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WO2017063491A1 - 脲拟肽硼酸化合物及其药物组合物、制备方法和用途 - Google Patents

脲拟肽硼酸化合物及其药物组合物、制备方法和用途 Download PDF

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Publication number
WO2017063491A1
WO2017063491A1 PCT/CN2016/099713 CN2016099713W WO2017063491A1 WO 2017063491 A1 WO2017063491 A1 WO 2017063491A1 CN 2016099713 W CN2016099713 W CN 2016099713W WO 2017063491 A1 WO2017063491 A1 WO 2017063491A1
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Prior art keywords
group
urea
boronic acid
leucine boronic
phenylalanyl
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PCT/CN2016/099713
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English (en)
French (fr)
Inventor
李润涛
安浩云
韩利强
葛泽梅
崔景荣
程铁明
Original Assignee
北京大学
郑州格然林医药科技有限公司
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Application filed by 北京大学, 郑州格然林医药科技有限公司 filed Critical 北京大学
Priority to CN201680059986.7A priority Critical patent/CN108368133B/zh
Priority to US15/767,945 priority patent/US10494384B2/en
Priority to JP2018538926A priority patent/JP6976955B2/ja
Priority to EP16854873.3A priority patent/EP3363803B8/en
Publication of WO2017063491A1 publication Critical patent/WO2017063491A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/04—Esters of boric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides

Definitions

  • the invention belongs to the field of medicine and relates to a urea peptidomimetic borate compound and a pharmaceutical composition thereof, a preparation method and use thereof.
  • the ubiquitin-proteasome pathway is responsible for the degradation of various tissue proteins in the body. Most of these substrate proteins are closely related to physiological functions, thereby regulating various cellular mechanisms. When these physiological functions or processes are abnormal, various diseases such as tumors, inflammation, and some neurodegenerative diseases are produced. Therefore, the proteasome is considered to be a very potential new target for anti-tumor drugs.
  • the peptide borate compound, bortezomib (PS-341) was the first to be marketed as a proteasome inhibitor by the US FDA and is clinically used to treat multiple myeloma. Since then, studies on peptide borate proteasome inhibitors have received great attention.
  • peptide borate compounds have many shortcomings such as backward synthesis process, poor metabolic stability, narrow anti-tumor spectrum, large side effects, and strong drug resistance.
  • a novel proteasome inhibitor is a novel proteasome inhibitor.
  • the present invention provides a novel urea peptidomimetic borate compound, which not only overcomes the difficulty in synthesizing the key intermediate ⁇ -aminoboronic acid compound in the bortezomib synthesis route, but also the separation and purification of the end product of the boric acid compound.
  • the anti-tumor activity of this novel urea-like peptide boronic acid compound was also fully confirmed by a large number of experiments.
  • n and n respectively represent the number of amino acid residues, each independently selected from 0, 1, 2, and not simultaneously 0;
  • the linking group L represents a divalent alkyl group
  • R 1 is selected from the group consisting of an aryl group, a heteroaryl group, a cycloalkyl group, a cycloalkenyl group, a heterocyclic group, and the above aryl group, heteroaryl group, cycloalkyl group, cycloalkenyl group or heterocyclic group is optional.
  • substituents each of which is independently selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroaryl Alkyl, heterocyclic, heterocyclylalkyl, alkoxy, cycloalkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, arylalkyloxy, heteroaryl Alkyloxy, heterocyclylalkyloxy, alkylthio, cycloalkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, acyl, thioacyl, acyloxy, Amido, ureido, sulfinyl, alkylsulfonyl, arylsulfonyl, haloalkyl, carbamoyl, halogen, cyano, isocyano, nitro,
  • R 2 and R 4 are amino acid side chains, and m R 2 and n R 4 are each independently selected from hydrogen, arylalkyl, heteroarylalkyl, heterocyclylalkyl, alkyl, aryl Alkyl, heteroarylalkyl, heterocyclylalkyl, alkyl optionally substituted by one or more substituents, each independently selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl , alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, cycloalkoxy, aryloxy, alkylthio , cycloalkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, acyl, thioacyl, acyloxy, amide, ureido, sulfinyl, alkylsulfony
  • R 3 is hydrogen or an alkyl group
  • R 5 and R 6 are both H or together form a glycol ester group
  • R 1 , L and R 3 may further form a 5, 6 or 7-membered heterocyclic ring together with the attached N atom, and the 5, 6 or 7-membered heterocyclic ring is in addition to the above-mentioned N atom, Still optionally further comprising a hetero atom selected from N, O, S, and optionally having an oxo group; and wherein the 5, 6 or 7 membered heterocyclic ring is fused with an aromatic or heteroaryl ring, said aryl
  • the ring or heteroaryl ring is optionally substituted by one or more substituents each independently selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, arylalkyl , heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, cycloalkoxy, aryloxy, alkylthio, cycloalkyl
  • the linking group L represents a C 1 -C 4 divalent alkyl group, preferably representing a methylene group or an ethylene group.
  • R 1 is selected from the group consisting of phenyl, naphthyl, heteroaryl, heterocyclyl, optionally phenyl, naphthyl, heteroaryl, heterocyclyl Substituted by a plurality of substituents, each of which is independently selected from C 1 -C 4 alkyl, aryl, aryl C 1 -C 4 alkyl, heteroaryl, heteroaryl C 1 -C 4 alkane , heterocyclic, heterocyclic C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, aryl C 1 -C 4 Alkyloxy, heteroaryl C 1 -C 4 alkyloxy, heterocyclyl C 1 -C 4 alkyloxy, halogen, cyano, isocyano, nitro, nitroso, thiocyano a group consisting of isothiocyanato groups.
  • R 1 is selected from the group consisting of phenyl, naphthyl, oxazolyl, isoxazolyl, imidazolyl, furyl, fluorenyl, isodecyl, pyrrolyl, triazolyl , triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzene Imidazolyl, benzothienyl, benzopyranyl, oxazolyl, quinolyl, isoquinolinyl, quinazolinyl, porphyrinyl, naphthyridyl, pteridinyl, fluorenyl, quinoxaline Lolinyl, thiadiazolyl,
  • R 1 is selected from the group consisting of phenyl, naphthyl, furyl, pyrazinyl, tetrahydrofuranyl, the above groups being optionally substituted by one or more substituents, said substitution
  • the groups are each independently selected from the group consisting of methyl, phenyl, benzyl, methoxy, phenyloxy, benzyloxy, fluoro, chloro, bromo, iodo, cyano, isocyano, nitro, nitros a group consisting of a thiocyanyl group and an isothiocyanato group.
  • m R 2 and n R 4 are each independently selected from hydrogen, phenyl C 1 -C 4 alkyl, heteroaryl C 1 -C 4 alkyl, heterocyclyl C 1 -C 4 alkyl, C 1 -C 4 alkyl, naphthyl C 1 -C 4 alkyl, the above phenyl C 1 -C 4 alkyl, heteroaryl C 1 -C 4 alkyl, heterocyclic C 1 -C 4 alkyl, C 1 -C 4 alkyl, naphthyl C 1 -C 4 alkyl optionally substituted by one or more substituents, each independently selected from carbamoyl, nitrate a group consisting of a base and a nitroso group.
  • m R 2 and n R 4 are each independently selected from the group consisting of hydrogen, benzyl, isobutyl, sec-butyl, isopropyl, methyl, carbamoylethyl, nitrate Base benzyl, phenylethyl, naphthylmethyl, benzopyrrolylmethyl.
  • R 3 is hydrogen or C 1 -C 4 alkyl. In a further preferred embodiment, R 3 is hydrogen or methyl.
  • R 5 and R 6 are both H or together form a cyclic glycol ester group. In a further preferred embodiment, R 5 and R 6 are both H or together form a decanediol ester group or a pinacol ester group.
  • R 1 , L and R 3 may further form a 5, 6 or 7-membered heterocyclic ring together with the attached N atom, in addition to the above 5, 6 or 7-membered heterocyclic ring In addition to the N atom, optionally further comprising a hetero atom selected from N, O, S, and optionally having an oxo group; and wherein the 5, 6 or 7 membered heterocyclic ring is fused with a benzene ring or a naphthalene ring Or a heteroaryl ring, the above benzene ring, naphthalene ring or heteroaryl ring being optionally substituted by one or more substituents, each of which is independently selected from an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, Alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycl
  • R 1 , L and R 3 may also form a 5, 6 or 7-membered heterocyclic ring together with the attached N atom, the 5, 6 or 7-membered heterocyclic ring
  • the 5, 6 or 7 membered heterocyclic ring is fused with a benzene ring, naphthalene a ring or heteroaryl ring, the above benzene ring, naphthalene ring or heteroaryl ring being optionally substituted by one or more substituents each independently selected from C 1 -C 4 alkoxy, nitro and a group consisting of nitro groups.
  • R 1 , L and R 3 may also form, together with the N atom to which they are attached, a piperidine ring, optionally having an oxo group;
  • the piperidine ring is fused with a benzene ring, and the above benzene ring is optionally substituted by one or more substituents each independently selected from the group consisting of a methoxy group and a nitro group.
  • a pharmaceutical composition comprising: the compound of the first aspect of the invention, or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier .
  • a process for the preparation of a compound according to the first aspect of the invention comprises the steps of forming an amide group, coupling to form a urea group, and optionally, further comprising hydrolysis of the pinacol ester and Further a step of forming an ester with a diol, preferably a decane diol.
  • the use of a compound of the first aspect of the invention, and a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for use as a proteasome inhibitor is for treating cancer, preferably selected from the group consisting of lung cancer, breast cancer, liver cancer, gastric cancer, cervical cancer, colon cancer, leukemia, ovarian cancer, A group consisting of pancreatic cancer and epithelial cancer.
  • alkyl refers to a group consisting only of carbon atoms and hydrogen atoms and having no degree of unsaturation (for example, a double bond, a triple bond or a ring), which covers various possible geometrical differences. a group and a stereoisomer. This group is attached to the rest of the molecule by a single bond.
  • alkyl group the following linear or branched groups may be mentioned: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl , n-pentyl and its other seven isomers, n-hexyl and its other sixteen isomers, n-heptyl and its various isomers, n-octyl and its various isomers, n-decyl And various isomers thereof, n-decyl groups and various isomers thereof.
  • cycloalkyl refers to a saturated non-aromatic ring system composed of at least 3 carbon atoms, which may be monocyclic, bicyclic, polycyclic, or fused, bridged, or spiro. ring.
  • cycloalkyl group the following groups may be mentioned: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl; One or more of the above-mentioned single rings of fused, bridged or spiro groups formed by a common side and a common carbon atom.
  • alkenyl refers to a group formed in the case where one or more double bonds are present in the above alkyl group (except for a methyl group).
  • cycloalkenyl refers to a group formed in the case where one or more double bonds are present in the above cycloalkyl group.
  • alkynyl refers to a group formed in the case where one or more triple bonds are present in the above alkyl group (except for a methyl group).
  • alkoxy refers to a group in which an oxygen atom is bonded to the above alkyl group and is bonded to the remainder of the molecule by a single bond of the oxygen atom, which encompasses various possible geometric isomers. With stereoisomeric groups.
  • alkoxy groups the following linear or branched groups may be mentioned: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, Sec-butoxy, tert-butoxy, n-pentyloxy and its other seven isomers, n-hexyloxy and its other sixteen isomers, n-heptyloxy and its various isomers, n-octyl Oxyl groups and their various isomers, n-decyloxy groups and various isomers thereof, n-decyloxy groups and various isomers thereof.
  • aryl refers to an aromatic ring system consisting of at least 6 carbon atoms, which ring system may be monocyclic, bicyclic or polycyclic, wherein the bicyclic and polycyclic rings may be bonded by a single ring through a single bond. Formed in a fused manner.
  • aryl group the following groups may be mentioned: phenyl, naphthyl, anthryl, phenanthryl, anthracenyl, fluorenyl, fluorenyl, pentenyl, heptene, anthracene Base, fluorenyl, phenalkenyl, fluorenyl, phenanthryl, benzofluorenyl, triphenylene, Tetraphenyl, fluorenyl, pentenyl, pentacene, tetra-o-phenylene, hexenyl, hexaphenyl, decyl, trimethylene, heptyl, heptaphenyl, pyr Sulfhydryl, egg phenyl, biphenyl, binaphthyl.
  • heteroaryl refers to a 5-14 membered aromatic heterocyclic ring system having one or more heteroatoms independently selected from N, O or S, which ring system may be monocyclic, Bicyclic and polycyclic, wherein the bicyclic ring and the polycyclic ring may be formed by a single ring by a single bond connection or a condensed manner.
  • heteroaryl groups the following groups may be mentioned: oxazolyl, isoxazolyl, imidazolyl, furyl, fluorenyl, isodecyl, pyrrolyl, triazolyl, triazinyl , tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, Benzothiophenyl, benzopyranyl, oxazolyl, quinolyl, isoquinolinyl, quinazolinyl, porphyrinyl, naphthyridyl, pteridinyl, fluorenyl, quinoxalinyl, thia Diazolyl, pyridazinyl, a
  • heterocyclyl refers to a non-aromatic 3-15 membered ring system consisting of a carbon atom and a hetero atom independently selected from N, O or S, which ring system may be monocyclic, bicyclic or
  • the polycyclic ring may also be a fused ring, a bridged ring, a spiro ring, and may optionally contain one or more double bonds.
  • aza Base acridinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholyl, decahydroiso Quinolinyl, indanyl, porphyrin, isoindolyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazole Alkyl, oxadiazolyl, 2-oxopiperrazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoaza Base, octahydroindenyl, octahydroisodecyl, perhydroaza Base, piperazinyl, 4-piperidinone, piperidinyl, phenothiazine,
  • arylalkyl refers to an alkyl group in which one or more hydrogen atoms are independently substituted by an aryl group, wherein the aryl group and the alkyl group are as defined above.
  • heteroarylalkyl refers to an alkyl group wherein one or more hydrogen atoms are independently substituted by a heteroaryl group, wherein said heteroaryl group and alkyl group are as defined above.
  • halogen or "halo" as used in the present invention means fluoro, chloro, bromo or iodo.
  • the pharmaceutical composition of the present invention contains the compound of the first aspect of the present invention as an active ingredient.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier including, but not limited to, water, saline solution, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, Lactose, gypsum powder, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or low alkyl ether , silicic acid, fatty acid, fatty acid amine, fatty acid monoglyceride and diglyceride, pentaerythritol fatty acid ether, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone.
  • a pharmaceutically acceptable carrier including, but not limited to, water, saline solution, alcohol, polyethylene glycol, polyhydroxy
  • the pharmaceutical composition may further comprise one or more pharmaceutically acceptable adjuvants, wetting agents, emulsifiers, suspending agents, preservatives, osmotic pressure adjusting agents, buffering agents, sweeteners, flavoring agents, coloring Agent or any combination of the above.
  • the pharmaceutical composition of the present invention can be formulated into any form, for example, a capsule, a tablet, an aerosol, a solution, a suspension, a sugar coating, a tablet, a syrup, an emulsion, an ointment, an ointment, an injection, a powder. , granules, pastes, sustained release agents, foaming agents.
  • the medicament of the present invention can be formulated into an oral administration preparation, a nasal administration preparation, a pulmonary administration preparation, an oral preparation preparation, a subcutaneous administration preparation, an intradermal administration preparation, and a transdermal administration preparation.
  • Cancer in the present invention includes various cancers known in the art including, but not limited to, lung cancer, liver cancer, gastric cancer, cervical cancer, colon cancer, breast cancer, leukemia, non-small cell carcinoma, prostate cancer or pigmentation.
  • Tumor brain cancer, skin cancer, bone cancer, lymphoma, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, duodenal cancer, small intestine cancer, colorectal cancer, pancreatic cancer, kidney cancer, reproductive organ cancer, thyroid cancer.
  • the compound of the present invention is synthesized by a method wherein each substituent is as defined in the formula (I).
  • Boc-L-phenylalanine (2.65 g, 10 mmol) was dissolved in 50 mL of THF. HOBt (1.48 g, 11 mmol) was added with stirring. After 5 min, DCC (2.47 g, 12 mmol) was added and the carboxyl group was activated for 30 min. The milky white suspension was added to p-methoxybenzylamine (1.3 mL, 10 mmol) and N-methylmorpholine (1.32 mL, 12 mmol).
  • the crude product intermediate c (1.2 g) obtained in the above step was dissolved in 40 mL of ethyl acetate. After filtration under normal pressure, 1.1 equivalents of diethanolamine was added dropwise with stirring, and the mixture was stirred at room temperature for 48 hours, and the resulting insoluble matter was obtained by suction filtration. The filter was washed with 20 mL x 2 of the ester and thoroughly drained. The solid was suspended in 20 mL of ethyl acetate, and 20 mL of distilled water and 1 mL of 4N hydrochloric acid were added, and the reaction was vigorously stirred for 6 hours.
  • Carbonyldiimidazole (CDI, 1.64 g, 10.1 mmol) was dissolved in a mixed solvent of 8 mL DMF / 40 mL of MeCN, and L-phenylalanine methyl ester hydrochloride (1.98 g, 9.2 mmol) was added in portions, before each addition. Make sure that the last addition is completely dissolved. After reacting for 2 h at room temperature, add pyrazine-2-methylamine (1 g, 9.2 mmol) and triethylamine (1.7 mL, 18.4 mmol). The system is clarified and reacted for 24 h. The reaction is complete by TLC. .
  • the intermediate a (1.19 g, 3.51 mmol) obtained in the above step was dissolved in 10 mL of THF.
  • 2N LiOH was slowly added dropwise to a pH of 12 to 13 in an ice bath, and the reaction in the ice bath was continued.
  • TLC detection reaction after 2 hours Finished.
  • the solvent THF was slowly distilled off, and hydrochloric acid was added dropwise to a pH of 2 to 3, and a large amount of white solid was obtained, which was filtered, and the filter cake was washed with water and diethyl ether to give a white solid product of 0.9 g, yield 77.8%. Used directly in the next step.
  • the insoluble material N,N'-dicyclohexylurea (DCU) was removed by filtration, and the solvent DCM was removed by rotary evaporation, and then dissolved in 50 mL of ethyl acetate, and then washed with 10% citric acid solution, 5% NaHCO 3 solution, and saturated brine. The water was dried Na 2 SO 4 . Evaporation of the solvent ethyl acetate afforded 1.23 g of crude product as a pale yellow foamy solid which was used for the next step.
  • DCU insoluble material N,N'-dicyclohexylurea
  • the crude product intermediate c (1.23g) obtained in the above step was dissolved in 40mL of ethyl acetate. After filtration under normal pressure, 1.1 equivalents of diethanolamine (0.2mL) was added dropwise with stirring, stirred at room temperature for 48h, and filtered to obtain insoluble matter. The filter cake was washed with ethyl acetate 20 mL x 2 and drained thoroughly. The solid was suspended in 20 mL of ethyl acetate and suction filtered again. The obtained solid was suspended in ethyl acetate (20 mL), and 20 mL of distilled water and 1 mL of 4N hydrochloric acid were added thereto, and the mixture was stirred vigorously for 6 hours.
  • Example 7 N-L-leucine borate decanediol-N'-pyrazin-2-aminoacyl-L-phenylalanine-urea (hlq-U54-3)
  • Example 8 N-L-leucine boronic acid-N'-p-methoxyanilinoyl-L-phenylalanine-urea (hlq-U55)
  • the title compound was synthesized in a similar manner to Example 1 except that pyrazin-2-amine was used instead of the material p-methoxybenzylamine, and Boc-D-phenylalanine was used instead of the starting material Boc-L-phenylalanine. A yellowish white foamy solid was obtained in a yield of 24%, m.p.: 138 - 141.
  • Example 11 N-L-leucine boronic acid-N'-pyrazine-2-aminoacyl-L-leucyl-L-leucine-urea (hlq-U61)
  • Example 2 A method similar to that of Example 1 was used except that N-pyrazinyl-L-leucine was used instead of the raw material p-methoxybenzylamine, and Boc-L-leucine was used instead of the raw material Boc-L-phenylalanine.
  • the title compound was synthesized to give a white solid,yield: 21%, mp.
  • Example 12 N-L-leucine boronic acid-N'-pyrazine-2-aminoacyl-L-leucyl-L-phenylalanine-urea (hlq-U62)
  • Example 13 N-L-leucine boronic acid pinacol ester-N'-pyrazine-2-aminoacyl-L-leucyl-L-phenylalanine-urea (hlq-U62-1)
  • the title compound was synthesized in a similar manner to Example 2 to give a white foamy solid (yield: 18%, m.p.: 118-120). .
  • Example 28 The compound of Example 28 was oxidized in air to give a white foamy solid (yield: 18%, mp.
  • Triphosgene (1.49 g, 5 mmol) was added to 20 mL of DCM, and a mixture of 1,2,3,4-tetrahydroquinoline (1.33 g, 10 mmol) and triethylamine (2.1 mL, 15 mmol) was slowly added dropwise in an ice bath.
  • the DCM solution was gradually warmed to room temperature for 6 h.
  • the reaction was quenched by the addition of water, and the mixture was evaporated. Filtration, L-phenylalanine methyl ester hydrochloride (2.16 g, 10 mmol) and DIEA (3.8 mL, 22 mmol).
