CN112010804A - Triaryl compound and preparation method and pharmaceutical application thereof - Google Patents

Triaryl compound and preparation method and pharmaceutical application thereof Download PDF

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CN112010804A
CN112010804A CN201910470503.8A CN201910470503A CN112010804A CN 112010804 A CN112010804 A CN 112010804A CN 201910470503 A CN201910470503 A CN 201910470503A CN 112010804 A CN112010804 A CN 112010804A
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isomer
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hydrogen
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肖志艳
杨亚军
杨颖�
王克
武波
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Institute of Materia Medica of CAMS
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

The invention discloses a triaryl compound shown as a compound in a formula I and a physiologically acceptable salt thereof, a preparation method of the compound, a pharmaceutical preparation containing the compound, and application of the compound in preparing medicines for treating proteasome related diseases, such as autoimmune diseases, inflammations, tumors and the like.

Description

Triaryl compound and preparation method and pharmaceutical application thereof
Technical Field
The invention relates to novel triaryl compounds of general formula (I), and to the stereoisomers and physiologically acceptable salts thereof. The use of these compounds in the treatment of proteasome-related disorders, as well as methods for their use in therapy and pharmaceutical compositions containing said compounds.
Background
The ubiquitin-proteasome pathway is a major pathway for protein degradation in eukaryotic cells and plays an important role in cell division, differentiation, growth and development, signal transduction, apoptosis and other processes. The proteasome inhibitors Bortezomib, Carfilzomib and ixazoib are FDA approved for marketing for the treatment of multiple myeloma, demonstrating the feasibility of proteasomes as anti-tumor targets.
Although many proteasome inhibitors are reported in the literature at present, and several inhibitors are on the market or are under clinical study, most of the inhibitors are peptide inhibitors of covalent binding type, and the structural characteristics of the inhibitors determine that the pharmacokinetic properties of the inhibitors are poor, so that the search and development of non-peptide proteasome inhibitors are important strategies for solving the problem. The proteasome inhibitor Bortezomib approved by FDA to be marketed has toxic and side effects of peripheral neuropathy, leukopenia and thrombopenia caused by bone marrow inhibition, gastrointestinal reaction and the like in the clinical process. Based on analysis of the mode of action of Bortezomib and reports in the literature that toxicity may result from boronic acid groups covalently bound to the proteasome, we wanted to find suitable non-covalently bound inhibitors to overcome this problem. In addition, selective inhibition of proteasome CT-L active sites is also of interest because it may be advantageous to induce apoptosis of blood-type tumor cells while reducing side effects.
The invention aims to provide a novel triaryl compound which has high proteasome inhibition activity and can be used for treating related diseases such as autoimmune diseases, inflammations, tumors and the like.
Disclosure of Invention
The invention aims to provide a novel triaryl compound shown as a formula I.
The invention also aims to provide a method for preparing the novel triaryl compound shown in the formula I and the analogues thereof.
The invention also aims to provide application of the compound shown in the formula I in preparing proteasome inhibitors and in preparing medicaments for preventing or treating autoimmune diseases, inflammations, tumors and the like.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
Figure BDA0002080693340000021
wherein n is 0 or 1;
Ar1selected from:
Figure BDA0002080693340000022
R1is hydrogen, C1-C5Alkyl, substituted or notSubstituted phenoxy radicals, the substituents being taken from C1-C3Alkyl radical, C1-C3Alkoxy and halogen;
r is selected from hydrogen and C1-C5An alkyl group;
Ar2selected from:
Figure BDA0002080693340000023
Ar3selected from:
Figure BDA0002080693340000024
in another aspect, the present invention provides a compound represented by the general formula (IA):
Figure BDA0002080693340000031
wherein n is 0 or 1;
Ar1selected from:
Figure BDA0002080693340000032
R1is hydrogen, C1-C5Alkyl, substituted or unsubstituted phenoxy, the substituents being taken from C1-C3Alkyl radical, C1-C3Alkoxy and halogen;
r is selected from hydrogen and C1-C5An alkyl group;
Ar3selected from:
Figure BDA0002080693340000033
in another aspect, the present invention provides a compound represented by the general formula (IA):
