227
将(4-环丙基-2-(((四氢-2H-吡喃-2-基)氧基)甲基)苯基)(亚氨基)(甲基)-λ 6-砜(300mg)溶于无水四氢呋喃(10mL)和N,N-二甲基甲酰胺(5mL)中，冷却至0℃，向体系内加入60％NaH固体(60mg),在0℃下搅拌半小时，加入碘甲烷(150mg)。反应液恢复至室温后搅拌过夜。加水(10mL)淬灭反应，用乙酸乙酯萃取，有机相经饱和食盐水洗并用无水硫酸钠干燥，过滤后蒸干滤液，所得残留物经过硅胶柱层析(2％-10％甲醇/二氯甲烷混合液)纯化得到产品(213mg)。
1H NMR(400MHz,CDCl 3)δ7.88(t,J＝8.0Hz,1H),7.34(dd,J＝7.6Hz,1.6Hz,1H),7.10(d,J＝8.0Hz,1H),4.93-5.06(m,2H),4.73-4.74(m,1H),3.86-3.91(m,1H),3.53-3.57(m,1H),3.12-3.26(m,3H),2.63-2.65(m,3H),1.92-1.98(m,2H),1.54-1.85(m,5H),1.04-1.09(m,2H),0.75-0.80(m,2H)。
步骤F：(4-环丙基-2-(羟甲基)苯基)(甲基亚氨基)(甲基)-λ 6-砜
Figure PCTCN2021072666-appb-000228
将(4-环丙基-2-(((四氢-2H-吡喃-2-基)氧基)甲基)苯基)(甲基亚氨基)(甲基)-λ 6-砜(210mg)和对甲苯磺酸一水合物(20mg)混于甲醇(15mL)中，室温下搅拌过夜。加入1mol/L氢氧化钠水溶液(5mL)淬灭反应，并用乙酸乙酯萃取，有机相经饱和食盐水洗并用无水硫酸钠干燥，过滤，滤液减压浓缩蒸干溶剂，所得残留物经过硅胶制备板(5％甲醇/二氯甲烷混合液)纯化得到产品(130mg)。
1H NMR(400MHz,CDCl 3)δ7.82(d,J＝8.4Hz,1H),7.14(d,J＝1.6Hz,1H),7.11(dd,J＝8.0Hz,1.6Hz,1H),4.69-4.85(m,2H),3.12(s,3H),2.75(s,3H), 1.89-1.95(m,1H),1.03-1.08(m,2H),0.75-0.79(m,2H)。
步骤G：((1R)-2-(苯并呋喃-3-基)-1-((((5-环丙基-2-(N,S-二甲基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯
Figure PCTCN2021072666-appb-000229
氮气保护下，将2-(苯并呋喃-3-基)-1-(R)-氨基乙基硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯盐酸盐(245mg)溶于二氯甲烷(15mL)中，冷却至-60℃，加入三光气(64mg)的二氯甲烷(2mL)溶液，缓慢滴加三乙胺(220mg)的二氯甲烷(5mL)溶液，保持低温搅拌30分钟，加入(4-氯-2-(羟甲基)苯基)(甲基亚氨基)(乙基)-λ 6-砜(130mg)，恢复至室温，搅拌1小时。用水淬灭反应，并用二氯甲烷萃取，有机相用1mol/L盐酸和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经硅胶制备板(1:3乙酸乙酯/石油醚)纯化得到产品(55mg)。
1H NMR(400MHz,CDCl 3)δ7.84(d,J＝8.0Hz,1H),7.52(d,J＝8.0Hz,1H),7.48(d,J＝8.0Hz,1H),7.39-7.43(m,2H),7.19-7.22(m,1H),7.14-7.16(m,1H),5.09-5.27(m,3H),4.46(t,J＝11.2Hz,1H),4.21-4.29(m,2H),3.49-3.56(m,1H),3.44(s,3H),3.08-3.14(m,1H),2.89-2.98(m,1H),2.25-2.31(m,1H),1.90-1.96(m,2H),1.84-1.86(m,1H),1.74-1.82(m,2H),1.31(d,J＝10.0Hz,1H),1.23(s,3H),1.17(s,3H),0.99-1.06(m,3H),0.78(s,3H),0.74-0.76(m,2H)。
步骤H：((1R)-2-(苯并呋喃-3-基)-1-((((5-环丙基-2-(N,S-二甲基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基)硼酸
Figure PCTCN2021072666-appb-000230