  • the reaction solution was washed with water and dried over anhydrous sodium sulfate. Column chromatography gave 2.2 g of a white solid, yield 65%, m.p.: 101-103.
  • the intermediate a (2.2 g, 6.5 mmol) obtained in the previous step was dissolved in 20 mL of THF, and 20 mL of water and sodium hydroxide (0.32 g, 8 mmol) was added.
  • the THF was evaporated under reduced pressure, and the mixture was adjusted to pH 2-3 with hydrochloric acid to yield a large solid.
  • the intermediate c obtained in the above step (0.80 g, 1.5 mmol) was dissolved in 20 mL of diethyl ether, and diethanolamine (0.15 g, 1.5 mmol). After suction filtration, the filter cake was washed thoroughly with diethyl ether and dried. The obtained solid was suspended in 20 mL of ethyl acetate, and 20 mL of distilled water and 1 mL of 4N hydrochloric acid were added and stirred vigorously for 30 min. The aqueous phase was separated by liquid separation, and the organic phase was washed twice with distilled water and brine, and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent in vacuo gave a white solid. Ethyl acetate / n-hexane was recrystallized to give 0.26 g of white solid,yield: 49%, m.
  • the intermediate a-c was synthesized in a similar manner to Example 38 except that 1-methyl-1,2,3,4-tetrahydroisoquinoline was used instead of the starting material 1,2,3,4-tetrahydroquinoline.
  • Intermediate c N-(L-phenylalanyl-L-leucine boronic acid pinacol ester)-N'-(1-methyl-1,2,3,4-tetrahydroisoquinoline) -Urea
  • 0.70 g, 1.3 mmol was dissolved in 20 mL of diethyl ether.
  • Anhydrous citric acid (0.25 g, 1.3 mmol) was added and allowed to react overnight. Pump Filter, filter cake ether washed thoroughly and drained.
  • Triphosgene (1.49 g, 5 mmol) was added to 20 mL of DCM, and 1,2,3,4-tetrahydroisoquinoline (1.33 g, 10 mmol) and triethylamine (2.1 mL, 15 mmol) were slowly added dropwise in an ice bath.
  • the DCM solution was mixed and gradually warmed to room temperature for 6 h. The reaction was quenched by the addition of water. Column chromatography gave 1.6 g of a colorless oil, yield 82%.
  • the precursor obtained in the previous step (1.37 g, 7 mmol) was dissolved in 20 mL of DCM, and then evaporated to ethyl ether (ethyl acetate) (1,7 g, 7 mmol) and DIEA (2.7 mL, 15.4 mmol). The reaction mixture was washed with water and dried over anhydrous sodium sulfate.
  • the intermediate a (NL-alanine methyl ester-N'- was synthesized in a similar manner to Example 40 except that L-alanine methyl ester hydrochloride was used instead of the starting material L-leucine methyl ester hydrochloride. 1,2,3,4-tetrahydroisoquinoline-urea) gave a colorless oil in 70% yield.
  • an intermediate b (NL-naphthylalanine-N'-1,2,3,4-tetrahydroisoquinoline-urea) was synthesized in the same manner as in Example 38 to obtain White solid, yield 88%.
  • the intermediate a (NL-tryptophan methyl ester-N'- was synthesized in a similar manner to Example 40 except that L-tryptophan methyl ester hydrochloride was used instead of the starting material L-leucine methyl ester hydrochloride. 1,2,3,4-tetrahydroisoquinoline-urea) gave a white solid, yield 83%, m.p.: 60-62.
  • an intermediate b (NL-tryptophan-N'-1,2,3,4-tetrahydroisoquinoline-urea) was synthesized in a similar manner to Example 38 to give white. Solid, yield 92%.
  • the intermediate a (NL-phenylbutyric acid methyl ester-N' was synthesized in a similar manner to Example 40 except that L-phenylbutyric acid methyl ester was used instead of the starting material L-leucine methyl ester hydrochloride. -1,2,3,4-tetrahydroisoquinoline-urea) gave a white foamy solid in a yield of 90%.
  • the intermediate a (N-(L-4-nitro) was synthesized in a similar manner to Example 40 except that L-4-nitrophenylalanine methyl ester was used instead of the starting material L-leucine methyl ester hydrochloride. Phenylalanine methyl ester)-N'-1,2,3,4-tetrahydroisoquinoline-urea) gave a white foamy solid, yield 83%.
  • the carbonyl diimidazole (1.43 g, 8.8 mmol) was dissolved in 20 mL of DCM, and a solution of L-phenylalanine methyl ester (1.73 g, 8 mmol) and DIEA (1.4 mL, 8 mmol) in 10 mL DCM was added dropwise. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.84 g, 8 mmol) and DIEA (1.4 mL, 8 mmol) were then weighed. The reaction mixture was washed with water and dried over anhydrous sodium sulfate.
  • Example 51 N-(L-phenylalanyl-L-leucine boronic acid)-N'-(7-methoxy-1,2,3,4-tetrahydroisoquinoline)-urea (cq24 )
  • Lithium aluminum hydride (0.5 g, 13 mmol) was slowly added under ice-cooled THF (20 mL), and then the title compound (1.
  • the reaction solution was ice-cooled, and 0.5 mL of water, 0.5 mL of 15% sodium hydroxide solution, 1.5 mL of water and several anhydrous magnesium sulfate solids were added in sequence, stirred for 30 min, filtered, and the filter cake was washed thoroughly with THF. dry. The solvent was evaporated under reduced pressure to give a white oil (yel.
  • Example 52 N-(L-phenylalanyl-L-leucine boronic acid)-N'-(6-methoxy-1,2,3,4-tetrahydroisoquinoline)-urea (cq25 )
  • the precursor II (6-methoxy-1,2,3,4-tetrahydroisoquinoline) was synthesized in the same manner as in Example 51 using m-methoxyphenethylamine as a starting material to give a yellow oil. The yield was 54%.
  • the intermediate a (NL-phenylalanine methyl ester-N'-(6-methoxy-1,2,3,4-tetra) was synthesized in a similar manner to that in Example 50.
  • Hydrogen isoquinoline)-urea gave a colorless oil in a yield of 65%.
  • the precursor II (8-methoxy-1,2,3,4-tetrahydroisoquinoline) was synthesized in the same manner as in Example 51 using m-methoxyphenethylamine as a crude material. The yield was 10%.
  • Example 54 N-(L-phenylalanyl-L-leucine boronic acid)-N'-(5-methoxy-1,2,3,4-tetrahydroisoquinoline)-urea (cq27 )
  • the precursor II (5-methoxy-1,2,3,4-tetrahydroisoquinoline) was synthesized in a similar manner to Example 51 to give a yellow oil.
  • the yield was 10%.
  • an intermediate b (NL-phenylalanine-N'-(4,5,6,7-tetrahydrothiophene [2,3-C] was synthesized in a similar manner to that in Example 38. ] and pyridine)-urea) gave a white solid in a yield of 91%.
  • Test Example 1 Proteasome inhibition of urea peptidomimetic borate
  • Test Example 2 In vitro anti-tumor activity preliminary screening test
  • test method employed in the test examples is a conventional antitumor activity test method in the pharmaceutical field, for example, see J. Immunol Method, 1983, 65, 55.
  • Test model A: MTT method (Hela, human cervical cancer); B: SRB method (BGC-823, liver cancer); C: SRB method (MCF-7, breast cancer); D: SRB method (A549, human lung cancer) , E: SRB method (PC3M1E8, prostate cancer).
  • the inhibition rate was measured at concentrations of 0.1 ⁇ M, 1 ⁇ M and 10 ⁇ M. The results are shown in Table 2.
  • Test Example 3 In vitro antitumor activity (IC 50 )
  • the cancer cell line was cultured in vitro. After the cells were grown to logarithmic growth phase, the cells were collected, centrifuged at 1000 rpm for 5 min, the supernatant was discarded, and the appropriate medium was suspended to adjust the cell concentration to 3.5 ⁇ 10 4 /mL.
  • the cell suspension was inoculated into a 96-well cell culture plate, 100 ⁇ L per well, placed in a cell culture incubator (37 ° C, 5% CO 2 ) for 24 h, and then added with different final concentrations of the test drug, and the negative control group was added to the final concentration. For 0.5% DMSO, each group was provided with 3 duplicate wells.
  • Table 5 Inhibitory activity of three compounds against various human tumor cells (IC 50 )

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Abstract

一种通式（I）所示的脲拟肽硼酸化合物及其药物组合物、制备方法被公开，该化合物可作为蛋白酶体抑制剂用于治疗癌症。

Description

脲拟肽硼酸化合物及其药物组合物、制备方法和用途 技术领域
本发明属于药物领域，涉及一种脲拟肽硼酸化合物及其药物组合物、制备方法和用途。
背景技术
泛素-蛋白酶体途径负责体内多种组织蛋白的降解，这些底物蛋白大多同生理功能密切相关，从而起到调节各种细胞机制的作用。当这些生理功能或过程发生异常便会产生各种各样的疾病，如肿瘤、炎症和一些神经退行性疾病等。因此，蛋白酶体被认为是一种非常有潜力的抗肿瘤药物新靶点。肽硼酸类化合物—硼替佐米(PS-341)是第一个被美国FDA批准上市蛋白酶体抑制剂类，临床上用于治疗多发性骨髓瘤。此后，肽硼酸类蛋白酶体抑制剂的研究受到高度重视。
然而，随着人们对蛋白酶体抑制剂研究的逐步深入，发现肽硼酸类化合物存在合成工艺落后、代谢稳定性差、抗瘤谱窄、毒副反应大、耐药性突出等诸多缺点，亟待需要研发新型的蛋白酶体抑制剂。
发明内容
为解决上述问题，本发明提供了一种新型的脲拟肽硼酸化合物，不仅克服了硼替佐米合成路线中关键中间体α-氨基硼酸化合物难于合成以及硼酸类化合物终产物分离与纯化难等几个问题，还通过大量实验充分证实了这种新型脲拟肽硼酸化合物的抗肿瘤活性。
在本发明的第一方面，提供了通式(I)所示的化合物或其药学上可接受的盐或溶剂化物：
Figure PCTCN2016099713-appb-000001
其中，
m和n分别表示氨基酸残基的数量，各自独立地选自0、1、2，且不同时为0；
连接基团L表示二价烷基；
R1选自于由芳基、杂芳基、环烷基、环烯基、杂环基所组成的组，上述芳基、杂芳基、环烷基、环烯基、杂环基任选被一个或多个取代基取代，上述取代基各自独立地选自于由烷基、环烷基、烯基、环烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环基、杂环基烷基、烷氧基、环烷氧基、芳基氧基、杂芳基氧基、杂环基氧基、芳基烷基氧基、杂芳基烷基氧基、杂环基烷基氧基、烷基硫基、环烷基硫基、芳基硫基、烷氧基羰基、芳基氧基羰基、酰基、硫代酰基、酰基氧基、酰胺基、脲基、亚硫酰基、烷基磺酰基、芳基磺酰基、卤代烷基、氨甲酰基、卤素、氰基、异氰基、硝基、亚硝基、硫氰基、异硫氰基、酰肼基、硫烷基、磺基和甲硅烷基所组成的组；
R2和R4为氨基酸侧链，m个R2和n个R4各自独立地选自于氢、芳基烷基、杂芳基烷基、杂环基烷基、烷基，上述芳基烷基、杂芳基烷基、杂环基烷基、烷基任选被一个或多个取代基取代，上述取代基各自独立地选自于由烷基、环烷基、烯基、环烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环基、杂环基烷基、烷氧基、环烷氧基、芳基氧基、烷基硫基、环烷基硫基、芳基硫基、烷氧基羰基、芳基氧基羰基、酰基、硫代酰基、酰基氧基、酰胺基、脲基、亚硫酰基、烷基磺酰基、芳基磺酰基、卤代烷基、氨甲酰基、卤素、氰基、异氰基、硝基、亚硝基、硫氰基、异硫氰 基、酰肼基、硫烷基、磺基和甲硅烷基所组成的组；
R3为氢或烷基；
R5和R6同时为H，或共同形成二醇酯基团；
并且其中，当m为0时，R1、L和R3还可以连同所连接的N原子共同形成5、6或7元杂环，该5、6或7元杂环除上述N原子外，还任选包含另外一个选自于N、O、S的杂原子，并任选具有氧代基团；同时，该5、6或7元杂环稠合有芳环或杂芳环，上述芳环或杂芳环任选被一个或多个取代基取代，上述取代基各自独立地选自于由烷基、环烷基、烯基、环烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环基、杂环基烷基、烷氧基、环烷氧基、芳基氧基、烷基硫基、环烷基硫基、芳基硫基、烷氧基羰基、芳基氧基羰基、酰基、硫代酰基、酰基氧基、酰胺基、脲基、亚硫酰基、烷基磺酰基、芳基磺酰基、卤代烷基、氨甲酰基、卤素、氰基、异氰基、硝基、亚硝基、硫氰基、异硫氰基、酰肼基、硫烷基、磺基和甲硅烷基所组成的组。
在优选的实施方式中，连接基团L表示C1-C4二价烷基，优选表示亚甲基、亚乙基。
在优选的实施方式中，R1选自于由苯基、萘基、杂芳基、杂环基所组成的组，上述苯基、萘基、杂芳基、杂环基任选被一个或多个取代基取代，上述取代基各自独立地选自于由C1-C4烷基、芳基、芳基C1-C4烷基、杂芳基、杂芳基C1-C4烷基、杂环基、杂环基C1-C4烷基、C1-C4烷氧基、芳基氧基、杂芳基氧基、杂环基氧基、芳基C1-C4烷基氧基、杂芳基C1-C4烷基氧基、杂环基C1-C4烷基氧基、卤素、氰基、异氰基、硝基、亚硝基、硫氰基、异硫氰基所组成的组。在进一步优选的实施方式中，R1选自于由苯基、萘基、噁唑基、异噁唑基、咪唑基、呋喃基、吲哚基、异吲哚基、吡咯基、三唑基、三嗪基、四唑基、噻吩基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并呋喃基、苯并噻唑基、苯并噁唑基、苯并咪唑基、苯并噻吩基、苯并吡喃基、咔唑基、喹啉基、异喹啉基、喹唑啉基、噌啉基、萘啶基、蝶啶基、嘌呤基、喹噁啉基、噻二唑基、吲哚嗪基、吖啶基、吩嗪基、酞嗪基、香豆素基、吡唑并吡啶基、吡啶并哒嗪基、吡咯并吡啶基、咪唑并吡啶基、吡唑并哒嗪基、氮杂
Figure PCTCN2016099713-appb-000002
基、吖啶基、苯并间二氧杂环戊烯基、苯并二氧杂环己基、苯并二氢吡喃基、二氧戊环基、二氧磷杂环戊基、十氢异喹啉基、茚满基、吲哚啉基、异吲哚啉基、异苯并二氢吡喃基、异噻唑烷基、异噁唑烷基、吗啉基、噁唑啉基、噁唑烷基、噁二唑基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂
Figure PCTCN2016099713-appb-000003
基、八氢吲哚基、八氢异吲哚基、全氢化氮杂
Figure PCTCN2016099713-appb-000004
基、哌嗪基、4-哌啶酮基、哌啶基、吩噻嗪基、吩噁嗪基、奎宁环基、四氢异喹啉基、四氢呋喃基、四氢吡喃基、四氢吡咯基、噻唑啉基、噻唑烷基、硫代吗啉基、硫代吗啉基亚砜和硫代吗啉基砜所组成的组，上述基团任选被一个或多个取代基取代，上述取代基各自独立地选自于由C1-C4烷基、苯基、苯基C1-C4烷基、杂芳基、杂芳基C1-C4烷基、杂环基、杂环基C1-C4烷基、C1-C4烷氧基、苯基氧基、杂芳基氧基、杂环基氧基、苯基C1-C4烷基氧基、杂芳基C1-C4烷基氧基、杂环基C1-C4烷基氧基、氟、氯、溴、碘、氰基、异氰基、硝基、亚硝基、硫氰基、异硫氰基所组成的组。在最优选的实施方式中，R1选自于由苯基、萘基、呋喃基、吡嗪基、四氢呋喃基所组成的组，上述基团任选被一个或多个取代基取代，上述取代基各自独立地选自于由甲基、苯基、苄基、甲氧基、苯基氧基、苄氧基、氟、氯、溴、碘、氰基、异氰基、硝基、亚硝基、硫氰基、异硫氰基所组成的组。