Figure BDA0002080693340000034
wherein n is 0 or 1;
Ar1selected from:
Figure BDA0002080693340000035
R1is hydrogen, C1-C5Alkyl, substituted or unsubstituted phenoxy, the substituents being taken from C1-C3Alkyl, C1-C3Alkoxy and halogen;
Ar3selected from:
Figure BDA0002080693340000041
another embodiment of the present invention provides a compound represented by the general formula (IB):
Figure BDA0002080693340000042
wherein n is 0 or 1;
Ar1selected from:
Figure BDA0002080693340000043
R1is hydrogen, C1-C5Alkyl, substituted or unsubstituted phenoxy, the substituents being taken from C1-C3Alkyl radical, C1-C3Alkoxy and halogen;
r is selected from hydrogen and C1-C5An alkyl group;
Ar3selected from:
Figure BDA0002080693340000044
still another aspect of the present invention is to provide a compound represented by general formula (IBa):
Figure BDA0002080693340000045
wherein n is 0 or 1;
Ar1selected from:
Figure BDA0002080693340000051
R1is hydrogen, C1-C5Alkyl, substituted or unsubstituted phenoxy, the substituents being taken from C1-C3Alkyl radical, C1-C3Alkoxy and halogen;
Ar3selected from:
Figure BDA0002080693340000052
still another embodiment of the present invention is to provide a compound represented by the general formula (IC):
Figure BDA0002080693340000053
wherein n is 0 or 1;
Ar1selected from:
Figure BDA0002080693340000054
R1is hydrogen, C1-C5Alkyl, substituted or unsubstituted phenoxy, the substituents being taken from C1-C3Alkyl radical, C1-C3Alkoxy and halogenA peptide;
r is selected from hydrogen and C1-C5An alkyl group;
Ar3selected from:
Figure BDA0002080693340000055
another aspect of the present invention is to provide the compound and a physiologically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure BDA0002080693340000061
Figure BDA0002080693340000071
Figure BDA0002080693340000081
the invention also provides a synthesis method of the compound shown in the formula I, which comprises the following steps:
the compound shown in the general formula (IA) is synthesized according to the following steps that substituted benzyl chloride is aminated firstly, then coupled and finally forms amide with acid;
Figure BDA0002080693340000082
the compound shown in the general formula (IB) is synthesized according to the following steps that substituted chloride is aminated firstly, then coupled and finally forms amide with acid;
Figure BDA0002080693340000083
the compound shown in the general formula (IC) is synthesized according to the following steps that substituted nitrile group is firstly condensed with hydroxylamine hydrochloride, then esterified, cyclized and aminated, and finally forms amide with acid;
Figure BDA0002080693340000084
for the preparation of medicaments, the compounds of the formula I are mixed in a known manner with suitable pharmaceutical carrier substances, fragrances, flavors and colors in a known manner and are tableted or coated, or are suspended or dissolved in water or oil with other additional substances.
The invention also relates to a pharmaceutical composition containing a pharmaceutically effective dose of the compound shown in the general formula I and a pharmaceutically acceptable carrier.
Pharmacological research shows that the compound of the general formula I has the activity of inhibiting proteasome, and can effectively reduce the level of hematuria acid in vivo, thereby achieving the purpose of treatment.
The compounds of the invention may be administered orally or parenterally. The oral preparation can be tablet, capsule, and coating agent, and the parenteral preparation can be injection and suppository. These formulations are prepared according to methods well known to those skilled in the art. Adjuvants used for the manufacture of tablets, capsules, coatings are the customary auxiliaries, such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms, such as water, ethanol, propylene glycol, vegetable oils, such as corn oil, peanut oil, olive oil, etc. The formulations containing the compounds of the present invention may also contain other adjuvants such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, coloring agents, and the like.
The invention also provides application of the compound in preparation of proteasome inhibitors and in preparation of medicaments for preventing or treating autoimmune diseases, inflammations, tumors and the like.
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS) or High Resolution Mass Spectrometry (HRMS). NMR shifts () are given in parts per million (ppm). m.p. is the melting point given in ° c, the temperature is uncorrected. The column chromatography generally uses 200-300 mesh silica gel as a carrier. NMR was measured using INOVA-300 and CDCl as the solvent3、DMSO-D6The internal standard is TMS and the chemical shifts are given in ppm. MS was measured using an Agilent LC/MSD TOF LC/MS spectrometer.