将((1R)-2-(苯并呋喃-3-基)-1-((((5-环丙基-2-(N,S-二甲基磺酰亚胺基)苄基)氧基)羰基)氨基)乙基)硼酸-(1S,2S,3R,5S)-(+)-蒎烷-2,3-二醇酯(50mg)溶于甲醇(5mL)中，向此溶液中加入异丁基硼酸(40mg)、1mol/L盐酸(0.1mL)和正己烷(5mL)，室温搅拌过夜，分液去除上层正己烷，将甲醇相用正己烷洗涤，减压浓缩得到产品(11mg)。
1H NMR(400MHz,CD 3OD)δ7.92-7.96(m,1H),7.39-7.56(m,5H),7.22-7.26(m,1H),7.16-7.18(m,1H),5.25-5.43(m,2H),3.92(s,3H),2.85-2.91(m,3H),2.82(s,3H),2.08-2.12(m,1H),1.18-1.20(m,2H),0.86-0.89(m,2H)。
生物测试
1.化合物对LMP7酶学抑制活性的测定：
LMP7是免疫蛋白酶体的催化亚基，本实验利用其水解酶活性建立了酶学检测方法平台，并用于化合物的活性检测。利用Ac-ANW-AMC(BonstonBiochem，Cat#S-320)作为LMP7的底物，水解之后释放的荧光基团AMC(7-Amino-4-methylcoumarin，7-氨基-4-甲基香豆素)的量可以反应酶学活性。MOLT-4细胞是人急性淋巴母细胞白血病细胞，经鉴定是LMP7高表达的细胞。我们用MOLT-4细胞裂解液作为LMP7的酶源建立了化合物对LMP7的酶学检测方法并进行了化合物抑制活性(半抑制浓度，IC 50)的检测。
MOLT-4细胞用含有10％胎牛血清(Biological Industries)和1％Pen Strep(Gibco)的RPMI-1640(Biological Industries)培养基在75cm 2细胞培养瓶(Corning)中进行培养(37℃，95％空气和5％的CO 2)，一周传代2-3次。收集1x10 7个MOLT-4细胞，用1ml PBS(Solarbio)重悬，3000rpm，离心5分钟。吸掉上清。用500μl裂解缓冲液(20mM Tris，pH 8.0，5mM EDTA，用时加Protease inhibitor(1：1000)和Phosphatase Inhibitor(1:100))重悬细胞，冰上放置30分钟。超声破碎细胞，0.5S on，0.5S off，超声时间2.5S。12000rpm，4℃，离心10分钟。上清即为细胞裂解液，用BCA法(Thermo，#23225)蛋白定量。
化合物用100％DMSO进行5倍的梯度稀释，共9个浓度，每个浓度取2μl加入到48μl的反应缓冲液中(20mM Tris，pH 8.0，0.5mM EDTA)混匀，作为4*化合物(终浓度为2000，400，80，16，3.2，0.64，0.128，0.0256，0nM)待用。使用反应缓冲液配制4*MOLT-4细胞裂解液，终浓度为20ng/μl，2*Ac-ANW-AMC，终浓度为100μM。取5μl的4*化合物加入到384孔板(OptiPlate-384，购买于PerkinElmer)，加入5μl 4*细胞裂解液，离心，23℃孵育箱中反应1小时。加入10μl的2*Ac-ANW-AMC，离心启动反应，23℃避光反应2小时。反应结束后在CLARIO star Plus(购买于BMG LRBTECH)上读取信号值(激发波长345nm/发射波长445nm)。每个化合物分别在9个浓度下测定酶的活性，数据使用GraphPad Prism软件进行处理，计算得到化合物对LMP7的半抑制浓度，即IC 50值。
2.化合物对β5酶学抑制活性的测定：
β5是蛋白酶体的催化亚基，本实验利用其水解酶活性建立了酶学检测方法平台，并用于化合物的活性检测。利用Ac-WLA-AMC(BonstonBiochem，Cat#S-330)作为β5的底物，水解之后释放的荧光基团AMC(7-Amino-4-methylcoumarin，7-氨基-4-甲基香豆素)的量可以反应酶学活性。HEK-293是人胚肾细胞，组成型表达蛋白酶体，不表达免疫蛋白酶体。我们用HEK-293细胞裂解液作为β5的酶源建立了化合物对β5的酶学检测方法并进行了化合物抑制活性(半抑制浓度，IC 50)的检测。化合物对β5的酶学抑制活性作为化合物选择性的检测指标。
HEK-293细胞用含有10％胎牛血清(Biological Industries)和1％Pen Strep(Gibco)的DMEM(Biological Industries)培养基在75cm 2细胞培养瓶(Corning)中进行培养(37℃，95％空气和5％的CO 2)，一周传代2-3次。收集1x10 7个HEK-293细胞，用1ml PBS(Solarbio)重悬，3000rpm，离心5分钟。吸掉上清。用500μl裂解缓冲液(20mM Tris，pH 8.0，5mM EDTA，用时加Protease inhibitor(1：1000)和Phosphatase Inhibitor(1:100))重悬细胞，冰上放置30分钟。超声破碎细胞，0.5S on，0.5S off，超声时间2.5S。12000rpm，4℃，离心10分钟。上清即为细胞裂解液，用BCA法(Thermo，#23225)蛋白定量。