在优选的实施方式中，m个R2和n个R4各自独立地选自于氢、苯基C1-C4烷基、杂芳基C1-C4烷基、杂环基C1-C4烷基、C1-C4烷基、萘基C1-C4烷基，上述苯基C1-C4烷基、杂芳基C1-C4烷基、杂环基C1-C4烷基、C1-C4烷基、萘基C1-C4烷基任选被一个或多个取代基取代，上述取代基各自独 立地选自于由氨甲酰基、硝基和亚硝基所组成的组。在进一步优选的实施方式中，m个R2和n个R4各自独立地选自于氢、苄基、异丁基、仲丁基、异丙基、甲基、氨甲酰基乙基、硝基苄基、苯基乙基、萘基甲基、苯并吡咯基甲基。
在优选的实施方式中，R3为氢或C1-C4烷基。在进一步优选的实施方式中，R3为氢或甲基。
在优选的实施方式中，R5和R6同时为H，或共同形成环状二醇酯基团。在进一步优选的实施方式中，R5和R6同时为H，或共同形成蒎烷二醇酯基团或频那醇酯基团。
在优选的实施方式中，当m为0时，R1、L和R3还可以连同所连接的N原子共同形成5、6或7元杂环，该5、6或7元杂环除上述N原子外，还任选包含另外一个选自于N、O、S的杂原子，并任选具有氧代基团；同时，该5、6或7元杂环稠合有苯环、萘环或杂芳环，上述苯环、萘环或杂芳环任选被一个或多个取代基取代，上述取代基各自独立地选自于由烷基、环烷基、烯基、环烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环基、杂环基烷基、烷氧基、环烷氧基、芳基氧基、烷基硫基、环烷基硫基、芳基硫基、烷氧基羰基、芳基氧基羰基、酰基、硫代酰基、酰基氧基、酰胺基、脲基、亚硫酰基、烷基磺酰基、芳基磺酰基、卤代烷基、氨甲酰基、卤素、氰基、异氰基、硝基、亚硝基、硫氰基、异硫氰基、酰肼基、硫烷基、磺基和甲硅烷基所组成的组。在进一步优选的实施方式中，当m为0时，R1、L和R3还可以连同所连接的N原子共同形成5、6或7元杂环，该5、6或7元杂环除上述N原子外，还任选包含另外一个选自于N、O、S的杂原子，并任选具有氧代基团；同时，该5、6或7元杂环稠合有苯环、萘环或杂芳环，上述苯环、萘环或杂芳环任选被一个或多个取代基取代，上述取代基各自独立地选自于由C1-C4烷氧基、硝基和亚硝基所组成的组。在最优选的实施方式中，当m为0时，R1、L和R3还可以连同所连接的N原子共同形成哌啶环，该哌啶环任选具有氧代基团；同时，该哌啶环稠合有苯环，上述苯环任选被一个或多个取代基取代，上述取代基各自独立地选自于由甲氧基和硝基所组成的组。
在本发明的第二方面，提供了一种药物组合物，所述药物组合物包含：本发明第一方面所述化合物或其药学上可接受的盐或溶剂化物；以及药学上可接受的载体。
在本发明的第三方面，提供了本发明第一方面所述化合物的制备方法，该方法主要包括形成酰胺基团、偶联形成脲基团等步骤，还任选包括频那醇酯水解以及进一步与二醇、优选蒎烷二醇成酯的步骤。
在本发明的第四方面，提供了本发明第一方面所述化合物及其药学上可接受的盐或溶剂化物在制备用作蛋白酶体抑制剂的药物方面的用途。在优选的实施方式中，所述用作蛋白酶体抑制剂的药物用于治疗癌症，所述癌症优选选自于由肺癌、乳腺癌、肝癌、胃癌、宫颈癌、结肠癌、白血病、卵巢癌、胰腺癌和上皮癌所组成的组。
具体实施方式
本发明中使用的术语“烷基”是指仅由碳原子和氢原子组成、且不具有不饱和度(例如双键、三键或环)的基团，其涵盖了各种可能的几何异构基团与立体异构基团。该基团通过单键与分子的其余部分相连。作为烷基的非限制性实例，可以列举以下直链或支链的基团：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基及其另外七种异构体、正己基及其另外十六种异构体、正庚基及其各种异构体、正辛基及其各种异构体、正壬基及其各种异构体、正癸基及其各种异构体。
本发明中使用的术语“环烷基”是指由至少3个碳原子组成的饱和非芳香环系，该环系可以是单环、双环、多环，也可以是稠环、桥环、螺环。作为环烷基的非限制性实例，可以列举以下基团：环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基；以及由两个或多个上述单环通过公共边和公共碳原子形成的稠环、桥环或螺环基团。
本发明中使用的术语“烯基”是指在上述烷基基团中(除甲基外)存在一个或多个双键的情况下所形成的基团。
本发明中使用的术语“环烯基”是指在上述环烷基基团中存在一个或多个双键的情况下所形成的基团。
本发明中使用的术语“炔基”是指在上述烷基基团中(除甲基外)存在一个或多个叁键的情况下所形成的基团。
本发明中使用的术语“烷氧基”是指氧原子与上述烷基相连、并且通过该氧原子以单键连接至分子其余部分的基团，其涵盖了各种可能的几何异构基团与立体异构基团。作为烷氧基的非限制性实例，可以列举以下直链或支链的基团：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基及其另外七种异构体、正己氧基及其另外十六种异构体、正庚氧基及其各种异构体、正辛氧基及其各种异构体、正壬氧基及其各种异构体、正癸氧基及其各种异构体。
本发明中使用的术语“芳基”是指由至少6个碳原子组成的芳香环系，该环系可以是单环、双环、多环，其中双环和多环可以由单环通过单键连接方式或稠合方式形成。作为芳基的非限制性实例，可以列举以下基团：苯基、萘基、蒽基、菲基、茚基、芘基、苝基、薁基、戊搭烯基、庚搭烯基、苊基、芴基、非那烯基、萤蒽基、醋菲烯基、苯并苊基、三亚苯基、
Figure PCTCN2016099713-appb-000005
基、并四苯基、苉基、戊芬基、并五苯基、四邻亚苯基、己芬基、并六苯基、蔻基、三亚萘基、庚芬基、并七苯基、吡蒽基、卵苯基、联苯基、联萘基。
本发明中使用的术语“杂芳基”是指具有一个或多个独立地选自N、O或S的杂原子的5-14元芳香族杂环环系，该环系可以是单环、双环、多环，其中双环和多环可以由单环通过单键连接方式或稠合方式形成。作为杂芳基的非限制性实例，可以列举以下基团：噁唑基、异噁唑基、咪唑基、呋喃基、吲哚基、异吲哚基、吡咯基、三唑基、三嗪基、四唑基、噻吩基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并呋喃基、苯并噻唑基、苯并噁唑基、苯并咪唑基、苯并噻吩基、苯并吡喃基、咔唑基、喹啉基、异喹啉基、喹唑啉基、噌啉基、萘啶基、蝶啶基、嘌呤基、喹噁啉基、噻二唑基、吲哚嗪基、吖啶基、吩嗪基、酞嗪基、香豆素基、吡唑并吡啶基、吡啶并哒嗪基、吡咯并吡啶基、咪唑并吡啶基、吡唑并哒嗪基；以及由上述杂芳基通过单键连接方式或稠合方式形成的基团。
本发明中使用的术语“杂环基”是指由碳原子和独立选自N、O或S的杂原子组成的非芳香族3-15元环系，该环系可以是单环、双环或多环，也可以是稠环、桥环、螺环，并且可以任选地包含一个或多个双键。作为杂环基的非限制性实例，可以列举以下基团：氮杂
Figure PCTCN2016099713-appb-000006
基、吖啶基、苯并间二氧杂环戊烯基、苯并二氧杂环己基、苯并二氢吡喃基、二氧戊环基、二氧磷杂环戊基、十氢异喹啉基、茚满基、吲哚啉基、异吲哚啉基、异苯并二氢吡喃基、异噻唑烷基、异噁唑烷基、吗啉基、噁唑啉基、噁唑烷基、噁二唑基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂
Figure PCTCN2016099713-appb-000007
基、 八氢吲哚基、八氢异吲哚基、全氢化氮杂
Figure PCTCN2016099713-appb-000008
基、哌嗪基、4-哌啶酮基、哌啶基、吩噻嗪基、吩噁嗪基、奎宁环基、四氢异喹啉基、四氢呋喃基、四氢吡喃基、四氢吡咯基、噻唑啉基、噻唑烷基、硫代吗啉基、硫代吗啉基亚砜和硫代吗啉基砜。
本发明中使用的术语“芳基烷基”是指一个或多个氢原子被芳基独立取代的烷基，其中所述的芳基和烷基如上文所定义。
本发明中使用的术语“杂芳基烷基”是指一个或多个氢原子被杂芳基独立取代的烷基，其中所述的杂芳基和烷基如上文所定义。
本发明中使用的术语“卤素”或“卤代”是指氟、氯、溴或碘。
本发明中的药物组合物含有本发明第一方面所述的化合物作为活性成分。此外，该药物组合物还可包含药学上可接受的载体，包括但不限于：水、盐溶液、醇、聚乙二醇、多羟基乙氧基化的蓖麻油、花生油、橄榄油、明胶、乳糖、石膏粉、蔗糖、糊精、碳酸镁、糖、环糊精、直链淀粉、硬脂酸镁、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸或纤维素低烷基醚、硅酸、脂肪酸、脂肪酸胺、脂肪酸单甘油酯和二甘油酯、季戊四醇脂肪酸醚、聚氧乙烯、羟甲基纤维素和聚乙烯吡咯烷酮。该药物组合物还可包含一种或多种药学上可接受的辅助剂、润湿剂、乳化剂、悬浮剂、防腐剂、渗透压调节剂、缓冲剂、甜味剂、矫味剂、着色剂或上述的任意组合。
本发明的药物组合物可以制成任何形式的制剂，例如胶囊剂、片剂、气雾剂、溶液剂、悬浮剂、糖衣剂、锭剂、糖浆剂、乳剂、软膏剂、膏剂、注射剂、散剂、颗粒剂、糊剂、缓释剂、泡沫剂。根据给药途径，本发明的药物可以制成口服给药制剂、鼻部给药制剂、肺部给药制剂、口腔含化制剂、皮下给药制剂、皮内给药制剂、经皮给药制剂、胃肠外给药制剂、直肠给药制剂、储库式给药制剂、静脉内给药制剂、尿道内给药制剂、肌内给药制剂、鼻内给药制剂、眼部给药制剂、硬膜外给药制剂或局部给药制剂。
本发明中的“癌症”包括本领域中已知的各种癌症，包括但不限于：肺癌、肝癌、胃癌、宫颈癌、结肠癌、乳腺癌、白血病、非小细胞癌、前列腺癌或累色素瘤、脑癌、皮肤癌、骨癌、淋巴癌、鼻咽癌、喉癌、食道癌、十二指肠癌、小肠癌、大肠癌、胰腺癌、肾癌、生殖器官癌、甲状腺癌。
实施例
接下来，通过实施例对本发明进行进一步详细地说明，但本发明不仅限于这些实施例。
在一个示例性的实施方式中，本发明的化合物通过以下方法进行合成，其中各取代基如通式(I)中所定义。
实施例1：N-L-亮氨酸硼酸-N′-对甲氧基苄胺酰-L-苯丙氨酸-脲(hlq-U51)
合成中间体a：N-Boc-L-苯丙氨酰-对甲氧基苄胺
Figure PCTCN2016099713-appb-000009
将Boc-L-苯丙氨酸(2.65g，10mmol)溶于50mL THF中，搅拌下加入HOBt(1.48g，11mmol)，反应5min后加入DCC(2.47g，12mmol)，活化羧基30min，体系为乳白色混悬液，加入对甲氧基苄胺(1.3mL，10mmol)及N-甲基吗啉(1.32mL，12mmol)，室温下反应24h，TLC检测反应完全。过滤除去不溶物N,N′-二环己基脲(DCU)，旋转蒸发除去溶剂THF，用50mL乙酸乙酯溶解， 依次用5％NaHCO3溶液、10％的柠檬酸溶液、5％NaHCO3溶液、饱和食盐水洗，无水Na2SO4干燥。柱层析(石油醚/EA＝3:1)得白色固体产物2.84g，收率74％，熔点：68-71℃。
1H NMR(400MHz,CDCl3)δ7.33–7.11(m,5H),7.00(d,J＝7.1Hz,2H),6.77(d,J＝8.5Hz,2H),6.40(s,1H),5.26(d,J＝6.7Hz,1H),4.40(d,J＝17.7Hz,1H),4.24(qd,J＝14.4,5.2Hz,2H),3.75(s,3H),3.04(d,J＝6.1Hz,2H),1.36(s,9H).13C NMR(101MHz,CDCl3)δ171.15,158.93,155.49,136.81,129.90,129.37,128.99,128.60,126.83,113.95,80.06,55.26,42.88,38.77,33.97,28.27.
合成中间体b：N-HCl-L-苯丙氨酰-对甲氧基苄胺
Figure PCTCN2016099713-appb-000010
将上步所得中间体a(2.66g，6.9mmol)溶于10mL二氯甲烷当中，开始冰浴，逐滴加入3当量的HCl/EtOH(10M，2mL，21mmol)，缓慢升至室温后再反应10h反应完全。后处理为直接蒸除所有可挥发物，得到白色但明显有绿色杂质的固体，加入20mL乙酸乙酯，小心铲起所有固体后剧烈搅拌，2h后抽滤固体并烘干，得产物2.2g(6.9mmol)，白色固体，收率99％，熔点：195-197℃。
合成中间体c：N-L-亮氨酸硼酸频哪醇酯-N′-对甲氧基苄胺酰-L-苯丙氨酸-脲
Figure PCTCN2016099713-appb-000011
0.49g羰基二咪唑(CDI，1.1当量，3.3mmol)溶于混合溶剂8mL DMF/40mL MeCN中，分批次加入1当量L-亮氨酸硼酸频哪醇酯盐酸盐(0.75g，3mmol)，每次加入前确保上次加入完全溶解，室温下反应2h后加入中间体b(0.96g，3mmol)及2当量三乙胺(0.83mL，6mmol)，体系变澄清后再反应24h，TLC检测反应完全。小心蒸除MeCN，加入50mL蒸馏水和50mL乙酸乙酯，充分震荡后分液，乙酸乙酯层用50mL×2的饱和食盐水洗涤，无水Na2SO4干燥。蒸除溶剂乙酸乙酯后得产物粗品1.2g，不再分离直接用于下一步反应。
合成标题化合物：N-L-亮氨酸硼酸-N′-对甲氧基苄胺酰-L-苯丙氨酸-脲
Figure PCTCN2016099713-appb-000012
上步所得产物粗品中间体c(1.2g)溶于40mL乙酸乙酯中，常压过滤后搅拌下逐滴加入1.1当量二乙醇胺，室温下搅拌48h，抽滤获得产生的不溶物，用乙酸乙酯20mL×2洗涤滤饼，充分抽干。固体混悬于20mL乙酸乙酯中，加入20mL蒸馏水及1mL的4N盐酸，剧烈搅拌6h反应完毕。分液除去水相，有机层用蒸馏水及饱和食盐水50mL各洗两次，无水Na2SO4干燥。蒸除溶剂后将所得泡沫状固体用乙酸乙酯重结晶，得白色固体120mg，收率24％，熔点：128-135℃。
1H NMR(400MHz,DMSO)δ8.36(s,1H),6.82-7.21(m,10H),4.34(s,1H),4.17(ddd,J＝29.3,14.6,5.2Hz,2H),3.71(s,3H),3.07–2.69(m,2H),1.67–1.42(m,1H),1.37–1.04(m,2H),0.79(t,J＝5.6Hz,6H).13C NMR(101MHz,DMSO)δ158.65,137.77,131.28,129.79,128.95,128.76,128.53,128.44,126.79,114.07,55.49,42.04,41.99,38.78,25.78,23.69,23.29.HRMS(ESI)calcd for C24H33BN3O4:438.25629[(M-H2O+CH2+H)+],found 438.25483.
实施例2：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-吡嗪-2-苄胺-脲(hlq-U78)
合成中间体a：N-L-苯丙氨酸甲酯-N′-吡嗪-2-苄胺-脲
Figure PCTCN2016099713-appb-000013
羰基二咪唑(CDI，1.64g，10.1mmol)溶于混合溶剂8mL DMF/40mL MeCN中，分批次加入L-苯丙氨酸甲酯盐酸盐(1.98g，9.2mmol)，每次加入前确保上次加入完全溶解，室温下反应2h后加入吡嗪-2-甲胺(1g，9.2mmol)及三乙胺(1.7mL，18.4mmol)，体系变澄清后再反应24h，TLC检测反应完全。小心蒸除MeCN，加入50mL蒸馏水和50mL乙酸乙酯，充分震荡后分液，乙酸乙酯层用50mL×2的饱和食盐水洗涤，无水Na2SO4干燥。蒸除溶剂乙酸乙酯后得混合物，经乙酸乙酯乙醚重结晶得产物纯品1.19g，收率42％，熔点：114-116℃。
1H NMR(400MHz,CDCl3)δ8.54(s,1H),8.41(d,J＝2.5Hz,1H),8.36(d,J＝1.6Hz,1H),7.26–7.13(m,3H),7.08(d,J＝6.8Hz,2H),6.09(d,J＝12.7Hz,1H),5.78(d,J＝14.9Hz,1H),4.78(dt,J＝8.0,6.0Hz,1H),4.62–4.34(m,2H),3.67(s,3H),3.03(qd,J＝13.8,6.1Hz,2H).13C NMR(101MHz,CDCl3)δ173.41,157.51,153.92,143.94,143.54,143.21,136.24,129.29,128.42,126.91,54.09,52.20,43.36,38.42.
合成中间体b：N-L-苯丙氨酸-N′-吡嗪-2-苄胺-脲
Figure PCTCN2016099713-appb-000014
将上步所得中间体a(1.19g，3.51mmol)溶于THF 10mL中，冰浴下缓慢滴加2N的LiOH至pH值为12～13，继续保持冰浴中反应，TLC检测，2h后反应完毕。缓慢蒸除溶剂THF，于冰浴下滴加盐酸至pH值为2～3，产生大量白色固体，过滤，滤饼用水、乙醚洗涤后烘干，得白色固体产物0.9g，收率77.8％，直接用于下一步反应。
合成中间体c：N-L-苯丙氨酰-L-亮氨酸硼酸频哪醇酯-N′-吡嗪-2-苄胺-脲
Figure PCTCN2016099713-appb-000015
将上步固体产物中间体b(0.9g，3mmol)悬浮于DCM 50mL中，搅拌下加入HOBt(0.45g，3.3mmol)，反应5min后加入DCC(0.74g，3.6mmol)，活化羧基30min，体系为乳白色混悬液，加入L-亮氨酸硼酸频哪醇酯盐酸盐(0.75g，3mmol)及DIPEA(0.52mL，3mmol)，室温下反应24h，TLC检测反应完全。过滤除去不溶物N,N′-二环己基脲(DCU)，旋转蒸发除去溶剂DCM后用50mL乙酸乙酯溶解，依次用10％的柠檬酸溶液、5％NaHCO3溶液、饱和食盐水洗，无水Na2SO4干燥。蒸除溶剂乙酸乙酯后得产物粗品1.23g，淡黄色泡沫状固体，不再分离直接用于下一步反应。
合成标题化合物：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-吡嗪-2-苄胺-脲
Figure PCTCN2016099713-appb-000016
上步所得产物粗品中间体c(1.23g)溶于40mL乙酸乙酯中，常压过滤后搅拌下逐滴加入1.1当量二乙醇胺(0.2mL)，室温下搅拌48h，抽滤获得产生的不溶物，用乙酸乙酯20mL×2洗涤滤饼，充分抽干。将固体混悬于20mL乙酸乙酯中，再次抽滤。所得固体混悬于乙酸乙酯20mL，中加入20mL蒸馏水及1mL的4N盐酸，剧烈搅拌6h反应完毕。分液除去水相，有机层用蒸馏水及饱和食盐水50mL各洗两次，无水Na2SO4干燥。蒸除溶剂后将所得泡沫状固体重结晶，得白色固体184mg，收率18％，熔点：154-157℃。
1H NMR(400MHz,DMSO)δ8.53(d,J＝1.2Hz,1H),8.49(d,J＝2.5Hz,1H),8.43(s,1H),7.35–7.08(m,5H),6.71(d,J＝5.7Hz,1H),6.58(dd,J＝13.4,5.1Hz,1H),4.70–4.50(m,1H),4.31(qd,J＝16.6,5.7Hz,2H),2.90(ddd,J＝22.2,13.4,6.6Hz,2H),2.66(d,J＝2.9Hz,1H),1.57(dd,J＝13.3,6.6Hz,1H),1.41–1.16(m,2H),0.82(d,J＝6.4Hz,6H).13C NMR(101MHz,DMSO)δ172.46,157.67,155.48,144.08,143.50,143.34,137.59,129.81,128.47,126.82,52.74,43.44,38.86,25.58,23.38,23.24,21.49.HRMS(ESI)calcd for C21H29BN5O3:410.23617[(M-H2O+CH2+H)+],found 410.23521.
实施例3：N-L-亮氨酸硼酸-N′-四氢呋喃-2-甲胺酰-L-苯丙氨酸-脲(hlq-U52)
Figure PCTCN2016099713-appb-000017
除采用四氢呋喃-2-甲胺代替原料对甲氧基苄胺以外，采用与实施例1类似的方法合成标题化合物，得到白色固体，收率21％。
1H NMR(400MHz,DMSO)δ10.1(s,1H),7.58–7.06(m,5H),6.73(d,J＝7.0Hz,1H),5.07(s,2H),4.53(s,1H),4.41-4.37(m,1H),4.22-4.10(m,1H),3.85-3.64(m,2H),3.60-3.58(t,J＝7.0Hz,1H),3.42-3.54(d,2H),3.38-3.31(d,J＝10.3Hz,7.0Hz,2H),2.23-1.92(m,4H),1.64–1.42(m,1H),1.20(dd,J＝14.5,8.5Hz,2H),0.85–0.68(d,J＝6.8Hz,6H).13C NMR(101MHz,DMSO)δ170.72,159.07,137.47,128.56,128.28,126.91,82.11,67.64,59.42,59.30,45.79,36.71,33.23,31.52,25.77,23.67,23.20,21.52.HRMS(ESI)calcd for C21H33BN3O4：402.31542[(M-H2O+CH2+H)+],found 402.31539.
实施例4：N-L-亮氨酸硼酸-N′-(3-苄氧基)-苯胺酰-L-苯丙氨酸-脲(hlq-U53)
Figure PCTCN2016099713-appb-000018
除采用3-苄氧基甲胺代替原料对甲氧基苄胺以外，采用与实施例1类似的方法合成标题化合物，得到白色泡沫状固体，收率27％，熔点：113-115℃。
1H NMR(400MHz,DMSO)δ10.12(s,1H),7.58–7.06(m,16H),6.73(d,J＝7.0Hz,1H),5.07(s,2H),4.53(s,1H),3.03(s,1H),2.90(s,1H),1.64–1.42(m,1H),1.20(dd,J＝14.5,8.5Hz,2H),0.85–0.68(s,6H).13C NMR(101MHz,DMSO)δ170.72,159.07,140.31,137.47,130.00,129.77,129.55,128.89,128.56,128.28,128.09,126.91,112.42,110.07,106.68,69.60,56.19,41.91,25.77,23.67,23.20,21.52.HRMS(ESI)calcd for C29H35BN3O4:500.27202[(M-H2O+CH2+H)+],found 500.27051.
实施例5：N-L-亮氨酸硼酸蒎烷二醇酯-N′-(3-苄氧基)-苯胺酰-L-苯丙氨酸-脲(hlq-U53-3)
Figure PCTCN2016099713-appb-000019
将实施例4的化合物0.2mmol溶于5mL乙酸乙酯中，搅拌下加入1.1当量(+)-蒎烷二醇，室温下反应2h完毕，采用滴管装硅胶过滤方式简单柱层析，得白色泡沫状固体，收率87％，熔点：78-80℃。
1H NMR(400MHz,CDCl3)δ7.48–7.30(m,6H),7.22–7.08(m,7H),6.97(d,J＝6.5Hz,1H),6.76–6.68(m,1H),6.64(s,1H),6.30(s,1H),4.95(s,2H),4.69(d,J＝6.0Hz,1H),4.19(d,J＝7.9Hz,1H),3.16(s,2H),2.55(s,1H),2.37–2.26(m,1H),2.19–2.12(m,1H),2.00(t,J＝5.4Hz,1H),1.88(s,2H),1.59–1.45(m,2H),1.35(s,3H),1.29(s,3H),1.27(s,2H),0.86(s,3H),0.81(d,J＝6.2Hz,3H),0.74(d,J＝6.3Hz,3H).13C NMR(101MHz,CDCl3)δ170.39,160.99,159.30,138.54,136.85,136.07,129.80,129.66,128.55,128.49,127.97,127.51,127.04,112.91,111.20,106.99,73.85,69.91,69.07,53.98,52.30,41.70,40.52,40.16,38.14,29.61,29.31,27.85,27.39,25.54,24.29,23.27,22.16.HRMS(ESI)calcd for C38H49BN3O5:638.37663[(M+H)+], found 638.37449.