Example 1: compound 1
Figure BDA0002080693340000101
a)1ml of 4-n-propylphenol (7.22mmol) is dissolved in 10ml of acetone, 3g of anhydrous potassium carbonate (21.66mmol) and 0.94ml of ethyl bromoacetate are respectively added, reflux reaction is carried out for 12 hours, TLC detection is carried out, the basic reaction is complete, filtration is carried out, and the filtrate is concentrated under reduced pressure to obtain 1.7g of oily liquid. The resulting 1.7g of oily liquid was dissolved in 10ml of anhydrous ethanol, 10ml of 1mol/L sodium hydroxide solution was added, reflux reaction was carried out for 6 hours, concentration was carried out under reduced pressure, a white precipitate was formed after adjusting the pH to 2 with 1mol/L HCl solution, filtration was carried out, and washing was carried out with water to obtain 1.3g of 4-n-propylphenoxyacetic acid as a white solid with a yield of 93%.
b)0.8ml of 3-bromobenzyl chloride (6mmol) is dissolved in 30ml of acetonitrile, 1ml of isopropylamine (12mmol) and 4.15g of anhydrous potassium carbonate (30mmol) are added, the reflux reaction is carried out for 6 hours, the TLC detection shows that the reaction is almost complete, the concentration under reduced pressure is carried out, the ethyl acetate is redissolved, the organic layer is dried by anhydrous sodium sulfate after the water washing, and the concentration under reduced pressure is carried out to obtain 1.35g of oily matter. 600mg of the obtained oily substance (2.6mmol) is dissolved in 10ml of toluene and 10ml of ethanol, 480mg of 3-pyridine boric acid (3.9mmol), 20mg of tetrakis (triphenylphosphine) palladium and 10ml of 2mol/L sodium carbonate solution are respectively added, the mixture is reacted for 6 hours at 100 ℃ under the protection of nitrogen, TLC detection shows that the basic reaction is complete, diatomite is filtered, the filtrate is concentrated under reduced pressure, the filtrate is dissolved by ethyl acetate, the solution is washed by distilled water, an organic layer is dried by anhydrous sodium sulfate, the concentration is carried out under reduced pressure, column chromatography is carried out, 505mg of the oily product is obtained, and the yield is 86%.
c) Dissolving 300mg of 4-n-propylphenoxyacetic acid in 30ml of anhydrous toluene, slowly dropwise adding 1ml of oxalyl chloride, refluxing and heating for 3h, detecting by TLC (thin layer chromatography), stopping reaction when the reaction is basically complete, and concentrating under reduced pressure to obtain yellow oily liquid. Taking 140mg of oily matter obtained from TM-39b, respectively adding 15ml of anhydrous tetrahydrofuran and 0.2ml of triethylamine, slowly adding 15ml of tetrahydrofuran solution of 4-n-propylphenoxyacetyl chloride, stirring for 30min, detecting by TLC (thin layer chromatography), basically completely reacting, concentrating under reduced pressure, dissolving by ethyl acetate, respectively washing by saturated sodium carbonate solution and distilled water, drying an organic layer by anhydrous sodium sulfate, concentrating under reduced pressure, and carrying out column chromatography to obtain 160mg of oily matter with the yield of 64%.
1H-NMR(300MHz,CDCl3):ppm 8.80(s,1H),8.59(s,1H),7.86-7.78(m,1H),7.49-7.32(m,4H),7.21(d,J＝6.6Hz,1H),7.07(d,J＝8.2Hz,2H,[7.00minor isomer]),6.90(d,J＝8.2Hz,2H,[6.72minor isomer]),4.80(s,2H,[4.66minor isomer]),4.63(s,2H,[4.55minor isomer]),4.45-4.36(m,1H),2.51(t,J＝9.0Hz,2H,[2.54minor isomer]),1.67-1.51(m,2H),1.22(d,J＝7.8Hz,6H,[1.26minor isomer]),0.92(t,J＝7.7Hz,3H,[0.95minor isomer]).HR-ESI-MS:m/z calcd for C26H31N2O2 +403.2386([M+H]+),found 403.2384.
Example 2: compound 2
Figure BDA0002080693340000111
The synthesis was the same as in example 1 except that 3-pyridineboronic acid was changed to 5-pyrimidineboronic acid.
1H-NMR(300MHz,CDCl3):ppm 9.20(s,1H),8.87(s,2H),7.49(brs,1H),7.41-7.37(m,3H),7.07(d,J＝8.1Hz,2H,[6.99minor isomer]),6.89(d,J＝8.1Hz,2H,[6.69minor isomer]),4.79(s,2H,[4.66minor isomer]),4.62(s,2H,[4.55minor isomer]),4.48-4.39(m,1H),2.53-2.44(m,2H),1.67-1.51(m,2H),1.22(d,J＝6.0Hz,6H,[1.18minor isomer]),0.92(t,J＝7.3Hz,3H,[0.89minor isomer])；HR-ESI-MS:m/z calcd for C25H30N3O2 +404.2338([M+H]+),found 404.2331.