化合物用100％DMSO进行5倍的梯度稀释，共9个浓度，每个浓度取2μl加入到48μl的反应缓冲液中(20mM Tris,pH 8.0,0.5mM EDTA)混匀，作为4*化合物(终浓度为100000，20000，4000，800，160，32，6.4，1.28，0nM)待用。使用反应缓冲液配制4*HEK-293细胞裂解液，终浓度为25ng/μl，2*Ac-WLA-AMC，终浓度为20μM。取5μl的4*化合物加入到384孔板(OptiPlate-384，购买于PerkinElmer)，加入5μl 4*HEK-293细胞裂解液，离心，23℃孵育箱中反应1小时。加入10μl的2*Ac-WLA-AMC，离心启动反应，23℃避光反应2小时。反应结束后在CLARIO star Plus(购买于BMG LRBTECH)上读取信号值(激发波长345nm/发射波长445nm)。每个化合物分别在9个浓度下测定酶的活性，数据使用GraphPad Prism软件进行处理，计算得到化合物对β5的半抑制浓度，即IC 50值。
前述“*”是指乘，表示倍数。
上述部分化合物的测试结果如表1所示。
表1：化合物的体外活性测试结果
Figure PCTCN2021072666-appb-000231
3.化合物的细胞活性的测定：
MOLT-4是人急性淋巴母细胞白血病细胞，经鉴定是LMP7高表达的细胞。本实验将化合物与MOLT-4预孵育，使用Ac-ANW-AMC(BonstonBiochem，Cat#S-320)作为LMP7的底物，建立了化合物对细胞内LMP7的酶活性的检测方法并进行了化合物抑制活性(半抑制浓度，IC 50)的检测。
细胞以每孔1.5 x 105个/ml的浓度铺于24孔板(Corning)中。第二天准备化合物，从2mM用100％DMSO进行5倍梯度稀释，共8个浓度，每个浓度化合物取2μl加入到1ml的细胞培养液中，补加1ml RPMI-1640only(FBS终浓度为5％，v/v)，将化合物与细胞混匀。在孵箱中孵育2小时后，以2000rpm离心8分钟，弃上清，用2ml PBS(Solarbio)洗1次，再次离心弃上清。用100μl裂解缓冲液(20mM Tris，pH 8.0，5mM EDTA，用时加Protease inhibitor(1：100)和Phosphatase Inhibitor(1:100))重悬细胞，4℃冰箱放置45分钟。2000rpm离心2min，把24孔板的裂解液转移到96孔板，2000rpm，4℃，离心15min，上清即为裂解液。用BCA法(Thermo，#23225)蛋白定量。用反应缓冲液(20mM Tris，pH 8.0，0.5mM EDTA)配制2*裂解液，终浓度20ng/μl。用反应缓冲液配制2*Ac-ANW-AMC，终浓度为100μM。取10μl的2*裂解液加入到384孔板(OptiPlate-384，购买于PerkinElmer)，加入10μl的2*Ac-ANW-AMC，离心启动反应，23℃避光反应1小时。反应结束后在CLARIO starPlus(购买于BMG LRBTECH)上读取信号值(激发波长345nm/发射波长445nm)。每个化合物分别在8个浓度下测定酶的活性，数据使用GraphPad Prism软件进行处理，计算得到化合物对MOLT-4细胞中LMP7水解酶的半抑制浓度，即IC 50值。
前述“*”是指乘，表示倍数
表2：化合物的细胞活性测试结果
Figure PCTCN2021072666-appb-000232
4.化合物的动物药代动力学研究：
动物药代实验使用3只健康成年雄性大鼠，来源于北京维通利华实验动物技术有限公司。化合物混悬于20％的磺丁基醚-β-环糊精中(W/W/V)溶液中，溶液浓度为1mg/mL，给药体积为5mL/kg，单次灌胃给药，剂量为5mg/kg。动物在实验前禁食过夜，禁食时间从给药前10小时至给药后4小时。给药后0.25、0.5、1、2、4、6、8和24小时采血。动物通过异氟烷浅麻醉，用玻璃采血管于眼眶静脉丛采血约0.4mL全血，放于肝素抗凝管中，样品于4℃、4200rpm离心5min，血浆转移至离心管中，并放于-80℃保存直到分析。血浆样品分析使用乙腈蛋白质沉淀法萃取大鼠血浆中的待测化合物和内标(华法林或普萘洛尔)， 萃取液通过LC/MS/MS分析。测到的个体动物的血浆浓度-时间数据用WinNonlin(版本5.2.1；Pharsight公司)软件的非房室模型进行分析，得到如下药代动力学参数：最大(峰值)血浆药物浓度C max；达峰时间T max；半衰期T 1/2和外推到无限长时间的血药浓度-时间曲线下面积AUC 0-inf。