实施例6：N-L-亮氨酸硼酸-N′-吡嗪-2-胺酰-L-苯丙氨酸-脲(hlq-U54)
Figure PCTCN2016099713-appb-000020
除采用吡嗪-2-胺代替原料对甲氧基苄胺以外，采用与实施例1类似的方法合成标题化合物，得到白色泡沫状固体，收率27％，熔点：145-148℃。
1H NMR(400MHz,DMSO)δ10.96(s,1H),9.30(s,1H),8.41(s,1H),8.38(d,J＝1.7Hz,1H),7.42–7.17(m,5H),7.17(d,J＝6.4Hz,1H),4.65(s,1H),3.14–2.81(m,2H),2.41(s,1H),1.45(dd,J＝12.7,6.3Hz,1H),1.32–1.05(m,2H),0.71(t,J＝7.0Hz,6H).13C NMR(101MHz,DMSO)δ161.07,148.94,143.12,140.40,137.51,136.63,129.80,128.56,126.95,56.03,41.74,25.69,23.56,23.14,21.51.HRMS(ESI)calcd for C20H27BN5O3:396.22050[(M-H2O+CH2+H)+],found 396.21936.
实施例7：N-L-亮氨酸硼酸蒎烷二醇酯-N′-吡嗪-2-胺酰-L-苯丙氨酸-脲(hlq-U54-3)
Figure PCTCN2016099713-appb-000021
从实施例6的化合物出发，采用与实施例5类似的酯化路线合成标题化合物，得到白色泡沫状固体，收率79％，熔点：93-95℃。
1H NMR(400MHz,CDCl3)δ9.52(s,1H),9.49(s,1H),8.31(d,J＝2.5Hz,1H),8.23–8.05(m,1H),7.24–7.04(m,5H),6.35(s,1H),6.08(s,1H),4.77(d,J＝6.8Hz,1H),4.18(d,J＝8.0Hz,1H),3.15(ddd,J＝35.8,13.9,7.0Hz,2H),2.81(s,1H),2.34–2.17(m,1H),2.08(dd,J＝10.3,5.9Hz,1H),1.93(t,J＝5.3Hz,1H),1.84–1.73(m,2H),1.58(dd,J＝13.2,6.5Hz,1H),1.35(qd,J＝14.0,7.8Hz,3H),1.25(s,3H),1.22(s,3H),0.82(t,J＝6.8Hz,6H),0.79(s,3H).13C NMR(101MHz,CDCl3)δ171.22,160.20,147.82,142.06,140.30,137.30,135.98,129.21,128.65,127.12,69.16,56.83,51.81,41.15,39.80,38.10,37.98,36.12,28.80,27.20,26.49,25.52,24.10,23.08,22.18.HRMS(ESI)calcd for C29H41BN5O4:534.32512[(M+H)+],found 534.32362.
实施例8：N-L-亮氨酸硼酸-N′-对甲氧基苯胺酰-L-苯丙氨酸-脲(hlq-U55)
Figure PCTCN2016099713-appb-000022
除采用对甲氧基苯胺代替原料对甲氧基苄胺以外，采用与实施例1类似的方法合成标题化合物，得到白色泡沫状固体，收率25％，熔点：146-148℃。
1H NMR(400MHz,DMSO)δ9.91(s,1H),7.45(d,J＝8.9Hz,2H),7.20(m,5H),7.18(d,J＝6.0Hz,1H),6.88(d,J＝9.0Hz,2H),4.50(d,J＝5.4Hz,1H),3.71(s,3H),3.13–2.79(m,2H),1.53(td,J＝12.9,6.3Hz,1H),1.34–1.09(m,2H),0.91–0.70(t,J＝4.0Hz,6H).13C NMR(101MHz,DMSO)δ172.46,169.90,155.90,137.66,132.15,129.78,128.54,126.86,121.50,114.30,55.61,41.95,38.85,25.78,23.69,23.20.HRMS(ESI)calcd for C23H31BN3O4:424.24062[(M-H2O+CH2+H)+],found 424.23945.
实施例9：N-L-亮氨酸硼酸蒎烷二醇酯-N′-对甲氧基苯胺酰-L-苯丙氨酸-脲(hlq-U55-3)
从实施例8的化合物出发，采用与实施例5类似的酯化路线合成标题化合物，得到白色泡沫状固体，收率86％，熔点：78-80℃。
1H NMR(400MHz,DMSO)δ9.96(d,J＝39.6Hz,1H),7.43(d,J＝9.0Hz,2H),7.32–7.21(m,6H),7.00(s,2H),6.88(d,J ＝9.1Hz,2H),4.48(d,J＝5.1Hz,1H),3.95(d,J＝7.7Hz,1H),3.72(s,3H),3.01(ddd,J＝21.3,13.7,6.6Hz,2H),2.39(t,J＝7.3Hz,1H),2.15(dd,J＝11.7,9.8Hz,1H),2.00–1.91(m,1H),1.77(dd,J＝11.4,5.5Hz,2H),1.68–1.54(m,2H),1.42(d,J＝9.7Hz,1H),1.20(s,3H),1.18(s,3H),0.84(t,J＝7.2Hz,6H),0.80(s,3H).13C NMR(101MHz,DMSO)δ169.42,161.81,155.93,137.36,132.07,129.79,128.62,127.02,121.56,114.27,81.77,75.49,56.35,55.60,52.75,42.25,38.07,37.38,29.80,27.77,26.58,25.78,24.52,23.77,22.51.HRMS(ESI)calcd for C32H45BN3O5:562.34523[(M+H)+],found 562.34326.
实施例10：N-L-亮氨酸硼酸-N′-吡嗪-2-胺酰-D-苯丙氨酸-脲(hlq-U56)
Figure PCTCN2016099713-appb-000024
除采用吡嗪-2-胺代替原料对甲氧基苄胺，采用Boc-D-苯丙氨酸代替原料Boc-L-苯丙氨酸以外，采用与实施例1类似的方法合成标题化合物，得到微黄白色泡沫状固体，收率24％，熔点：138-141℃。
1H NMR(400MHz,DMSO)δ11.12–10.93(m,1H),9.45–9.22(m,1H),8.40(s,1H),8.37(s,1H),7.28(d,J＝18.4Hz,5H),7.21–7.15(m,1H),6.52(s,1H),4.68(s,1H),2.92(dd,J＝50.3,43.2Hz,2H),2.44(s,1H),1.45(dd,J＝12.6,6.3Hz,1H),1.13(ddd,J＝20.3,12.1,6.9Hz,3H),0.77–0.61(dd,J＝6.9,4.2Hz,6H).13C NMR(101MHz,DMSO)δ172.45,160.69,148.96,143.11,140.39,137.52,136.66,129.83,128.53,126.92,55.88,41.92,25.66,23.61,23.57,23.06,21.49.HRMS(ESI)calcd for C20H27BN5O3:396.22050[(M-H2O+CH2+H)+],found 396.21952.
实施例11：N-L-亮氨酸硼酸-N′-吡嗪-2-胺酰-L-亮氨酰-L-亮氨酸-脲(hlq-U61)
Figure PCTCN2016099713-appb-000025
除采用N-吡嗪基-L-亮氨酰胺代替原料对甲氧基苄胺，采用Boc-L-亮氨酸代替原料Boc-L-苯丙氨酸以外，采用与实施例1类似的方法合成标题化合物，得到白色泡沫状固体，收率21％，熔点：157-162℃。
1H NMR(400MHz,DMSO)δ10.95(s,1H),9.29(s,1H),8.40(s,1H),8.36(d,J＝2.3Hz,1H),8.13(d,J＝7.2Hz,1H),6.67(s,1H),4.63(s,1H),4.20(dd,J＝15.8,12.3Hz,1H),1.77–1.10(m,9H),0.99–0.73(m,18H).13C NMR(101MHz,DMSO)δ173.57,172.60,149.09,143.10,140.31,140.27,136.80,52.37,52.02,42.10,41.07,25.69,24.66,24.49,23.71,23.58,23.30,22.36,21.89,21.83.HRMS(ESI)calcd for C23H40BN6O4:475.32027[(M-H2O+CH2+H)+],found 475.31908.
实施例12：N-L-亮氨酸硼酸-N′-吡嗪-2-胺酰-L-亮氨酰-L-苯丙氨酸-脲(hlq-U62)
Figure PCTCN2016099713-appb-000026
除采用N-吡嗪基-L-亮氨酰胺代替原料对甲氧基苄胺以外，采用与实施例1类似的方法合成标题化合物，得到白色泡沫状固体，收率38％，熔点：154-157℃。
1H NMR(400MHz,DMSO)δ10.93(s,1H),9.33(s,1H),8.42(d,J＝1.4Hz,1H),8.39(d,J＝2.4Hz,1H),8.24(dd,J＝18.5,7.8Hz,1H),7.31–6.97(m,5H),4.66(dd,J＝13.8,7.5Hz,1H),4.50–4.26(m,1H),3.14–2.69(m,2H),1.75–1.47(m,4H),1.39–1.11(m,2H),0.89(dd,J＝11.9,6.4Hz,6H),0.80(t,J＝5.6Hz,6H).13C NMR(101MHz,DMSO)δ172.45,172.43,149.08,143.11,140.35,137.68,136.86,129.83,129.51,128.34,126.65,52.03,42.04,41.12,25.71,24.66,23.73,23.52,23.24,22.02,21.49.HRMS(ESI)calcd for C26H38BN6O4:509.30467[(M-H2O+CH2+H)+],found 509.30313.
实施例13：N-L-亮氨酸硼酸频哪醇酯-N′-吡嗪-2-胺酰-L-亮氨酰-L-苯丙氨酸-脲(hlq-U62-1)
Figure PCTCN2016099713-appb-000027
除采用N-吡嗪基-L-亮氨酰胺代替原料对甲氧基苄胺以及不进行中间体c的水解步骤以外，采用 与实施例1类似的方法合成标题化合物，得到白色固体，收率58％，熔点：196-198℃。
1H NMR(400MHz,DMSO)δ11.00(s,1H),9.32(s,1H),8.45–8.41(m,1H),8.39(d,J＝2.6Hz,1H),7.13(m,7H),4.66(s,1H),4.43(dd,J＝12.9,7.6Hz,1H),3.04(d,J＝9.0Hz,1H),2.88–2.80(m,1H),2.30(d,J＝28.5Hz,1H),1.68(m,1H),1.56(m,3H),1.16–1.07(m,2H),1.04(s,12H),0.91(dd,J＝11.5,6.6Hz,6H),0.82(dd,J＝12.0,6.5Hz,6H).13C NMR(101MHz,DMSO)δ172.60,170.74,162.08,149.10,143.12,140.34,136.85,129.83,128.44,128.26,126.83,79.02,52.07,42.18,40.93,36.27,25.79,24.73,24.19,23.53,22.10,22.03.
实施例14：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-苄胺-脲(hlq-U05)
Figure PCTCN2016099713-appb-000028
除采用苄胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率15％，熔点：133-136℃。
1H NMR(400MHz,DMSO)δ7.41–7.14(m,9H),7.17–7.02(m,2H),6.51(s,1H),6.35(dd,J＝8.4,4.6Hz,1H),4.70–4.52(m,1H),4.16(ddd,J＝20.4,15.4,5.8Hz,2H),3.00(dd,J＝8.9,4.1Hz,1H),2.91–2.77(m,1H),2.68(s,1H),1.60(dd,J＝13.0,6.6Hz,1H),1.32(ddd,J＝26.5,15.3,6.7Hz,2H),0.84(d,J＝6.2Hz,6H).13C NMR(101MHz,DMSO)δ174.88,157.71,140.93,137.53,129.86,128.61,128.50,127.29,126.96,126.80,43.25,38.96,25.57,23.48,23.20,23.02,21.51.HRMS(ESI)calcd for C23H31BN3O3:408.24571[(M-H2O+CH2+H)+],found 408.24429.
实施例15：N-L-苯丙氨酰-L亮氨酸硼酸-N′-对甲氧基苄胺-脲(hlq-U07)
Figure PCTCN2016099713-appb-000029
除采用对甲氧基苄胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率31％，熔点：126-128℃。
1H NMR(400MHz,DMSO)δ7.31–7.19(m,5H),7.06(d,J＝8.5Hz,2H),6.83(d,J＝8.6Hz,2H),6.42(s,1H),6.30(d,J＝8.5Hz,1H),4.63(dd,J＝13.7,7.9Hz,1H),4.20–3.98(m,2H),3.71(s,3H),3.04–2.76(m,2H),2.67(d,J＝2.7Hz,1H),1.59(dd,J＝13.1,6.5Hz,1H),1.40–1.20(m,2H),0.84(d,J＝4.0Hz,6H).13C NMR(101MHz,DMSO)δ174.96,158.53,157.65,137.61,132.78,129.86,128.64,128.50,126.80,114.04,55.46,42.76,38.97,25.59,23.40,23.27,21.49.HRMS(ESI)calcd for C24H33BN3O4:438.25629[(M-H2O+CH2+H)+],found 438.25508.
实施例16：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-(3-苄氧基)苯胺-脲(hlq-U21)
Figure PCTCN2016099713-appb-000030
除采用3-苄氧基苯胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率26％，熔点：112-115℃。
1H NMR(400MHz,DMSO)δ8.84(d,J＝17.7Hz,1H),8.67(d,J＝9.8Hz,1H),7.52–7.16(m,11H),7.10(dt,J＝13.7,6.8Hz,1H),6.86(d,J＝6.6Hz,1H),6.57(d,J＝8.1Hz,1H),6.45(dd,J＝19.5,8.9Hz,1H),5.04(s,2H),4.77–4.57(m,1H),3.12–2.87(m,2H),2.72(s,1H),1.59(dt,J＝13.1,9.2Hz,1H),1.45–1.20(m,2H),0.84(d,J＝5.4Hz,6H).13C NMR(101MHz,DMSO)δ174.37,159.25,154.75,141.85,137.64,137.26,129.93,129.87,128.84,128.57,128.18,128.00,126.91,110.77,108.01,104.91,69.52,52.18(m),38.97,33.84,25.54,23.60,22.94,21.49.HRMS(ESI)calcd for C29H35BN3O4:500.27202[(M-H2O+CH2+H)+],found 500.27025.
实施例17：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-吡嗪-2-胺-脲(hlq-U22)
Figure PCTCN2016099713-appb-000031
除采用吡嗪-2-胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到黄白色泡沫状固体，收率17％，熔点：135-138℃。
1H NMR(400MHz,DMSO)δ9.54(s,1H),8.86(d,J＝14.4Hz,1H),8.76(d,J＝6.0Hz,1H),8.17(dd,J＝9.2,5.6Hz,2H),7.94(d,J＝6.6Hz,1H),7.22(dt,J＝27.6,4.1Hz,5H),4.82–4.62(m,1H),3.14–2.90(m,2H),2.64(br,1H),1.56(dt,J＝13.1,6.6Hz,1H),1.39–1.12(m,2H),0.78(dd,J＝6.1,2.6Hz,6H).13C NMR(101MHz,DMSO)δ173.89,154.06,150.00,141.47,137.59,136.92,135.47,130.00,128.59,127.07,52.47,38.61,25.48,23.49,23.01,22.93.HRMS(ESI)calcd for C20H27BN5O3:396.22050[(M-H2O+CH2+H)+],found 396.21998.
实施例18：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-2,5-二甲氧基苄胺-脲(hlq-U23)
Figure PCTCN2016099713-appb-000032
除采用2,5-二甲氧基苄胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色固体，收率28％，熔点：156-159℃。
1H NMR(400MHz,DMSO)δ7.23–7.10(m,5H),6.83(d,J＝8.8Hz,1H),6.76–6.68(m,2H),4.30(dt,J＝13.9,6.2Hz,0H),4.08(d,J＝5.0Hz,2H),3.97(m,2H),3.69(s,3H),3.63(s,3H),3.10–2.83(m,2H),2.81–2.65(m,1H),1.50–1.14(m,1H),0.90–0.58(dd,6H).13C NMR(101MHz,DMSO)δ171.93,158.22,153.46,151.14,137.86,129.56,129.27,128.53,126.73,114.62,112.29,111.83,56.13,55.73,38.45,25.18,24.96,23.55,23.52,22.26,22.02.HRMS(ESI)calcd for C25H35BN3O5:468.26687[(M-H2O+CH2+H)+],found 468.26590.
实施例19：N-L-苯丙氨酰-L-亮氨酸硼酸蒎烷二醇酯-N′-2,5-二甲氧基苄胺-脲(hlq-U23-3)
Figure PCTCN2016099713-appb-000033
从实施例18的化合物出发，采用与实施例5类似的酯化路线合成标题化合物，得到白色固体，收率89％，熔点：88-90℃。
1H NMR(400MHz,CDCl3)δ7.32–7.18(m,5H),6.99–6.83(m,1H),6.80–6.68(m,2H),6.14(s,1H),4.38(dd,J＝15.2,6.0Hz,1H),4.31–4.23(m,1H),3.76(s,3H),3.73(s,3H),3.17(d,J＝6.6Hz,1H),3.10–2.63(m,2H),2.03(d,J＝17.3Hz,2H),1.98–1.73(m,2H),1.68–1.42(m,2H),1.28(s,3H),1.23(s,3H),1.14(d,J＝9.7Hz,3H),0.90–0.79(m,6H),0.76(s,3H).13C NMR(101MHz,CDCl3)δ158.46,153.67,151.35,137.20,129.48,129.24,128.48,126.59,115.44,115.10,112.34,111.10,55.69,51.89,51.61,40.35,39.72,37.99,35.70,28.90,28.56,27.23,27.14,26.36,26.28,25.76,25.34,23.99,23.04,23.00,21.94.HRMS(ESI)calcd for C34H49BN3O6:606.37148[(M+H)+],found 606.36972.
实施例20：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-2,3-二氯苄胺-脲(hlq-U24)
Figure PCTCN2016099713-appb-000034
除采用2,3-二氯苄胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率32％，熔点：119-122℃。
1H NMR(400MHz,DMSO)δ7.22(m,8H),7.12(d,J＝4.3Hz,1H),6.49(s,1H),6.33(d,J＝8.7Hz,1H),4.58(d,J＝5.9Hz,1H),4.12(dt,J＝15.3,10.3Hz,2H),2.98(d,J＝12.4Hz,1H),2.90–2.74(m,1H),2.64(s,1H),1.70–1.45(m,1H),1.28(m,2H),0.83(d,J＝5.5Hz,6H).13C NMR(101MHz,DMSO)δ175.00,157.69,140.98,137.54,129.89,129.82,128.59,128.50,128.40(m,18H),127.29,126.95,126.79,43.24,38.99,25.54,23.60,23.01,21.50.HRMS(ESI)calcd for C23H29BCl2N3O3:462.25222[(M-H2O+CH2+H)+],found 462.25277.
实施例21：N-甘氨酰-L-亮氨酸硼酸-N′-(3-苄氧基)-苯胺-脲(hlq-U25)
Figure PCTCN2016099713-appb-000035
除采用3-苄氧基苯胺代替原料吡嗪-2-甲胺，采用甘氨酸甲酯代替原料L-苯丙氨酸甲酯以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率36％，熔点：109-113℃。
1H NMR(400MHz,DMSO)δ8.82(s,1H),8.77(s,1H),7.37(m,5H),7.26(s,1H),7.13(t,J＝8.1Hz,1H),6.92(d,J＝7.8Hz,1H),6.64–6.54(m,1H),6.47(t,J＝5.2Hz,1H),5.05(s,2H),3.92(d,J＝4.6Hz,2H),2.64(s,1H),1.62(dt,J＝13.2,6.6Hz,1H),1.44–1.20(m,2H),0.83(d,J＝4.9Hz,6H).13C NMR(101MHz,DMSO)δ173.08,159.24,155.44,142.00,137.65,129.87,128.84,128.18,128.00,110.86,108.02,104.97,69.51,43.5(m),40.85,25.62,23.39,23.25,21.49.HRMS(ESI)calcd for C22H29BN3O4:410.22495[(M-H2O+CH2+H)+],found 410.22377.
实施例22：N-甘氨酰-L-亮氨酸硼酸-N′-2,5-二氯苯胺-脲(hlq-U26)
Figure PCTCN2016099713-appb-000036
除采用2,5-二氯苯胺代替原料吡嗪-2-甲胺，采用甘氨酸甲酯代替原料L-苯丙氨酸甲酯以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率17％，熔点：125-129℃。
1H NMR(400MHz,DMSO)δ8.79(s,1H),8.47(d,J＝10.7Hz,1H),8.30(d,J＝2.2Hz,1H),7.57(dd,J＝10.3,5.3Hz,1H),7.41(dd,J＝8.5,4.3Hz,1H),7.00(dd,J＝8.5,2.2Hz,1H),3.95(d,J＝4.8Hz,2H),3.37(m,1H),1.61(m,1H),1.38–1.17(m,2H),0.83(dd,J＝13.9,3.7Hz,6H).13C NMR(101MHz,DMSO)δ172.63,168.84,155.05,138.26,132.30,130.79,122.41,119.91,43.04,25.60,23.34,23.17,22.91.HRMS(ESI)calcd for C15H21BCl2N3O3:372.10502[(M-H2O+CH2+H)+],found 372.10413.
实施例23：N-L-苯丙氨酰-L-苯丙氨酰-L-亮氨酸硼酸-N′-(3-苄氧基)-苯胺-脲(hlq-U31)
Figure PCTCN2016099713-appb-000037
除采用3-苄氧基苯胺代替原料吡嗪-2-甲胺，采用L-苯丙氨酰-L-苯丙氨酸甲酯代替原料L-苯丙氨酸甲酯以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率18％，熔点：130-133℃。
1H NMR(400MHz,DMSO)δ8.72(d,J＝5.6Hz,1H),8.65(d,J＝16.6Hz,1H),8.55(s,1H),7.48–7.06(m,16H),6.87(d,J＝8.3Hz,1H),6.80(d,J＝4.0Hz,1H),6.64–6.50(m,1H),6.24(d,J＝5.9Hz,1H),5.04(s,2H),4.68(dd,J＝14.3,6.5Hz,1H),4.51(dd,J＝16.6,6.0Hz,1H),3.00(dd,J＝35.2,22.1Hz,2H),2.88–2.64(m,2H),1.59(s,1H),1.31(dd,J＝23.7,18.0Hz,2H),0.79(dd,J＝21.1,5.3Hz,6H).13C NMR(101MHz,DMSO)δ172.42,171.75,159.25,154.96,141.92,137.64,129.88,129.84,129.74,128.84,128.83,128.51,128.36,128.18,127.99,126.69,126.60,110.69,107.92,104.87,69.54,54.30,37.81,25.51,23.67,23.41,22.98,22.80,21.49.HRMS(ESI)calcd for C38H44BN4O5:647.34057[(M-H2O+CH2+H)+],found 647.33814.
实施例24：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-吡嗪-2-氨酰-L-苯丙氨酸-脲(hlq-U32)
Figure PCTCN2016099713-appb-000038
除采用N-吡嗪基-L-苯丙氨酰胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率14％，熔点：170-174℃。
1H NMR(400MHz,DMSO)δ10.89(s,1H),9.31(s,1H),8.40(s,1H),8.37(s,1H),7.47(s,1H),7.31–7.09(m,10H),6.54(d,J＝7.7Hz,1H),6.40(d,J＝7.6Hz,1H),4.67(d,J＝4.3Hz,1H),4.29(d,J＝5.5Hz,1H),3.10–2.94(m,2H),2.79(ddd,J＝21.0,13.6,8.0Hz,2H),1.50(dd,J＝12.7,6.4Hz,1H),1.41–1.10(m,2H),0.78(dd,J＝27.1,6.5Hz,6H).13C NMR(101MHz,DMSO)δ172.61,171.53,157.53,149.07,143.11,140.24,138.27,137.80,136.69,129.80,129.76,128.55,128.37,126.82,126.47,55.49,54.67,38.77,38.35,25.18,23.71,23.66,22.46.HRMS(ESI)calcd for C29H36BN6O4:543.28907[(M-H2O+CH2+H)+],found543.28785.
实施例25：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-苯乙胺-脲(hlq-U71)
Figure PCTCN2016099713-appb-000039
除采用苯乙胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率18％，熔点：134-137℃。
1H NMR(400MHz,DMSO)δ8.63(d,J＝17.7Hz,1H),7.33–7.06(m,10H),6.37–6.24(m,1H),6.05(s,1H),4.55(dd,J＝16.1,8.1Hz,1H),3.26–3.09(m,2H),2.87(ddd,J＝21.9,13.6,7.1Hz,2H),2.61(m,3H),1.75–1.44(m,1H),1.45–1.13(m,2H),0.82(d,J＝5.9Hz,6H).13C NMR(101MHz,DMSO)δ174.98,157.58,140.06,137.66,129.83,129.08,128.73,128.49,126.79,126.42,52.62,41.39,38.95,36.47,25.53,23.40,23.26.HRMS(ESI)calcd for C24H33BN3O3:422.26137[(M-H2O+CH2+H)+],found 422.26053.
实施例26：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-(R)-2-甲基苄胺-脲(hlq-U72)
Figure PCTCN2016099713-appb-000040
除采用(R)-2-甲基苄胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率23％，熔点：151-154℃。
1H NMR(400MHz,DMSO)δ8.61(s,1H),7.38–7.07(m,10H),6.53(d,J＝7.9Hz,1H),6.12(d,J＝8.5Hz,1H),4.69(p,J＝6.8Hz,1H),4.52(dd,J＝14.4,7.5Hz,1H),2.89(ddd,J＝21.2,13.6,6.8Hz,2H),2.63(s,1H),1.53(dt,J＝13.1,6.5Hz,1H),1.34–1.15(m,2H),1.27(d,J＝4.8Hz,3H),0.79(t,J＝6.2Hz,6H).13C NMR(101MHz,DMSO)δ174.69,156.86,145.73,137.49,129.91,128.60,128.48,126.87,126.78,126.22,52.49,49.07,39.09,25.46,23.74,23.66,22.86.HRMS(ESI)calcd for C24H33BN3O3:422.26137[(M-H2O+CH2+H)+],found 422.26043.
实施例27：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-(S)-2-甲基苄胺-脲(hlq-U73)
除采用(S)-2-甲基苄胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率32％，熔点：164-167℃。
1H NMR(400MHz,DMSO)δ8.58(s,1H),7.31–7.17(m,10H),6.51(d,J＝7.8Hz,1H),6.15(d,J＝8.7Hz,1H),4.72–4.62(m,1H),4.53(dd,J＝14.3,8.0Hz,1H),3.01–2.74(m,2H),2.62(d,J＝3.4Hz,1H),1.54(dt,J＝13.2,6.6Hz,1H),1.30–1.17(m,2H),1.25(d,J＝5.3Hz,3H),0.79(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO)δ174.77,156.92,145.62,137.51,129.86,128.64,128.49,126.90,126.82,126.25,52.64,49.10,39.07,25.54,23.76,23.37,23.24.HRMS(ESI)calcd for C24H33BN3O3:422.26137[(M-H2O+CH2+H)+],found 422.26051.
实施例28：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-1,2,3,4-四氢异喹啉-脲(hlq-U74)
Figure PCTCN2016099713-appb-000041
除采用1,2,3,4-四氢异喹啉代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率28％，熔点：158-160℃。
1H NMR(400MHz,DMSO)δ8.64(s,1H),7.39–6.93(m,9H),6.76(d,J＝8.2Hz,1H),4.57(dd,J＝14.2,8.7Hz,1H),4.52–4.36(m,2H),3.50(t,J＝5.7Hz,2H),3.01(ddd,J＝22.8,13.4,7.4Hz,2H),2.66(d,J＝5.5Hz,2H),1.58(td,J＝13.2,6.6Hz,1H),1.38–1.16(m,2H),0.81(dd,J＝6.5,2.7Hz,6H).13C NMR(101MHz,DMSO)δ175.25,172.44,157.02,138.32,135.20,134.39,129.80,128.90,128.42,126.60,126.53,126.38,53.97,45.73,41.50,37.81,28.61,25.58,23.47,23.15,21.50.HRMS(ESI)calcd for C25H33BN3O3:434.26139[(M-H2O+CH2+H)+],found 434.26060.
实施例29：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-(N-甲基)-苄胺-脲(hlq-U75)
Figure PCTCN2016099713-appb-000042
除采用N-甲基苄胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率31％，熔点：111-114℃。
1H NMR(400MHz,DMSO)δ8.71(s,1H),7.31–7.18(m,8H),6.99(d,J＝6.9Hz,2H),6.60(d,J＝8.4Hz,1H),4.66(td,J＝9.1,5.2Hz,1H),4.36(dd,J＝75.5,15.8Hz,2H),3.04(ddd,J＝23.6,13.6,7.5Hz,2H),2.70(s,3H),1.65(td,J＝13.3,6.7Hz,1H),1.46–1.20(m,2H),0.87(d,J＝6.5Hz,6H).13C NMR(101MHz,DMSO)δ175.43,157.65,138.85,138.34,129.80,128.73,128.49,127.51,127.17,126.68,53.92,51.53,37.80,34.13,25.66,23.54,23.29.HRMS(ESI)calcd for C24H33BN3O3:422.26137[(M-H2O+CH2+H)+],found 422.26058.
实施例30：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-(2,3-二甲基)-苄胺-脲(hlq-U76)
Figure PCTCN2016099713-appb-000043
除采用2,3-二甲基苄胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率19％，熔点：137-139℃。
1H NMR(400MHz,DMSO)δ7.24(s,5H),7.07–6.89(m,3H),6.33(s,1H),6.27(d,J＝8.2Hz,1H),4.71–4.52(m,1H),4.13(ddd,J＝26.3,18.5,6.4Hz,2H),3.07–2.77(m,2H),2.67(s,1H),2.21(s,3H),2.07(s,3H),1.60(td,J＝13.2,6.6Hz,1H),1.30(ddd,J＝21.8,12.4,6.2Hz,2H),0.84(d,J＝5.9Hz,6H).13C NMR(101MHz,DMSO)δ174.86,157.46,138.14,137.51,136.58,134.39,129.89,129.84,128.78,128.49,126.79,125.84,125.56,52.64,42.11,38.99,25.57,23.61,23.47,23.01,20.46,14.67.HRMS(ESI)calcd for C25H35BN3O3:436.27704[(M-H2O+CH2+H)+],found 436.27918.
实施例31：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-2,5-二氯苄胺-脲(hlq-U79)
Figure PCTCN2016099713-appb-000044
除采用2,5-二氯苄胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率18％，熔点：118-120℃。
1H NMR(400MHz,DMSO)δ7.41(m,1H),7.23(m,7H),6.65(d,J＝3.2Hz,1H),6.53(dd,J＝10.2,5.7Hz,1H),4.59(dd,J＝13.7,6.7Hz,1H),4.26(d,J＝5.9Hz,1H),4.16(d,J＝15.6Hz,3H),3.01(d,J＝11.9Hz,1H),2.88(d,J＝9.3Hz,1H),2.69(s,1H),1.59(dt,J＝17.1,6.5Hz,1H),1.40–1.22(m,2H),0.84(d,J＝6.2Hz,6H).13C NMR(101MHz,DMSO)δ174.25,157.85,140.58,137.94,132.34,131.09,130.80,129.69,128.61,128.50,126.88,54.41,41.02,37.88,25.56,23.52,23.45,23.10,23.00.HRMS(ESI)calcd for C23H29BCl2N3O3:476.16776[(M-H2O+CH2+H)+],found 476.16698.
实施例32：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-对苯基苄胺-脲(hlq-U80)
Figure PCTCN2016099713-appb-000045
除采用对苯基苄胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率19％，熔点：164-167℃。
1H NMR(400MHz,DMSO)δ7.63(d,J＝8.3Hz,2H),7.56(d,J＝7.1Hz,2H),7.45(t,J＝7.5Hz,2H),7.35(t,J＝7.3Hz,1H),7.31–7.19(m,7H),6.59(s,1H),6.48–6.32(m,1H),4.66(dd,J＝14.4,7.0Hz,1H),4.23(ddd,J＝20.6,15.6,5.8Hz,2H),3.14–2.82(m,2H),2.73(t,J＝16.0Hz,1H),1.71–1.55(m,1H),1.34(ddd,J＝24.5,12.7,6.3Hz,2H),0.86(d,J＝6.0Hz,6H).13C NMR(101MHz,DMSO)δ172.45,157.72,140.54,140.23,139.01,137.54,129.94,129.89,129.34,128.53,127.94,127.70, 127.00,126.96,52.52,43.04,39.02,25.61,23.62,23.05,21.50.HRMS(ESI)calcd for C29H35BN3O3:484.27710[(M-H2O+CH2+H)+],found 484.27583.
实施例33：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-呋喃-2-甲胺-脲(hlq-U81)
Figure PCTCN2016099713-appb-000046
除采用呋喃-2-甲胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率30％，熔点：120-124℃。
1H NMR(400MHz,DMSO)δ8.67(s,1H),7.53(d,J＝0.9Hz,1H),7.32–7.18(m,5H),6.52–6.25(m,3H),6.10(d,J＝2.7Hz,1H),4.58(dd,J＝14.0,7.9Hz,1H),4.13(qd,J＝15.7,5.7Hz,2H),3.04–2.75(m,2H),2.64(d,J＝3.3Hz,1H),1.57(dt,J＝13.2,6.6Hz,1H),1.37–1.28(m,1H),1.26–1.17(m,1H),0.82(dd,J＝6.4,3.2Hz,7H).13C NMR(101MHz,DMSO)δ174.82,157.35,153.71,142.28,137.51,129.84,128.50,126.82,110.81,106.64,52.64,38.94,36.85,25.56,23.38,23.24.HRMS(ESI)calcd for C21H29BN3O4:398.22494[(M-H2O+CH2+H)+],found 398.22437.
实施例34：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-萘-1-甲胺-脲(hlq-U82)
Figure PCTCN2016099713-appb-000047
除采用萘-1-甲胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率32％，熔点：171-174℃。
1H NMR(400MHz,DMSO)δ8.12–7.98(m,1H),7.93(dd,J＝6.5,2.8Hz,1H),7.81(d,J＝8.2Hz,1H),7.63–7.50(m,2H),7.50–7.37(m,1H),7.36–7.28(m,1H),7.29–7.18(m,5H),6.59(d,J＝3.0Hz,1H),6.50–6.30(m,1H),4.70(dd,J＝15.4,6.0Hz,2H),4.57(dd,J＝15.1,5.3Hz,1H),2.93(ddd,J＝27.6,13.7,7.1Hz,2H),2.71(s,1H),1.61(dd,J＝13.3,6.6Hz,1H),1.50–1.23(m,2H),0.86(d,J＝6.3Hz,6H).13C NMR(101MHz,DMSO)δ174.94,157.59,137.63,136.04,133.73,131.26,129.87,128.91,128.51,127.74,126.81,126.57,126.15,125.87,125.21,123.82,52.70,41.34,38.99,25.61,23.49,23.23.HRMS(ESI)calcd for C27H33BN3O3:458.26142[(M-H2O+CH2+H)+],found 458.26050.
实施例35：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-3,4-二氟苄胺-脲(hlq-U83)
Figure PCTCN2016099713-appb-000048
除采用3,4-二氟苄胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得到白色泡沫状固体，收率35％，熔点：163-166℃。
1H NMR(400MHz,DMSO)δ7.67–7.43(m,1H),7.30–7.17(m,6H),7.13(ddd,J＝6.9,6.2,2.5Hz,1H),6.93(d,J＝7.9Hz,1H),6.67–6.56(m,1H),6.50–6.36(m,1H),4.57(dd,J＝14.0,8.1Hz,1H),4.23–4.01(m,2H),3.07–2.75(m,2H),2.65(d,J＝6.7Hz,1H),1.67–1.48(m,1H),1.35–1.23(m,2H),0.82(d,J＝5.9Hz,6H).13C NMR(101MHz,DMSO)δ174.84,157.61,150.30(dd,J＝12.7Hz,107.18Hz),147.93(d,J＝12.7Hz,105.52Hz),139.08,137.55,129.85,128.47,126.80,123.73,117.43(d,J＝16.9Hz),116.07(d,J＝17.0Hz),52.53,42.24,38.84,32.76,25.53,23.57,23.53,22.96.HRMS(ESI)calcd for C23H29BF2N3O3:444.22549[(M-H2O+CH2+H)+],found 444.22596.
实施例36：N-L-苯丙氨酰-L-亮氨酸硼酸-N′-3-硝基苄胺-脲(hlq-U84)
Figure PCTCN2016099713-appb-000049
除采用3-硝基苄胺代替原料吡嗪-2-甲胺以外，采用与实施例2类似的方法合成标题化合物，得 到白色泡沫状固体，收率35％，熔点：146-149℃。
1H NMR(400MHz,DMSO)δ8.12–7.96(m,2H),7.55(dt,J＝5.2,2.8Hz,2H),7.36–7.10(m,5H),6.72(s,1H),6.47(dd,J＝16.3,8.6Hz,1H),4.60(dd,J＝14.2,7.9Hz,1H),4.43–4.11(m,2H),3.14–2.79(m,2H),2.67(d,J＝6.3Hz,1H),1.58(dd,J＝13.6,6.8Hz,1H),1.43–1.21(m,2H),0.83(d,J＝4.8Hz,6H).13C NMR(101MHz,DMSO)δ174.77,157.66,148.20,143.77,137.49,134.01,130.04,129.87,128.46,126.76,121.90,121.82,52.55,42.65,38.86,25.55,23.55,22.97.HRMS(ESI)calcd for C23H30BN4O5:453.23078[(M-H2O+CH2+H)+],found 453.22971.
实施例37：N-(1-氧代-1,2,3,4-二氢异喹啉-2-甲酰基)-L-苯丙氨酰-L-亮氨酸硼酸(hlq-U85)
Figure PCTCN2016099713-appb-000050
将实施例28的化合物在空气中氧化，得到白色泡沫状固体，收率18％，熔点：182-184℃。
1H NMR(400MHz,DMSO)δ8.95(s,1H),8.04(s,1H),7.46(d,J＝7.5Hz,1H),7.39–7.09(m,7H),6.83(t,J＝6.5Hz,1H),4.21(d,J＝5.5Hz,1H),3.52–3.38(m,2H),2.95–2.72(m,4H),1.77(dd,J＝12.9,6.8Hz,1H),1.47(ddd,J＝20.9,13.0,6.3Hz,2H),0.89(t,J＝5.7Hz,6H).13C NMR(101MHz,DMSO)δ173.57,171.24,156.69,138.09,136.00,132.04,131.12,130.96,130.11,128.55,127.13,126.79,57.41,50.95,38.93,37.15,25.84,23.56,23.24,21.58.HRMS(ESI)calcd for C24H31BN3O4:448.24065[(M-H2O+CH2+H)+],found 448.23982.
实施例38：N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢喹啉-脲(cq01)
Figure PCTCN2016099713-appb-000051
合成中间体a：N-L-苯丙氨酸甲酯-N′-1,2,3,4-四氢喹啉-脲
Figure PCTCN2016099713-appb-000052
将三光气(1.49g，5mmol)加入20mL DCM中，冰浴下缓慢滴加1,2,3,4-四氢喹啉(1.33g，10mmol)和三乙胺(2.1mL，15mmol)的混合DCM溶液，逐渐升至室温反应6h。加入水淬灭反应，分液，DCM层水洗后无水硫酸钠干燥。过滤，加入L-苯丙氨酸甲酯盐酸盐(2.16g，10mmol)和DIEA(3.8mL，22mmol)，室温反应过夜。反应液直接水洗，有机层无水硫酸钠干燥。柱层析得2.2g白色固体，收率65％，熔点：101-103℃。
1H NMR(400MHz,CDCl3)δ7.30–7.21(m,3H),7.14–7.09(m,1H),7.07(dd,J＝7.6,1.8Hz,2H),7.05–6.97(m,3H),5.51(d,J＝7.6Hz,1H),4.80(td,J＝7.3,5.7Hz,1H),3.79(ddd,J＝12.4,7.0,5.4Hz,1H),3.72(s,3H),3.60(ddd,J＝12.5,7.2,5.3Hz,1H),3.17(dd,J＝13.8,5.6Hz,1H),3.01(dd,J＝13.9,7.0Hz,1H),2.72(t,J＝6.7Hz,2H),1.97–1.81(m,2H).13C NMR(101MHz,CDCl3)δ173.00,155.85,138.78,136.27,132.17,129.46,129.22,128.67,127.12,126.59,124.38,123.11,54.77,52.30,43.48,37.95,27.05,23.88.
合成中间体b：N-L-苯丙氨酸-N′-1,2,3,4-四氢喹啉-脲
Figure PCTCN2016099713-appb-000053
将上步所得中间体a(2.2g，6.5mmol)溶于20mL THF中，加入20mL水和氢氧化钠(0.32g，8mmol)，1h后TLC检测反应完全。减压蒸除THF，盐酸调节pH值为2-3，产生大量固体，抽滤，干燥后得黄色固体2.1g，收率95％。
合成中间体c：N-(L-苯丙氨酰-L-亮氨酸硼酸频哪醇酯)-N′-1,2,3,4-四氢喹啉-脲
Figure PCTCN2016099713-appb-000054
20mL DCM中依次加入上步所得中间体b(0.65g，2mmol)、HOBt(0.30g，2.2mmol)和EDCI(0.46g，2.4mmol)，反应30min后加入L-亮氨酸硼酸频哪醇酯盐酸盐(0.50g，2mmol)和DIEA(0.85mL，4.8mmol)，反应过夜。加入少量水淬灭反应，减压蒸除DCM，加入乙酸乙酯，分别用0.5N盐酸、2N碳酸钠溶液和饱和食盐水洗涤，有机相用无水硫酸钠干燥。过滤，减压蒸除溶剂得粗品0.80g，直接用于下一步反应。
合成标题化合物：N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢喹啉-脲
将上步所得中间体c(0.80g，1.5mmol)溶于20mL乙醚中，加入二乙醇胺(0.15g，1.5mmol)，室温反应过夜。抽滤，滤饼用乙醚充分洗涤，抽干。所得固体悬浮于20mL乙酸乙酯中，加入20mL蒸馏水和1mL 4N盐酸，剧烈搅拌30min。分液除去水相，有机相用蒸馏水和饱和食盐水各洗2次，无水硫酸钠干燥。过滤，减压蒸除溶剂得到白色泡沫状固体。乙酸乙酯/正己烷重结晶得0.26g白色固体，收率49％，熔点：101-103℃。
1H NMR(400MHz,DMSO-d6)δ8.85–8.59(m,1H),7.33–6.87(m,9H),6.63(d,J＝8.2Hz,1H),4.61(td,J＝8.7,5.2Hz,1H),3.59(dt,J＝12.1,5.9Hz,1H),3.40(dt,J＝12.3,6.1Hz,1H),3.06(dd,J＝13.7,5.2Hz,1H),2.95(dd,J＝13.7,9.4Hz,1H),2.74–2.52(m,3H),1.71(h,J＝6.2Hz,2H),1.60(dq,J＝13.5,6.7Hz,1H),1.41–1.22(m,2H),0.82(d,J＝6.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ174.32,155.73,138.89,137.43,129.90,129.34,128.58,128.03,126.33,125.68,123.25,122.66,53.30,43.97,40.21,37.21,26.55,25.11,23.15,23.04,22.59.HRMS(ESI)calcd for C25H33BN3O3:434.26095[(M-H2O+CH2+H)+],found 434.26180.