Figure PCTCN2021072666-appb-000233
工业实用性
本发明涉及硼酸衍生物；本发明提供了式(I)化合物或其药学上可接受的盐、溶剂化物、多晶型物或异构体、包含这些化合物的药物组合物，以及此类化合物在治疗跟lmp7相关的疾病中的用途，具有较好的经济价值和应用前景。
Figure PCTCN2021072666-appb-000234

Claims (11)

  1. 式I化合物、或其药学上可接受的盐、溶剂化物、多晶型物或异构体，
    Figure PCTCN2021072666-appb-100001
    其中，
    R a和R b各自独立地选自H和C 1-6烷基，或者R a和R b可以连到一起形成一个3-10元杂环；
    X为键、-O-、或者-NR 4-；
    Y为键或者-(CR 4R 5) m-；
    R 4和R 5各自独立地选自H、C 1-6烷基和C 3-8环烷基；
    m为1、2、或者3；
    R 2选自H和C 1-6烷基；
    R 3选自C 6-10芳基和C 5-10杂芳基，所述芳基和杂芳基可任选地被卤素、-OH、-NH 2、-O-C 1-6烷基、-N(C 1-6烷基)(C 1-6烷基)、-CN、NO 2、C 1-6烷基、C 3-8环烷基、或者C 3-8杂环烷基取代；
    R 1选自C 1-6烷基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基和C 5-10杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基被
    Figure PCTCN2021072666-appb-100002
    中的一个取代，并且可任选地被卤素、-OH、-NH 2、-(CH 2) 1-3-C 3-8环烷基、-(CH 2) 0-6-CF 3、-O-C 1-6烷基、-NR 9R 8、-CN、NO 2、C 1-6烷基、-(CH 2) 0-3-(CO)-R 8、-(CH 2) 0-3-(CO)-NH-R 8、-(CH 2) 0-3-NH-(CO)-R 8、或者R 10取代；
    R 6a和R 6b各自独立地选自C 1-6烷基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基和C 5-10杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基可任选地被卤素、C 1-6烷基、C 3-8环烷基、-OH、-NH 2、-O-C 1-6烷基、-NR 9R 8、-NO 2、或者-CN取代，或者
    R 6a和R 6b可以连在一起形成一个3-8元杂环；
    R 7选自H、C 1-6烷基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基和C 5-10杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基可任选地被卤素、C 1-6烷基、C 3-8环烷基、-OH、-NH 2、-O-C 1-6烷基、-NR 9R 8、-NO 2、或者-CN取代；
    R 8选自C 1-6烷基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基和C 5-10杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基可任选地被卤素、C 1-6烷基、-O-C 1-6烷基、C 6-10芳基、或者C 5-10杂芳基取代；
    R 9选自H和C 1-6烷基；
    R 10选自C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基和C 5-10杂芳基，所述环烷基、杂环烷基、芳基和杂芳基可任选地被卤素、-OH、-NH 2、-O-C 1-6烷基、-N(C 1-6烷基)(C 1-6烷基)、-CN、NO 2、或者C 1-6烷基取代。
  2. 根据权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、多晶型物或异构体，其中X为键、-O-、或者-NR 4-，R 4为H。
  3. 根据权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、多晶型物或异构体，其中Y为键或者-(CR 4R 5) m-，R 4和R 5各自独立地选自H和C 1-6烷基，m为1或2。