实施例39：N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-(1-甲基-1,2,3,4-四氢异喹啉)-脲(cq02)
Figure PCTCN2016099713-appb-000055
除采用1-甲基-1,2,3,4-四氢异喹啉代替原料1,2,3,4-四氢喹啉以外，采用与实施例38类似的方法合成中间体a-c。将中间体c(N-(L-苯丙氨酰-L-亮氨酸硼酸频哪醇酯)-N′-(1-甲基-1,2,3,4-四氢异喹啉)-脲)(0.70g，1.3mmol)溶于20mL乙醚中，加入无水柠檬酸(0.25g，1.3mmol)，反应过夜。抽 滤，滤饼乙醚充分洗涤，抽干。所得固体悬浮于20mL乙酸乙酯中，加入20mL饱和碳酸氢钠溶液，剧烈搅拌30min。分液，乙酸乙酯层用饱和碳酸氢钠溶液洗涤2次，用饱和氯化钠洗涤2次，再用无水硫酸钠干燥。过滤，减压蒸除溶剂得白色泡沫状固体。乙酸乙酯/正己烷重结晶得0.27g白色固体，收率30％。
1H NMR(400MHz,DMSO-d6)δ8.65(d,J＝16.9Hz,1H),7.32–7.01(m,9H),6.74(d,J＝8.0Hz,1H),5.15(dq,J＝14.0,6.6Hz,1H),4.60(p,J＝7.7Hz,1H),3.96(t,J＝14.3Hz,1H),3.01(ddt,J＝47.3,14.2,8.0Hz,3H),2.81–2.55(m,3H),1.56(dq,J＝13.0,6.4Hz,1H),1.27(m,J＝24.3,10.6,9.0Hz,5H),0.79(q,J＝7.0Hz,6H).13C NMR(101MHz,DMSO-d6)δ174.92,174.81,155.99,155.87,138.89,138.83,137.92,137.84,133.99,129.34,129.23,128.63,127.97,127.91,126.72,126.21,126.11,126.02,125.87,53.39,49.31,49.05,40.24,37.37,37.20,36.72,36.51,28.29,25.11,25.05,23.03,22.97,22.70,22.64,21.80,21.51.HRMS(ESI)calcd for C26H35BN3O3:434.27660[(M-H2O+CH2+H)+],found 434.27612.
实施例40：N-(L-亮氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲(cq04)
Figure PCTCN2016099713-appb-000056
合成前体：2-氯甲酰基-1,2,3,4-四氢异喹啉
Figure PCTCN2016099713-appb-000057
将三光气(1.49g，5mmol)加入20mL DCM中，冰浴下缓慢滴加1,2,3,4-四氢异喹啉(1.33g，10mmol)和三乙胺(2.1mL，15mmol)的混合DCM溶液，逐渐升至室温反应6h。加入水淬灭反应，分液，DCM层水洗后用无水硫酸钠干燥。柱层析得1.6g无色油状物，收率82％。
合成中间体a：N-L-亮氨酸甲酯-N′-1,2,3,4-四氢异喹啉-脲
Figure PCTCN2016099713-appb-000058
将上步所得前体(1.37g,7mmol)溶于20mL DCM中，加入L-亮氨酸甲酯盐酸盐(1.27g,7mmol)和DIEA(2.7mL,15.4mmol)，室温反应过夜。反应液水洗后用无水硫酸钠干燥，柱层析得1.8g油状物，收率84％。
1H NMR(400MHz,CDCl3)δ7.26–7.01(m,4H),5.23(d,J＝8.2Hz,1H),4.58(dt,J＝8.6,4.4Hz,1H),4.54(d,J＝1.7Hz,2H),3.73(s,3H),3.66(ddd,J＝11.9,6.7,5.0Hz,1H),3.53(ddd,J＝12.2,7.0,5.0Hz,1H),2.93–2.73(m,2H),1.75(dq,J＝8.0,6.3Hz,1H),1.68–1.50(m,2H),0.95(d,J＝6.5Hz,6H).13C NMR(101MHz,CDCl3)δ175.30,157.13,134.98,133.29,128.30,126.57,126.32,52.15,45.37,41.76,41.19,28.95,24.88,22.91,21.92.
从上步所得中间体a出发，采用与实施例38类似的方法合成标题化合物，得到白色固体，收率43％，熔点：108-110℃。
1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),7.14(td,J＝7.5,6.7,3.3Hz,4H),6.65(d,J＝8.1Hz,1H),4.70–4.26(m,3H),3.58(qd,J＝6.6,3.8Hz,2H),2.76(t,J＝6.2Hz,2H),2.54(dd,J＝7.6,3.4Hz,1H),1.61(dhept,J＝20.4,7.5,6.9Hz,3H),1.48(dq,J＝12.6,7.5,6.5Hz,1H),1.24(ddq,J＝36.5,13.4,7.1Hz,2H),0.93–0.72(m,12H).13C NMR(101MHz,DMSO-d6)δ175.91,156.66,134.79,134.01,128.48,126.20,126.15,125.95,50.09,45.28,41.00,40.52,40.20,28.32,25.15,24.09,22.96,22.91,21.50.HRMS(ESI)calcd for C22H35BN3O3:400.27660[(M-H2O+CH2+H)+],found 400.27683.
实施例41：N-(L-丙氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲(cq05)
Figure PCTCN2016099713-appb-000059
除采用L-丙氨酸甲酯盐酸盐代替原料L-亮氨酸甲酯盐酸盐以外，采用与实施例40类似的方法合成中间体a(N-L-丙氨酸甲酯-N′-1,2,3,4-四氢异喹啉-脲)，得到无色油状物，收率70％。
1H NMR(400MHz,CDCl3)δ7.15(ddd,J＝18.7,9.5,4.4Hz,4H),5.21(d,J＝7.3Hz,1H),4.64–4.49(m,3H),3.75(s,3H),3.70–3.53(m,2H),2.95–2.80(m,2H),1.43(d,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ175.00,156.78,135.06,133.31,128.41,126.70,126.43,126.39,52.41,49.39,45.46,41.21,29.04,19.08.
从上步所得中间体a出发，采用与实施例38类似的方法得到标题化合物，白色固体，收率21％，熔点：111-113℃。
1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),7.14(td,J＝7.2,6.4,4.3Hz,4H),6.74(d,J＝7.6Hz,1H),4.61–4.44(m,2H),4.40(p,J＝7.2Hz,1H),3.58(q,J＝6.2Hz,2H),2.77(t,J＝5.8Hz,2H),2.57(q,J＝6.7Hz,1H),1.60(dt,J＝13.4,6.7Hz,1H),1.36–1.17(m,5H),0.80(d,J＝7.2Hz,6H).13C NMR(101MHz,DMSO-d6)δ176.19,156.50,134.82,133.96,128.48,126.20,126.16,125.99,47.36,45.23,40.90,40.19,28.34,25.17,22.93,22.90,18.18.HRMS(ESI)calcd for C19H29BN3O3:358.22965[(M-H2O+CH2+H)+],found 358.22831.
实施例42：N-(L-缬氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲(cq06)
Figure PCTCN2016099713-appb-000060
除采用L-缬氨酸甲酯盐酸盐代替原料L-亮氨酸甲酯盐酸盐以外，采用与实施例40类似的方法合成中间体a(N-L-缬氨酸甲酯-N′-1,2,3,4-四氢异喹啉-脲)，得到无色油状物，收率64％。
1H NMR(400MHz,CDCl3)δ7.25–7.06(m,4H),5.06(d,J＝8.4Hz,1H),4.58(s,2H),4.51(dd,J＝8.3,5.0Hz,1H),3.74(s,3H),3.72–3.66(m,1H),3.59(ddd,J＝12.2,6.8,5.2Hz,1H),2.88(q,J＝5.3Hz,2H),2.16(qd,J＝7.1,5.3Hz,1H),0.95(dd,J＝11.3,6.8Hz,6H).13C NMR(101MHz,CDCl3)δ174.01,157.21,135.09,133.35,128.39,126.71,126.44,126.40,58.54,52.10,45.49,41.31,31.45,29.06,19.08,18.11.
从上步所得中间体a出发，采用与实施例38类似的方法得到标题化合物，白色固体，收率33％，熔点：114-115℃。
1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),7.15(td,J＝6.3,2.6Hz,4H),6.48(d,J＝8.5Hz,1H),4.63–4.44(m,2H),4.11(t,J＝8.2Hz,1H),3.59(t,J＝5.9Hz,2H),2.77(t,J＝5.9Hz,2H),2.57(dt,J＝10.0,4.8Hz,1H),2.03(dq,J＝13.9,6.7Hz,1H),1.61(dp,J＝13.4,6.6Hz,1H),1.24(ddq,J＝20.6,13.9,7.2Hz,2H),0.93–0.73(m,12H).13C NMR(101MHz,DMSO-d6)δ174.74,156.81,134.74,133.99,128.47,126.17,126.14,125.94,57.34,45.37,41.13,40.25,30.08,28.28,25.08,23.13,22.50,19.10,18.97.HRMS(ESI)calcd for C21H33BN3O3:386.26095[(M-H2O+CH2+H)+],found 386.26223.
实施例43：N-(L-萘丙氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲(cq07)
Figure PCTCN2016099713-appb-000061
除采用L-萘丙氨酸甲酯盐酸盐代替原料L-亮氨酸甲酯盐酸盐以外，采用与实施例40类似的方法合成中间体a(N-L-萘丙氨酸甲酯-N′-1,2,3,4-四氢异喹啉-脲)，得到白色泡沫状固体，收率77％。
1H NMR(400MHz,CDCl3)δ7.85–7.65(m,3H),7.57(d,J＝1.6Hz,1H),7.44(dt,J＝6.3,3.5Hz,2H),7.27–7.22(m,1H),7.16(dt,J＝7.4,3.8Hz,2H),7.13–7.09(m,1H),7.07–7.02(m,1H),5.02(d,J＝7.5Hz,1H),4.94(dt,J＝7.5,5.8Hz,1H),4.58–4.39(m,2H),3.72(s,3H),3.59(ddd,J＝12.0,6.6,5.1Hz,1H),3.49(ddd,J＝12.2,6.7,5.2Hz,1H),3.37–3.23(m,2H),2.80(q,J＝5.3Hz,2H).13C NMR(101MHz,CDCl3)δ173.30,156.59,135.03,133.95,133.50,133.30,132.51,128.44,128.25,128.11,127.74,127.59,127.53,126.75,126.47,126.41,126.24,125.78,54.55,52.36,45.47,41.30,38.67,28.97.
从上步所得中间体a出发，采用与实施例38类似的方法合成中间体b(N-L-萘丙氨酸-N′-1,2,3,4-四氢异喹啉-脲)，得到白色固体，收率88％。
从上步所得中间体b出发，采用与实施例39类似的方法合成标题化合物，白色固体，收率30％，熔点：112-114℃。
1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),7.76(ddd,J＝19.2,11.8,5.9Hz,4H),7.50–7.36(m,3H),7.20–6.97(m,4H),6.86(d,J＝8.2Hz,1H),4.69(q,J＝7.8Hz,1H),4.44(q,J＝16.5Hz,2H),3.48(t,J＝6.0Hz,2H),3.32–3.08(m,2H),2.79– 2.54(m,3H),1.57(dq,J＝13.8,6.9Hz,1H),1.31(ddt,J＝56.5,13.7,7.4Hz,2H),0.79(dd,J＝20.2,6.4Hz,6H).13C NMR(101MHz,DMSO-d6)δ174.75,156.51,135.50,134.65,133.86,132.94,131.80,128.41,127.99,127.74,127.38,126.11,126.03,125.89,125.76,125.31,53.55,45.25,40.99,37.59,28.11,25.10,22.97,22.69.HRMS(ESI)calcd for C29H35BN3O3:484.27660[(M-H2O+CH2+H)+],found 484.27549.
实施例44：N-(L-异亮氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲(cq08)
Figure PCTCN2016099713-appb-000062
除采用L-异亮氨酸甲酯盐酸盐代替原料L-亮氨酸甲酯盐酸盐以外，采用与实施例40类似的方法合成中间体a(N-L-异亮氨酸甲酯-N′-1,2,3,4-四氢异喹啉-脲)，得到无色油状物，收率84％。
1H NMR(400MHz,CDCl3)δ7.24–7.09(m,4H),5.12(d,J＝8.2Hz,1H),4.60–4.52(m,3H),3.74(s,3H),3.72–3.65(m,1H),3.58(ddd,J＝12.0,6.8,5.1Hz,1H),2.98–2.76(m,2H),1.89(dddt,J＝11.1,6.6,4.2,1.8Hz,1H),1.49(ddt,J＝14.8,7.6,3.8Hz,1H),1.21(ddd,J＝13.6,9.1,7.2Hz,1H),1.02–0.86(m,6H).13C NMR(101MHz,CDCl3)δ173.98,157.05,135.06,133.30,128.36,126.67,126.40,126.36,57.79,52.03,45.41,41.21,38.16,29.02,25.40,15.51,11.64.
从上步所得中间体a出发，采用与实施例38类似的方法合成标题化合物，白色固体，收率35％，熔点：108-110℃。
1H NMR(400MHz,DMSO-d6)δ8.76–8.45(m,1H),7.31–6.99(m,4H),6.49(d,J＝8.4Hz,1H),4.52(d,J＝3.7Hz,2H),4.16(t,J＝8.4Hz,1H),3.57(t,J＝5.8Hz,2H),2.76(t,J＝5.8Hz,2H),2.57(q,J＝7.3,6.4Hz,1H),1.92–1.73(m,1H),1.68–1.43(m,2H),1.20(dtt,J＝40.7,14.2,7.0Hz,3H),0.81(dt,J＝15.7,5.6Hz,12H).13C NMR(101MHz,DMSO-d6)δ174.66,156.74,134.74,134.00,128.47,126.16,125.94,56.03,45.37,41.11,40.27,35.91,28.30,25.09,24.82,23.16,22.51,15.23,10.69.HRMS(ESI)calcd for C22H35BN3O3:400.27660[(M-H2O+CH2+H)+],found 400.27769.
实施例45：N-(L-色氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲(cq09)
Figure PCTCN2016099713-appb-000063
除采用L-色氨酸甲酯盐酸盐代替原料L-亮氨酸甲酯盐酸盐以外，采用与实施例40类似的方法合成中间体a(N-L-色氨酸甲酯-N′-1,2,3,4-四氢异喹啉-脲)，得到白色固体，收率83％，熔点：60-62℃。
1H NMR(400MHz,CDCl3)δ8.67(s,1H),7.58–7.50(m,1H),7.32(dd,J＝8.2,0.9Hz,1H),7.19–6.89(m,7H),5.05(d,J＝7.6Hz,1H),4.87(dt,J＝7.6,5.3Hz,1H),4.38(q,J＝15.6Hz,2H),3.67(s,3H),3.52(ddd,J＝12.0,6.8,5.1Hz,1H),3.42(ddd,J＝12.2,6.7,5.1Hz,1H),3.38–3.27(m,2H),2.74(q,J＝5.6Hz,2H).13C NMR(101MHz,CDCl3)δ173.59,156.89,136.29,135.02,133.22,128.38,127.86,126.69,126.40,126.37,122.95,122.17,119.54,118.54,111.53,110.11,54.73,52.31,45.41,41.16,28.93,27.98.
从上步所得中间体a出发，采用与实施例38类似的方法合成中间体b(N-L-色氨酸-N′-1,2,3,4-四氢异喹啉-脲)，得到白色固体，收率92％。
从上步所得中间体b出发，采用与实施例39类似的方法合成标题化合物，白色固体，收率29％，熔点：130-132℃。
1H NMR(400MHz,DMSO-d6)δ10.96–10.72(m,1H),8.74(s,1H),7.60(d,J＝7.9Hz,1H),7.32(d,J＝8.1Hz,1H),7.23(d,J＝2.3Hz,1H),7.18–6.99(m,5H),6.93(t,J＝7.4Hz,1H),6.60(d,J＝8.0Hz,1H),4.64(q,J＝7.3Hz,1H),4.55–4.32(m,2H),3.49(t,J＝6.0Hz,2H),3.27–3.08(m,2H),2.68(dq,J＝13.0,6.8Hz,3H),1.63(dt,J＝13.3,6.7Hz,1H),1.34(ddt,J＝63.6,13.3,6.8Hz,2H),0.82(dd,J＝6.6,2.9Hz,6H).13C NMR(101MHz,DMSO-d6)δ175.39,156.56,136.06,134.75,133.83,128.41,127.43,126.16,126.06,125.95,124.02,120.81,118.37,118.26,111.31,109.86,52.94,45.19,40.94,40.24,28.24,27.40,25.24,22.99,22.93.HRMS(ESI)calcd for C27H34BN4O3:473.27185[(M-H2O+CH2+H)+],found 473.27289.
实施例46：N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-(7-硝基-1,2,3,4-四氢异喹啉)-脲(cq10)
Figure PCTCN2016099713-appb-000064
合成前体：7-硝基-1,2,3,4-四氢异喹啉盐酸盐
取11mL浓硫酸冰浴，加入1,2,3,4-四氢异喹啉(2.9g，21mmol)，然后缓慢加入硝酸钾(2.4g，24mmol)，逐渐升至室温，反应过夜。将反应液倒入冰水中，浓氨水调节pH至10左右，DCM萃取3次，有机层合并，用无水硫酸钠干燥。过滤，减压蒸除溶剂得油状物；溶于16mL乙醇中，冰浴，加入3mL浓盐酸，产生大量固体，抽滤，干燥。甲醇重结晶得1.9g米色固体，收率42％。
从上步所得前体出发，采用与实施例38类似的方法合成中间体c(N-(L-苯丙氨酰-L-亮氨酸硼酸频哪醇酯)-N′-(7-硝基-1,2,3,4-四氢异喹啉)-脲)，得到0.61g泡沫状固体，直接用于下一步。
将上步所得中间体c(0.61g，1.1mmol)溶于20mL乙酸乙酯中，加入二乙醇胺(0.12g，1.1mmol)，室温反应过夜。体系无固体产生，加入20mL蒸馏水和1mL 4N盐酸，剧烈搅拌30min。分液除去水相，有机相用饱和食盐水洗2次，无水硫酸钠干燥。过滤，减压蒸除溶剂得到黄色泡沫状固体。柱层析得80mg白色固体，收率11％，熔点：128-130℃。
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.06–7.89(m,2H),7.36(d,J＝8.4Hz,1H),7.27–7.10(m,5H),6.95(d,J＝8.3Hz,1H),4.66–4.43(m,3H),3.54(q,J＝7.1,6.0Hz,2H),3.04(dd,J＝13.8,5.5Hz,1H),2.97–2.87(m,1H),2.75(tq,J＝17.5,10.9,8.4Hz,2H),2.61(q,J＝6.6Hz,1H),1.54(dh,J＝14.6,7.4,6.9Hz,1H),1.24(ddt,J＝42.7,13.8,7.3Hz,2H),0.77(t,J＝5.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ174.69,156.42,145.64,143.18,137.79,135.98,130.00,129.30,129.22,127.95,127.89,126.19,121.13,120.98,53.52,45.17,40.63,37.32,28.14,25.08,23.01,22.67.HRMS(ESI)calcd for C25H32BN4O5:479.24603[(M-H2O+CH2+H)+],found 479.24737.
实施例47：N-(L-苯丁氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲(cq14)
Figure PCTCN2016099713-appb-000065
除采用L-苯基丁氨酸甲酯代替原料L-亮氨酸甲酯盐酸盐以外，采用与实施例40类似的方法合成中间体a(N-L-苯基丁氨酸甲酯-N′-1,2,3,4-四氢异喹啉-脲)，得到白色泡沫状固体，收率90％。
1H NMR(400MHz,CDCl3)δ7.31–7.05(m,10H),5.07(d,J＝7.6Hz,1H),4.65(td,J＝7.6,4.9Hz,1H),4.53–4.34(m,2H),3.72(s,3H),3.60(ddd,J＝12.0,6.6,5.0Hz,1H),3.48(ddd,J＝12.2,6.9,5.1Hz,1H),2.82(q,J＝5.5Hz,2H),2.71(t,J＝7.7Hz,2H),2.22(dtd,J＝15.9,7.9,4.9Hz,1H),2.11–2.00(m,1H).13C NMR(101MHz,CDCl3)δ174.23,156.86,141.15,135.04,133.26,128.55,128.50,128.40,126.67,126.40,126.37,126.18,53.66,52.34,45.31,41.10,34.09,31.96,29.03.