  4. 根据权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、多晶型物或异构体，其中R 2为H。
  5. 根据权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、多晶型物或异构体，其中R 3选自C 5-10杂芳基，所述杂芳基可任选地被卤素、NO 2、C 1-6烷基、C 3-8环烷基、或者C 3-8杂环烷基取代。
  6. 根据权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、多晶型物或异构体，其中R 1选自C 3-8环烷基、C 6-10芳基和C 5-10杂芳基，所述环烷基、芳基和杂芳基被
    Figure PCTCN2021072666-appb-100003
    中的一个取代，并且可任选地被卤素、-CF 3、-O-C 1-6烷基、NO 2、C 1-6烷基、-(CO)-R 8、-(CO)-NH-R 8、或者R 10取代；
    R 6a和R 6b各自独立地选自C 1-6烷基、C 3-8环烷基、C 6-10芳基和C 5-10杂芳基，所述烷基、环烷基、芳基和杂芳基可任选的被卤素、C 1-6烷基、-O-C 1-6烷基、C 3-8环烷基、C 3-8杂环烷基、或者NR 8R 9取代，或者R 6a和R 6b可以连在一起形成一个3-8元杂环；
    R 7选自H、C 1-6烷基、C 3-8环烷基、C 6-10芳基和C 5-10杂芳基，所述烷基、环烷基、芳基和杂芳基可任选的被卤素、C 1-6烷基、-O-C 1-6烷基、C 3-8环烷基、C 3-8杂环烷基、或者NR 8R 9取代；
    R 8选自C 1-6烷基和C 3-8环烷基，所述环烷基可任选地被C 1-6烷基取代；
    R 9选自H和C 1-6烷基
    R 10选自C 3-8环烷基和C 3-8杂环烷基，所述环烷基和杂环烷基可任选地被C 1-6烷基取代。
  7. 以下化合物
    Figure PCTCN2021072666-appb-100004
    或其药学上可接受的盐、溶剂化物、多晶型物或异构体。
  8. 以下化合物
    Figure PCTCN2021072666-appb-100005
    Figure PCTCN2021072666-appb-100006
    或其药学上可接受的盐、溶剂化物、多晶型物或异构体。
  9. 一种药物组合物，其包含根据权利要求1-8中任一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物或异构体，以及药学上可接受的载体。
  10. 根据权利要求1-8中任一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物或异构体或者根据权利要求9所述的组合物在制备用来治疗跟lmp7活性相关的疾病的药物中的用途。
  11. 根据权利要求10所述的用途，其中所述跟lmp7活性相关的疾病为多发性骨髓瘤、急性骨髓性白血病、髓细胞白血病、套细胞淋巴瘤、慢性淋巴细胞白血病、急性淋巴细胞白血病、弥漫大B细胞淋巴瘤、浆细胞瘤、滤泡性淋巴瘤、免疫细胞瘤、乳腺癌、肝癌、结直肠癌、卵巢癌、食道癌、肺癌、头颈癌、胰腺癌、肾癌、胃癌、甲状腺癌、前列腺癌、膀胱癌、类风湿性关节炎、系统性红斑狼疮、炎性肠病、多发性硬化、硬皮病、关节黏连性脊椎炎、动脉粥样硬化、白塞病、克罗恩病、炎性肠病、溃疡性结肠炎、自身免疫性肝炎、干燥综合症、狼疮肾炎、哮喘、肌萎缩性侧索硬化(ALS)、牛皮癣、A型免疫球蛋白肾病、过敏性紫癜、阿兹海默氏症(AD)。
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WO2018136401A1 (en) * 2017-01-18 2018-07-26 Principia Biopharma Inc. Immunoproteasome inhibitors

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WO2016050359A1 (en) * 2014-10-01 2016-04-07 Merck Patent Gmbh Boronic acid derivatives
WO2016050356A1 (en) * 2014-10-01 2016-04-07 Merck Patent Gmbh Boronic acid derivatives
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