从上步所得中间体a出发，采用与实施例38类似的方法合成标题化合物，得到白色固体，收率24％，熔点：103-104℃。
1H NMR(400MHz,DMSO-d6)δ8.57(t,J＝3.4Hz,1H),7.30–7.05(m,9H),6.71(d,J＝8.0Hz,1H),4.52(q,J＝16.5Hz,2H),4.42–4.25(m,1H),3.59(dt,J＝11.6,5.7Hz,2H),2.78(q,J＝7.5,6.1Hz,2H),2.58(dtd,J＝17.9,12.2,10.1,4.7Hz,3H),2.03–1.86(m,2H),1.67–1.51(m,1H),1.25(ddq,J＝42.7,13.3,7.0Hz,2H),0.77(dd,J＝18.5,6.7Hz,6H).13C NMR(101MHz,DMSO-d6)δ175.31,156.69,141.32,134.80,133.99,128.48,128.28,128.22,128.19,126.17,126.13,125.95,125.72,51.51,45.32,41.01,33.56,31.63,28.29,25.14,22.87,22.81.HRMS(ESI)calcd for C26H35BN3O3:448.27660[(M-H2O+CH2+H)+],found448.27649.
实施例48：N-((L-4-硝基苯丁氨酰)-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲(cq15)
Figure PCTCN2016099713-appb-000066
除采用L-4-硝基苯丙氨酸甲酯代替原料L-亮氨酸甲酯盐酸盐以外，采用与实施例40类似的方法合成中间体a(N-(L-4-硝基苯丙氨酸甲酯)-N′-1,2,3,4-四氢异喹啉-脲)，得到白色泡沫状固体，收率83％。
1H NMR(400MHz,CDCl3)δ8.16–8.04(m,2H),7.29(dd,J＝9.1,7.2Hz,2H),7.25–7.04(m,4H),5.15(d,J＝7.1Hz,1H),5.00–4.87(m,1H),4.61–4.44(m,2H),3.75(s,3H),3.65(ddd,J＝11.9,6.6,5.0Hz,1H),3.53(ddd,J＝12.3,7.0,5.1Hz,1H),3.35–3.17(m,2H),2.85(q,J＝5.7Hz,2H).13C NMR(101MHz,CDCl3)δ172.69,156.41,147.06,144.50,134.87,133.10,130.28,128.48,126.90,126.55,126.35,123.62,54.28,52.61,45.54,41.38,38.50,28.85.
从上步所得中间体a出发，采用与实施例38类似的方法合成标题化合物，得到白色固体，收率15％，熔点：126-128℃。
1H NMR(400MHz,DMSO-d6)δ8.84–8.66(m,1H),8.02(d,J＝8.2Hz,2H),7.52(dd,J＝11.1,7.1Hz,2H),7.21–6.99(m,4H),6.89(d,J＝8.3Hz,1H),4.64(q,J＝8.1Hz,1H),4.50–4.35(m,2H),3.49(dtd,J＝19.0,12.8,6.2Hz,2H),3.13(ddd,J＝35.7,13.2,7.4Hz,2H),2.65(q,J＝9.2,6.5Hz,3H),1.52(dq,J＝13.1,6.6Hz,1H),1.22(ddt,J＝39.4,13.7,7.1Hz,2H),0.78(q,J＝7.4,5.7Hz,6H).13C NMR(101MHz,DMSO-d6)δ174.22,156.45,146.08,134.61,133.79,130.68,128.41,126.15,126.02,125.88,122.96,52.90,45.27,40.98,37.14,27.99,25.02,22.94,22.52.HRMS(ESI)calcd for C25H32BN4O5:479.24603[(M-H2O+CH2+H)+],found 479.24483.
实施例49：N-(L-谷氨酰氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲(cq18)
Figure PCTCN2016099713-appb-000067
除采用L-谷氨酰胺甲酯盐酸盐代替原料L-亮氨酸甲酯盐酸盐以外，采用与实施例40类似的方法合成中间体a(N-L-谷氨酰胺甲酯-N′-1,2,3,4-四氢异喹啉-脲)，得到白色固体，收率44％，熔点：122-124℃。
1H NMR(400MHz,CDCl3)δ7.22–7.06(m,4H),6.74(s,1H),6.04(d,J＝20.5Hz,2H),4.54(s,2H),4.44(dd,J＝9.1,4.3Hz,1H),3.71(s,3H),3.66–3.52(m,2H),2.84(t,J＝6.0Hz,2H),2.36(tddd,J＝15.6,12.6,7.6,3.8Hz,2H),2.18–2.08(m,1H),2.01(dddd,J＝14.3,8.4,5.3,3.7Hz,1H).13C NMR(101MHz,CDCl3)δ175.68,173.78,157.39,134.93,133.33,128.38,126.66,126.38,126.35,53.74,52.39,45.41,41.28,31.95,28.90,27.70.
从上步所得中间体a出发，采用与实施例38类似的方法合成标题化合物，得到白色固体，收率7％，熔点：122-124℃。
1H NMR(400MHz,DMSO-d6)δ8.75–8.50(m,0H),7.33(s,1H),7.15(q,J＝6.9,5.2Hz,4H),6.81(d,J＝9.6Hz,2H),4.64–4.40(m,2H),4.30(td,J＝8.4,5.0Hz,1H),3.57(q,J＝5.7,4.6Hz,2H),2.78(t,J＝5.7Hz,2H),2.56(q,J＝6.7Hz,1H),2.15(hept,J＝7.5Hz,2H),1.88(dtq,J＝32.1,17.7,9.7,8.3Hz,2H),1.58(dt,J＝13.3,6.7Hz,1H),1.25(ddq,J＝31.6,12.9,6.7,6.3Hz,2H),0.90–0.66(m,6H).13C NMR(101MHz,DMSO-d6)δ175.35,174.11,156.67,134.87,133.97,128.46,126.19,126.15,125.98,51.73,45.17,40.93,40.09,31.48,28.35,27.34,25.15,22.90,22.88.HRMS(ESI)calcd for C21H32BN4O4:415.25111[(M-H2O+CH2+H)+],found 415.24994.
实施例50：N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-(6,7-二甲氧基-1,2,3,4-四氢异喹啉)-脲(cq22)
Figure PCTCN2016099713-appb-000068
合成中间体a：N-L-苯丙氨酸甲酯-N′-(6,7-二甲氧基-1,2,3,4-四氢异喹啉)-脲
Figure PCTCN2016099713-appb-000069
将羰基二咪唑(1.43g，8.8mmol)溶于20mL DCM中，逐滴加入L-苯丙氨酸甲酯(1.73g，8mmol)和DIEA(1.4mL，8mmol)混合的10mL DCM溶液，2h后加入6,7-二甲氧基-1,2,3,4-四氢异喹啉盐酸盐(1.84g，8mmol)和DIEA(1.4mL，8mmol)，反应过夜。反应液水洗后用无水硫酸钠干燥，柱层析得2.0g白色固体，收率63％，熔点：122-124℃。
1H NMR(400MHz,CDCl3)δ7.30–7.22(m,3H),7.15–7.09(m,2H),6.62(s,1H),6.57(s,1H),5.11(d,J＝7.5Hz,1H),4.84(dt,J＝7.6,5.9Hz,1H),4.50–4.33(m,2H),3.83(d,J＝6.7Hz,6H),3.72(s,3H),3.64–3.56(m,1H),3.49(ddd,J＝12.3,6.9,5.0Hz,1H),3.19–3.07(m,2H),2.82–2.66(m,2H).13C NMR(101MHz,CDCl3)δ173.30,156.52,147.65,147.59,136.33,129.26,128.45,126.92,126.68,124.90,111.25,109.17,55.92,55.90,54.48,52.19,45.11,41.27,38.31,28.32.
从上步所得中间体a出发，采用与实施例38类似的方法合成标题化合物，得到白色固体，收率35％，熔点：112-113℃。
1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),7.29–7.12(m,5H),6.81–6.55(m,3H),4.54(h,J＝5.7Hz,1H),4.44–4.26(m,2H),3.70(d,J＝5.3Hz,6H),3.48(qd,J＝9.1,6.0Hz,2H),3.10–2.88(m,2H),2.61(dp,J＝18.6,6.7Hz,3H),1.55(tt,J＝13.1,6.6Hz,1H),1.26(ddt,J＝42.5,13.5,7.2Hz,2H),0.80(dd,J＝6.4,3.8Hz,6H).13C NMR(101MHz,DMSO-d6)δ174.70,156.52,147.25,147.22,137.88,129.33,127.97,126.38,126.19,125.58,111.95,109.64,55.49,53.52,44.95,41.14,40.22,37.32,27.64,25.09,23.04,22.70.HRMS(ESI)calcd for C27H37BN3O5:494.28208[(M-H2O+CH2+H)+],found 494.28207.
实施例51：N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-(7-甲氧基-1,2,3,4-四氢异喹啉)-脲(cq24)
Figure PCTCN2016099713-appb-000070
合成前体I：7-甲氧基-3,4-二氢异喹啉-1-酮
在100mL无水THF中加入对甲氧基苯乙胺(4.56g,30mmol)和三乙胺(5mL,36mmol)，在冰浴下逐滴加入氯甲酸乙酯(3.4mL,36mmol)，室温反应过夜。加入100mL水，减压蒸除THF，加入100mL乙酸乙酯，分液，乙酸乙酯水洗2次后用无水硫酸钠干燥。过滤，减压蒸除溶剂得6.28g黄色油状物；将其逐滴加入至120℃的多聚磷酸中，反应30min。将反应体系倒入冰水中，乙酸乙酯萃取3次，合并乙酸乙酯层，用饱和碳酸氢钠洗涤至碱性，无水硫酸钠干燥。柱层析得1.17g白色固体，收率22％。
合成前体II：7-甲氧基-1,2,3,4-四氢异喹啉
在20mL无水THF冰浴下缓慢加入氢化铝锂(0.5g,13mmol)，然后加入上步所得前体I(1.14g,6.4mmol)，加热回流反应3h。反应液冰浴，依次加入0.5mL水、0.5mL 15％氢氧化钠溶液、1.5mL水及若干无水硫酸镁固体，搅拌30min，抽滤，滤饼用THF充分洗涤，滤液用无水硫酸钠干燥。减压蒸除溶剂得0.98g黄色油状物，收率94％。
从上步所得前体II出发，采用与实施例50类似的方法合成中间体a(N-L-苯丙氨酸甲酯-N′-(7-甲氧基-1,2,3,4-四氢异喹啉)-脲)，得到无色油状物，收率63％。
1H NMR(400MHz,CDCl3)δ7.30–7.20(m,3H),7.15–7.09(m,2H),7.03(d,J＝8.4Hz,1H),6.74(dd,J＝8.4,2.6Hz,1H),6.62(d,J＝2.6Hz,1H),5.03(d,J＝7.5Hz,1H),4.84(dt,J＝7.6,5.9Hz,1H),4.57–4.35(m,2H),3.76(s,3H),3.72(s,3H),3.58(ddd,J＝12.0,6.7,5.1Hz,1H),3.48(ddd,J＝12.2,6.8,5.1Hz,1H),3.19–3.07(m,2H),2.75(q,J＝5.5Hz,2H).13C NMR(101MHz,CDCl3)δ173.29,158.14,156.55,136.36,134.37,129.33,129.31,128.53,127.02,126.98,112.89,111.19,55.34,54.50,52.26,45.58,41.61,38.41,28.05.
从上步所得中间体a出发，采用与实施例38类似的方法合成标题化合物，得到白色固体，收率 24％，熔点：107-109℃。
1H NMR(400MHz,DMSO-d6)δ8.82–8.55(m,1H),7.30–7.13(m,5H),7.00(d,J＝8.4Hz,1H),6.82–6.59(m,3H),4.54(td,J＝8.8,5.2Hz,1H),4.49–4.31(m,2H),3.70(s,3H),3.58–3.40(m,2H),3.09–2.86(m,2H),2.60(dq,J＝19.0,7.2,6.4Hz,3H),1.55(tt,J＝12.7,6.4Hz,1H),1.39–1.16(m,2H),0.80(td,J＝6.5,5.9,3.3Hz,6H).13C NMR(101MHz,DMSO-d6)δ174.84,157.48,156.51,137.88,135.03,129.40,129.36,127.99,126.57,126.22,112.53,110.78,54.99,53.49,45.44,41.36,40.22,37.32,27.29,25.10,23.05,22.72.HRMS(ESI)calcd for C26H35BN3O4:464.27151[(M-H2O+CH2+H)+],found 464.27071.
实施例52：N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-(6-甲氧基-1,2,3,4-四氢异喹啉)-脲(cq25)
Figure PCTCN2016099713-appb-000071
以间甲氧基苯乙胺为原料，采用与实施例51类似的方法合成前体II(6-甲氧基-1,2,3,4-四氢异喹啉)，得到黄色油状物，收率54％。
从上步所得前体II出发，采用与实施例50类似的方法合成中间体a(N-L-苯丙氨酸甲酯-N′-(6-甲氧基-1,2,3,4-四氢异喹啉)-脲)，得到无色油状物，收率65％。
1H NMR(400MHz,CDCl3)δ7.30–7.21(m,3H),7.14–7.08(m,2H),6.99(d,J＝8.4Hz,1H),6.74(dd,J＝8.4,2.7Hz,1H),6.67(d,J＝2.6Hz,1H),5.01(d,J＝7.5Hz,1H),4.84(dt,J＝7.5,5.9Hz,1H),4.51–4.34(m,2H),3.77(s,3H),3.72(s,3H),3.60(ddd,J＝11.9,6.5,4.9Hz,1H),3.49(ddd,J＝12.2,6.8,5.1Hz,1H),3.20–3.07(m,2H),2.79(q,J＝5.6Hz,2H).13C NMR(101MHz,CDCl3)δ173.28,158.30,156.57,136.37,136.29,129.33,128.53,127.35,127.02,125.35,113.25,112.49,55.32,54.50,52.25,44.90,41.07,38.42,29.25.
从上步所得中间体a出发，采用与实施例38类似的方法合成标题化合物，得到白色固体，收率17％，熔点：106-108℃。
1H NMR(400MHz,DMSO-d6)δ8.62(d,J＝4.3Hz,1H),7.36–7.08(m,5H),6.97(d,J＝8.4Hz,1H),6.82–6.55(m,3H),4.51(td,J＝8.7,5.2Hz,1H),4.43–4.24(m,2H),3.70(s,3H),3.45(t,J＝5.9Hz,2H),3.10–2.84(m,2H),2.62(dq,J＝10.0,5.3Hz,3H),1.54(dq,J＝13.4,6.7Hz,1H),1.24(dtd,J＝33.8,13.6,7.2Hz,2H),0.78(dd,J＝6.8,2.9Hz,6H).13C NMR(101MHz,DMSO-d6)δ174.73,157.56,156.47,137.82,135.96,129.29,127.93,127.02,126.16,125.87,113.08,112.24,54.96,53.41,44.68,40.86,37.25,28.41,25.05,22.99,22.67.HRMS(ESI)calcd for C26H35BN3O4:464.27151[(M-H2O+CH2+H)+],found 464.27270.
实施例53：N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-(8-甲氧基-1,2,3,4-四氢异喹啉)-脲(cq26)
Figure PCTCN2016099713-appb-000072
以间甲氧基苯乙胺为原料，采用与实施例51类似的方法合成前体II(8-甲氧基-1,2,3,4-四氢异喹啉)，得到黄色油状物，收率10％。
从上步所得前体II出发，采用与实施例50类似的方法合成中间体a(N-L-苯丙氨酸甲酯-N′-(8-甲氧基-1,2,3,4-四氢异喹啉)-脲)，得到无色油状物，收率68％。
1H NMR(400MHz,CDCl3)δ7.32–7.04(m,7H),6.71(dd,J＝14.0,7.9Hz,2H),5.08(d,J＝7.6Hz,1H),4.85(dt,J＝7.5,6.0Hz,1H),4.36(d,J＝2.0Hz,2H),3.81(s,3H),3.70(s,3H),3.68–3.62(m,1H),3.53(ddd,J＝12.5,6.9,5.0Hz,1H),3.18–3.08(m,2H),2.79(q,J＝5.8Hz,2H).13C NMR(101MHz,CDCl3)δ173.31,156.69,155.91,136.44,136.14,129.36,128.51,127.13,126.98,121.43,120.79,107.46,55.23,54.55,52.20,41.41,40.48,38.55,28.92.
从上步所得中间体a出发，采用与实施例38类似的方法合成标题化合物，得到白色固体，收率29％，熔点：108-110℃。
1H NMR(400MHz,DMSO-d6)δ8.79–8.51(m,1H),7.28–7.07(m,6H),6.80(dd,J＝18.9,8.2Hz,2H),6.69(d,J＝7.9Hz,1H),4.55(td,J＝8.7,5.2Hz,1H),4.32(q,J＝17.4Hz,2H),3.77(s,3H),3.47(h,J＝7.8Hz,2H),2.99(qd,J＝13.4,7.2Hz,2H),2.63(h,J＝6.9,6.3Hz,3H),1.55(dq,J＝13.6,6.7Hz,1H),1.37–1.15(m,2H),0.79(dd,J＝6.7,3.9Hz,6H).13C NMR(101MHz,DMSO-d6)δ174.82,156.60,155.51,137.88,135.72,129.35,127.96,126.75,126.19,122.01,120.71,107.63,55.15,53.43,41.27,40.60,40.21,37.28,28.21,25.09,23.02,22.71.HRMS(ESI)calcd for C26H35BN3O4:464.27151[(M-H2O+CH2+H)+],found464.27131.
实施例54：N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-(5-甲氧基-1,2,3,4-四氢异喹啉)-脲(cq27)
Figure PCTCN2016099713-appb-000073
以邻甲氧基苯乙胺为原料，采用与实施例51类似的方法合成前体II(5-甲氧基-1,2,3,4-四氢异喹啉)，得到黄色油状物，收率10％。
从上步所得前体II出发，采用与实施例50类似的方法合成中间体a(N-L-苯丙氨酸甲酯-N′-(5-甲氧基-1,2,3,4-四氢异喹啉)-脲)，得到无色油状物，收率74％。
1H NMR(400MHz,CDCl3)δ7.32–7.21(m,3H),7.17–7.08(m,3H),6.76–6.65(m,2H),5.01(d,J＝7.5Hz,1H),4.84(dt,J＝7.6,5.8Hz,1H),4.48(q,J＝15.9Hz,2H),3.81(s,3H),3.71(s,3H),3.63–3.55(m,1H),3.53–3.44(m,1H),3.19–3.07(m,2H),2.83–2.69(m,2H).13C NMR(101MHz,CDCl3)δ173.26,156.91,156.54,136.37,134.51,129.37,128.56,127.05,126.88,123.66,118.47,107.88,55.39,54.49,52.27,45.46,41.02,38.47,22.59.
从上步所得中间体a出发，采用与实施例38类似的方法合成标题化合物，得到白色固体，收率19％，熔点：111-113℃。
1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),7.31–7.05(m,6H),6.79(dd,J＝21.9,8.2Hz,2H),6.67(d,J＝7.8Hz,1H),4.60–4.49(m,1H),4.49–4.27(m,2H),3.75(s,3H),3.49(q,J＝6.5Hz,2H),3.10–2.85(m,2H),2.62(q,J＝7.4,6.8Hz,1H),2.52(q,J＝5.1,4.3Hz,2H),1.56(dt,J＝13.5,6.8Hz,1H),1.25(ddt,J＝43.6,13.9,7.3Hz,2H),0.78(dd,J＝6.6,3.4Hz,6H).13C NMR(101MHz,DMSO-d6)δ174.81,156.64,156.52,137.85,134.98,129.33,127.95,126.55,126.18,122.86,118.16,107.80,55.20,53.45,45.29,40.61,37.27,25.08,23.01,22.67,22.37.HRMS(ESI)calcd for C26H35BN3O4:464.27151[(M-H2O+CH2+H)+],found 464.27210.
实施例55：N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-(4,5,6,7-四氢噻吩[2,3-C]并吡啶)-脲(cq29)
Figure PCTCN2016099713-appb-000074
除采用4,5,6,7-四氢噻吩[2,3-C]并吡啶代替原料6,7-二甲氧基-1,2,3,4-四氢异喹啉盐酸盐以外，采用与实施例50类似的方法合成中间体a(N-L-苯丙氨酸甲酯-N′-(4,5,6,7-四氢噻吩[2,3-C]并吡啶)-脲)，得到白色泡沫状固体，收率70％。
1H NMR(400MHz,CDCl3)δ7.29–7.20(m,3H),7.14–7.08(m,3H),6.74(d,J＝5.2Hz,1H),5.09(d,J＝7.5Hz,1H),4.82(dt,J＝7.5,5.9Hz,1H),4.49–4.29(m,2H),3.77–3.72(m,1H),3.72(s,3H),3.60(ddd,J＝13.3,6.7,4.9Hz,1H),3.20–3.06(m,2H),2.89–2.73(m,2H).13C NMR(101MHz,CDCl3)δ173.27,156.64,136.32,133.65,131.54,129.32,128.54,127.04,124.83,123.28,54.55,52.28,44.23,41.54,38.35,24.98.
从上步所得中间体a出发，采用与实施例38类似的方法合成中间体b(N-L-苯丙氨酸-N′-(4,5,6,7-四氢噻吩[2,3-C]并吡啶)-脲)，得到白色固体，收率91％。
从上步所得中间体b出发，采用与实施例46类似的方法合成标题化合物，得到白色固体，收率17％，熔点：117-119℃。
1H NMR(400MHz,DMSO-d6)δ8.83–8.65(m,1H),7.22(dtd,J＝22.6,14.9,6.0Hz,6H),6.94(d,J＝8.4Hz,1H),6.80(d,J＝5.2Hz,1H),4.51(td,J＝8.9,5.4Hz,1H),4.45–4.24(m,2H),3.58(q,J＝7.2,6.1Hz,2H),3.08–2.87(m,2H),2.66(ddt,J＝27.9,13.8,8.1Hz,3H),1.56(dt,J＝13.4,6.7Hz,1H),1.38–1.13(m,2H),0.79(dd,J＝6.5,3.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ174.88,156.62,137.91,132.99,132.73,129.34,127.98,126.21,125.07,123.25,53.57,43.83,41.39,40.21,37.27,25.11,24.44,23.06,22.71.HRMS(ESI)calcd for C23H31BN3O3S:440.21737[(M-H2O+CH2+H)+],found 440.21765.
试验实施例1：脲拟肽硼酸类化合物的蛋白酶体抑制作用
37℃下将1μg从大鼠肝脏中提取20S蛋白酶体用含有不同浓度的化合物、50μM的荧光肽和20mM三羟甲基氨基甲烷盐酸盐的100μL溶液分别培养一小时，在380/440nm和335/410nm的激发/ 发射波长下分别用Fluostar OPTIMA和BMG Germany光谱荧光剂测定AMC及βNA物质的释放的荧光，用0.1％DMSO作为溶剂空白。比较溶剂空白的荧光来计算抑制率，或测出IC50。所述的试验以抗肿瘤药物硼替佐米(bortezomib)(白血病治疗药，即PS341)作为阳性对照的比较化合物。试验结果见下表1和表3。
试验实施例2：体外抗肿瘤活性初筛试验
本试验实施例所采用的试验方法是药学领域常规的抗肿瘤活性试验方法，例如可参见下述文献：J.Immunol Method,1983,65,55。
测试模型：A：MTT法(Hela，人宫颈癌)；B：SRB法(BGC-823，肝癌)；C：SRB法(MCF-7，乳腺癌)；D：SRB法(A549，人肺癌)，E：SRB法(PC3M1E8，前列腺癌)。
在0.1μM、1μM和10μM浓度下，测定其抑制率。结果见表2。
试验实施例3：体外抗肿瘤活性(IC50)
体外培养癌细胞株，当细胞生长至对数生长期后，收集细胞，1000rpm离心5min，弃上清，适量培养基悬浮，调整细胞浓度至3.5×104/mL。将细胞悬液接种到96孔细胞培养板中，每孔100μL，放置细胞培养箱(37℃，5％CO2)中培养24h后，加入不同终浓度的待测药物，阴性对照组加入终浓度为0.5％DMSO，各组均设3个复孔。培养箱中培养72h后，每孔加入5mg/mL的MTT 20μL，于37℃放置3h。每孔加入150μL DMSO，37℃摇床振荡5min，492nm/620nm测吸光度(OD)。运用Prism Graphpad统计软件计算IC50值。结果见表4、表5和表6。
表1：本发明化合物的蛋白酶体抑制作用
Figure PCTCN2016099713-appb-000075
Figure PCTCN2016099713-appb-000076
表2：细胞水平活性结果
Figure PCTCN2016099713-appb-000077
Figure PCTCN2016099713-appb-000078
表3：酶水平活性结果
Figure PCTCN2016099713-appb-000079
表4：化合物对肝癌和胃癌细胞增殖的抑制
Figure PCTCN2016099713-appb-000080
表5：三种化合物对多种人体肿瘤细胞的抑制活性(IC50)
Figure PCTCN2016099713-appb-000081
表6：化合物对胃癌细胞(MGC80-3)增殖的抑制
Figure PCTCN2016099713-appb-000082

Claims (9)

  1. 通式(I)所示的化合物或其药学上可接受的盐或溶剂化物：
    Figure PCTCN2016099713-appb-100001
    其中，
    m和n分别表示氨基酸残基的数量，各自独立地选自0、1、2，且不同时为0；
    连接基团L表示二价烷基；
    R1选自于由芳基、杂芳基、环烷基、环烯基、杂环基所组成的组，上述芳基、杂芳基、环烷基、环烯基、杂环基任选被一个或多个取代基取代，上述取代基各自独立地选自于由烷基、环烷基、烯基、环烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环基、杂环基烷基、烷氧基、环烷氧基、芳基氧基、杂芳基氧基、杂环基氧基、芳基烷基氧基、杂芳基烷基氧基、杂环基烷基氧基、烷基硫基、环烷基硫基、芳基硫基、烷氧基羰基、芳基氧基羰基、酰基、硫代酰基、酰基氧基、酰胺基、脲基、亚硫酰基、烷基磺酰基、芳基磺酰基、卤代烷基、氨甲酰基、卤素、氰基、异氰基、硝基、亚硝基、硫氰基、异硫氰基、酰肼基、硫烷基、磺基和甲硅烷基所组成的组；
    R2和R4为氨基酸侧链，m个R2和n个R4各自独立地选自于氢、芳基烷基、杂芳基烷基、杂环基烷基、烷基，上述芳基烷基、杂芳基烷基、杂环基烷基、烷基任选被一个或多个取代基取代，上述取代基各自独立地选自于由烷基、环烷基、烯基、环烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环基、杂环基烷基、烷氧基、环烷氧基、芳基氧基、烷基硫基、环烷基硫基、芳基硫基、烷氧基羰基、芳基氧基羰基、酰基、硫代酰基、酰基氧基、酰胺基、脲基、亚硫酰基、烷基磺酰基、芳基磺酰基、卤代烷基、氨甲酰基、卤素、氰基、异氰基、硝基、亚硝基、硫氰基、异硫氰基、酰肼基、硫烷基、磺基和甲硅烷基所组成的组；
    R3为氢或烷基；
    R5和R6同时为H，或共同形成二醇酯基团；
    并且其中，当m为0时，R1、L和R3还可以连同所连接的N原子共同形成5、6或7元杂环，该5、6或7元杂环除上述N原子外，还任选包含另外一个选自于N、O、S的杂原子，并任选具有氧代基团；同时，该5、6或7元杂环稠合有芳环或杂芳环，上述芳环或杂芳环任选被一个或多个取代基取代，上述取代基各自独立地选自于由烷基、环烷基、烯基、环烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环基、杂环基烷基、烷氧基、环烷氧基、芳基氧基、烷基硫基、环烷基硫基、芳基硫基、烷氧基羰基、芳基氧基羰基、酰基、硫代酰基、酰基氧基、酰胺基、脲基、亚硫酰基、烷基磺酰基、芳基磺酰基、卤代烷基、氨甲酰基、卤素、氰基、异氰基、硝基、亚硝基、硫氰基、异硫氰基、酰肼基、硫烷基、磺基和甲硅烷基所组成的组。
  2. 如权利要求1所述的化合物或其药学上可接受的盐或溶剂化物，其中，各基团的定义满足以下的一项或多项：
    连接基团L表示C1-C4二价烷基；
    R1选自于由苯基、萘基、杂芳基、杂环基所组成的组，上述苯基、萘基、杂芳基、杂环基任选 被一个或多个取代基取代，上述取代基各自独立地选自于由C1-C4烷基、芳基、芳基C1-C4烷基、杂芳基、杂芳基C1-C4烷基、杂环基、杂环基C1-C4烷基、C1-C4烷氧基、芳基氧基、杂芳基氧基、杂环基氧基、芳基C1-C4烷基氧基、杂芳基C1-C4烷基氧基、杂环基C1-C4烷基氧基、卤素、氰基、异氰基、硝基、亚硝基、硫氰基、异硫氰基所组成的组；
    R2和R4为氨基酸侧链，m个R2和n个R4各自独立地选自于氢、苯基C1-C4烷基、杂芳基C1-C4烷基、杂环基C1-C4烷基、C1-C4烷基、萘基C1-C4烷基，上述苯基C1-C4烷基、杂芳基C1-C4烷基、杂环基C1-C4烷基、C1-C4烷基、萘基C1-C4烷基任选被一个或多个取代基取代，上述取代基各自独立地选自于由氨甲酰基、硝基和亚硝基所组成的组；
    R3为氢或C1-C4烷基；
    R5和R6同时为H，或共同形成环状二醇酯基团；
    并且其中，当m为0时，R1、L和R3还可以连同所连接的N原子共同形成5、6或7元杂环，该5、6或7元杂环除上述N原子外，还任选包含另外一个选自于N、O、S的杂原子，并任选具有氧代基团；同时，该5、6或7元杂环稠合有苯环、萘环或杂芳环，上述苯环、萘环或杂芳环任选被一个或多个取代基取代，上述取代基各自独立地选自于由烷基、环烷基、烯基、环烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环基、杂环基烷基、烷氧基、环烷氧基、芳基氧基、烷基硫基、环烷基硫基、芳基硫基、烷氧基羰基、芳基氧基羰基、酰基、硫代酰基、酰基氧基、酰胺基、脲基、亚硫酰基、烷基磺酰基、芳基磺酰基、卤代烷基、氨甲酰基、卤素、氰基、异氰基、硝基、亚硝基、硫氰基、异硫氰基、酰肼基、硫烷基、磺基和甲硅烷基所组成的组。
  3. 如权利要求1所述的化合物或其药学上可接受的盐或溶剂化物，其中，各基团的定义满足以下的一项或多项：
    连接基团L表示亚甲基、亚乙基；
    R1选自于由苯基、萘基、噁唑基、异噁唑基、咪唑基、呋喃基、吲哚基、异吲哚基、吡咯基、三唑基、三嗪基、四唑基、噻吩基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并呋喃基、苯并噻唑基、苯并噁唑基、苯并咪唑基、苯并噻吩基、苯并吡喃基、咔唑基、喹啉基、异喹啉基、喹唑啉基、噌啉基、萘啶基、蝶啶基、嘌呤基、喹噁啉基、噻二唑基、吲哚嗪基、吖啶基、吩嗪基、酞嗪基、香豆素基、吡唑并吡啶基、吡啶并哒嗪基、吡咯并吡啶基、咪唑并吡啶基、吡唑并哒嗪基、氮杂
    Figure PCTCN2016099713-appb-100002
    基、吖啶基、苯并间二氧杂环戊烯基、苯并二氧杂环己基、苯并二氢吡喃基、二氧戊环基、二氧磷杂环戊基、十氢异喹啉基、茚满基、吲哚啉基、异吲哚啉基、异苯并二氢吡喃基、异噻唑烷基、异噁唑烷基、吗啉基、噁唑啉基、噁唑烷基、噁二唑基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂
    Figure PCTCN2016099713-appb-100003
    基、八氢吲哚基、八氢异吲哚基、全氢化氮杂
    Figure PCTCN2016099713-appb-100004
    基、哌嗪基、4-哌啶酮基、哌啶基、吩噻嗪基、吩噁嗪基、奎宁环基、四氢异喹啉基、四氢呋喃基、四氢吡喃基、四氢吡咯基、噻唑啉基、噻唑烷基、硫代吗啉基、硫代吗啉基亚砜和硫代吗啉基砜所组成的组，上述基团任选被一个或多个取代基取代，上述取代基各自独立地选自于由C1-C4烷基、苯基、苯基C1-C4烷基、杂芳基、杂芳基C1-C4烷基、杂环基、杂环基C1-C4烷基、C1-C4烷氧基、苯基氧基、杂芳基氧基、杂环基氧基、苯基C1-C4烷基氧基、杂芳基C1-C4烷基氧基、杂环基C1-C4烷基氧基、氟、氯、溴、碘、氰基、异氰基、硝基、亚硝基、硫氰基、异硫氰基所组成的组；
    m个R2和n个R4各自独立地选自于氢、苄基、异丁基、仲丁基、异丙基、甲基、氨甲酰基乙基、硝基苄基、苯基乙基、萘基甲基、苯并吡咯基甲基；
    R3为氢或甲基；
    R5和R6同时为H，或共同形成蒎烷二醇酯基团或频那醇酯基团；
    并且其中，当m为0时，R1、L和R3还可以连同所连接的N原子共同形成5、6或7元杂环，该5、6或7元杂环除上述N原子外，还任选包含另外一个选自于N、O、S的杂原子，并任选具有氧代基团；同时，该5、6或7元杂环稠合有苯环、萘环或杂芳环，上述苯环、萘环或杂芳环任选被一个或多个取代基取代，上述取代基各自独立地选自于由C1-C4烷氧基、硝基和亚硝基所组成的组。
  4. 如权利要求1所述的化合物或其药学上可接受的盐或溶剂化物，其中，各基团的定义满足以下的一项或多项：
    连接基团L表示亚甲基、亚乙基；
    R1选自于由苯基、萘基、呋喃基、吡嗪基、四氢呋喃基所组成的组，上述基团任选被一个或多个取代基取代，上述取代基各自独立地选自于由甲基、苯基、苄基、甲氧基、苯基氧基、苄氧基、氟、氯、溴、碘、氰基、异氰基、硝基、亚硝基、硫氰基、异硫氰基所组成的组；
    m个R2和n个R4各自独立地选自于氢、苄基、异丁基、仲丁基、异丙基、甲基、氨甲酰基乙基、硝基苄基、苯基乙基、萘基甲基、苯并吡咯基甲基；
    R3为氢或甲基；
    R5和R6同时为H，或共同形成蒎烷二醇酯基团或频那醇酯基团；
    并且其中，当m为0时，R1、L和R3还可以连同所连接的N原子共同形成哌啶环，该哌啶环任选具有氧代基团；同时，该哌啶环稠合有苯环，上述苯环任选被一个或多个取代基取代，上述取代基各自独立地选自于由甲氧基和硝基所组成的组。
  5. 如权利要求1所述的化合物或其药学上可接受的盐或溶剂化物，所述化合物选自于由下述化合物(1)至(55)所组成的组：
    (1)N-L-亮氨酸硼酸-N′-对甲氧基苄胺酰-L-苯丙氨酸-脲；
    (2)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-吡嗪-2-苄胺-脲；
    (3)N-L-亮氨酸硼酸-N′-四氢呋喃-2-甲胺酰-L-苯丙氨酸-脲；
    (4)N-L-亮氨酸硼酸-N′-(3-苄氧基)-苯胺酰-L-苯丙氨酸-脲；
    (5)N-L-亮氨酸硼酸蒎烷二醇酯-N′-(3-苄氧基)-苯胺酰-L-苯丙氨酸-脲；
    (6)N-L-亮氨酸硼酸-N′-吡嗪-2-胺酰-L-苯丙氨酸-脲；
    (7)N-L-亮氨酸硼酸蒎烷二醇酯-N′-吡嗪-2-胺酰-L-苯丙氨酸-脲；
    (8)N-L-亮氨酸硼酸-N′-对甲氧基苯胺酰-L-苯丙氨酸-脲；
    (9)N-L-亮氨酸硼酸蒎烷二醇酯-N′-对甲氧基苯胺酰-L-苯丙氨酸-脲；
    (10)N-L-亮氨酸硼酸-N′-吡嗪-2-胺酰-D-苯丙氨酸-脲；
    (11)N-L-亮氨酸硼酸-N′-吡嗪-2-胺酰-L-亮氨酰-L-亮氨酸-脲；
    (12)N-L-亮氨酸硼酸-N′-吡嗪-2-胺酰-L-亮氨酰-L-苯丙氨酸-脲；
    (13)N-L-亮氨酸硼酸频哪醇酯-N′-吡嗪-2-胺酰-L-亮氨酰-L-苯丙氨酸-脲；
    (14)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-苄胺-脲；
    (15)N-L-苯丙氨酰-L亮氨酸硼酸-N′-对甲氧基苄胺-脲；
    (16)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-(3-苄氧基)苯胺-脲；
    (17)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-吡嗪-2-胺-脲；
    (18)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-2,5-二甲氧基苄胺-脲；
    (19)N-L-苯丙氨酰-L-亮氨酸硼酸蒎烷二醇酯-N′-2,5-二甲氧基苄胺-脲；
    (20)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-2,3-二氯苄胺-脲；
    (21)N-甘氨酰-L-亮氨酸硼酸-N′-(3-苄氧基)-苯胺-脲；
    (22)N-甘氨酰-L-亮氨酸硼酸-N′-2,5-二氯苯胺-脲；
    (23)N-L-苯丙氨酰-L-苯丙氨酰-L-亮氨酸硼酸-N′-(3-苄氧基)-苯胺-脲；
    (24)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-吡嗪-2-氨酰-L-苯丙氨酸-脲；
    (25)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-苯乙胺-脲；
    (26)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-(R)-2-甲基苄胺-脲；
    (27)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-(S)-2-甲基苄胺-脲；
    (28)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-1,2,3,4-四氢异喹啉-脲；
    (29)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-(N-甲基)-苄胺-脲；
    (30)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-(2,3-二甲基)-苄胺-脲；
    (31)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-2,5-二氯苄胺-脲；
    (32)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-对苯基苄胺-脲；
    (33)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-呋喃-2-甲胺-脲；
    (34)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-萘-1-甲胺-脲；
    (35)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-3,4-二氟苄胺-脲；
    (36)N-L-苯丙氨酰-L-亮氨酸硼酸-N′-3-硝基苄胺-脲；
    (37)N-(1-氧代-1,2,3,4-二氢异喹啉-2-甲酰基)-L-苯丙氨酰-L-亮氨酸硼酸；
    (38)N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢喹啉-脲；
    (39)N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-(1-甲基-1,2,3,4-四氢异喹啉)-脲；
    (40)N-(L-亮氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲；
    (41)N-(L-丙氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲；
    (42)N-(L-缬氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲；
    (43)N-(L-萘丙氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲；
    (44)N-(L-异亮氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲；
    (45)N-(L-色氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲；
    (46)N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-(7-硝基-1,2,3,4-四氢异喹啉)-脲；
    (47)N-(L-苯丁氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲；
    (48)N-((L-4-硝基苯丁氨酰)-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲；
    (49)N-(L-谷氨酰氨酰-L-亮氨酸硼酸)-N′-1,2,3,4-四氢异喹啉-脲；
    (50)N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-(6,7-二甲氧基-1,2,3,4-四氢异喹啉)-脲；
    (51)N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-(7-甲氧基-1,2,3,4-四氢异喹啉)-脲；
    (52)N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-(6-甲氧基-1,2,3,4-四氢异喹啉)-脲；
    (53)N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-(8-甲氧基-1,2,3,4-四氢异喹啉)-脲；
    (54)N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-(5-甲氧基-1,2,3,4-四氢异喹啉)-脲；
    (55)N-(L-苯丙氨酰-L-亮氨酸硼酸)-N′-(4,5,6,7-四氢噻吩[2,3-C]并吡啶)-脲。
  6. 一种药物组合物，所述药物组合物包含：权利要求1-5中任一项所述化合物或其药学上可接受的盐或溶剂化物；以及药学上可接受的载体。
  7. 制备权利要求1-5中任一项所述化合物的方法，其中，当m不为0时，所述化合物通过下述流程(A)制备得到；当n不为0时，所述化合物通过下述流程(B)制备得到；
    所述流程(A)包括以下步骤：
    (A1)形成酰胺基团；
    Figure PCTCN2016099713-appb-100005
    其中PG为氨基保护基团，例如Boc；
    (A2)氨基基团脱保护；
    Figure PCTCN2016099713-appb-100006
    (A3)偶联形成脲基团；
    Figure PCTCN2016099713-appb-100007
    (A4)任选形成硼酸化合物或二醇酯化合物；
    任选进行将(A3)步骤得到的频那醇酯进行水解的步骤，得到相应的硼酸化合物；以及进一步任选将上述硼酸化合物与二醇、优选蒎烷二醇进行酯化反应，得到相应的二醇酯、优选蒎烷二醇酯化合物；
    所述流程(B)包括以下步骤：
    (B1)偶联形成脲基团：
    Figure PCTCN2016099713-appb-100008
    (B2)甲酯基团水解；
    Figure PCTCN2016099713-appb-100009
    (B3)形成酰胺基团；
    Figure PCTCN2016099713-appb-100010
    (B4)任选形成硼酸化合物或二醇酯化合物；
    任选进行将(B3)步骤得到的频那醇酯进行水解的步骤，得到相应的硼酸化合物；以及进一步任选将上述硼酸化合物与二醇、优选蒎烷二醇进行酯化反应，得到相应的二醇酯、优选蒎烷二醇酯化合物。
  8. 权利要求1-5中任一项所述的化合物及其药学上可接受的盐或溶剂化物在制备用作蛋白酶体抑制剂的药物方面的用途。
  9. 如权利要求8所述的用途，所述用作蛋白酶体抑制剂的药物用于治疗癌症，所述癌症优选选自于由肺癌、乳腺癌、肝癌、胃癌、宫颈癌、结肠癌、白血病、卵巢癌、胰腺癌和上皮癌所组成的组。
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