Example 3: compound 3
Figure BDA0002080693340000112
a)243mg of 3-bromo-5- (chloromethyl) pyridine hydrochloride (1mmol) was dissolved in 20ml of acetonitrile, 0.17ml of isopropylamine (2mmol) and 691mg of anhydrous potassium carbonate (5mmol) were added, the reaction was refluxed for 6 hours, and checked by TLC, the reaction was substantially completed, concentrated under reduced pressure, redissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 240mg of oil. 240mg of oily substance (1.05mmol) is dissolved in 10ml of toluene and 10ml of ethanol, 185mg of 3-pyridine boric acid (1.5mmol), 15mg of tetrakis (triphenylphosphine) palladium and 15ml of 2mol/L sodium carbonate solution are respectively added, reaction is carried out for 6h at 100 ℃ under the protection of nitrogen, TLC detection shows that the reaction is complete, diatomite is filtered, the filtrate is concentrated under reduced pressure, the filtrate is dissolved by ethyl acetate, then washing is carried out by distilled water, an organic layer is dried by anhydrous sodium sulfate, reduced pressure concentration and column chromatography are carried out, 210mg of oily product is obtained, and the yield is 88%.
b) Dissolving 250mg (1.3mmol) of 4-n-propylphenoxyacetic acid in 30ml of anhydrous toluene, slowly dropwise adding 1ml of oxalyl chloride, refluxing and heating for 3h, detecting by TLC (thin layer chromatography), stopping reaction, and concentrating under reduced pressure to obtain yellow oily liquid.
c) And taking 124mg (0.55mmol) of the obtained oily substance, respectively adding 15ml of anhydrous tetrahydrofuran and 0.17ml of triethylamine, slowly adding 15ml of the obtained tetrahydrofuran solution of 4-n-propylphenoxyacetyl chloride, stirring for 30min, detecting by TLC (thin layer chromatography), basically completely reacting, concentrating under reduced pressure, dissolving by using ethyl acetate, respectively washing by using saturated sodium carbonate solution and distilled water, drying an organic layer by using anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography to obtain 165mg of a white solid.
The yield was 74%. mp 69-70 ℃;1H-NMR(300MHz,CD3OD):ppm 9.40(s,1H),9.28(s,1H),9.05-8.99(m,2H),8.89(d,J＝8.8Hz,2H),8.27(brs,1H),7.08(d,J＝8.2Hz,2H,[7.00minor isomer]),6.89(d,J＝8.2Hz,2H,[6.65minor isomer]),4.97(s,2H,[4.87minor isomer]),4.84(s,2H,[4.75minor isomer]),4.46-4.37(m,1H),2.50(t,J＝7.5Hz,2H),1.62-1.54(m,2H),1.35(d,J＝6.3Hz,6H,[1.23minor isomer]),0.90(t,J＝7.3Hz,3H)；HR-ESI-MS:m/z calcd for C25H30N3O2 +404.2338([M+H]+),found 404.2339.
example 4: compound 4
Figure BDA0002080693340000121
The synthesis was the same as in example 3 except that 3-pyridineboronic acid was changed to 5-pyrimidineboronic acid.
1H-NMR(300MHz,CD3OD):ppm 9.33(s,1H),9.20(s,2H),8.86(s,1H),8.79-8.75(m,2H),7.06(d,J＝8.6Hz,2H),6.88(d,J＝8.6Hz,2H),4.95(s,2H,[4.93minor isomer]),4.82(s,2H,[4.72minor isomer]),4.46-4.37(m,1H),2.48(t,J＝7.5Hz,2H,[2.54minor isomer]),1.61-1.53(m,2H),1.33(d,J＝6.4Hz,6H,[1.23minor isomer]),0.90(t,J＝7.3Hz,3H)；HR-ESI-MS:m/z calcd for C24H29N4O2 +405.2291([M+H]+),found 405.2276.
Example 5: compound 5
Figure BDA0002080693340000131
The synthesis was the same as in example 1 except that 4-n-propylphenoxyacetic acid was changed to 2-benzofurancarboxylic acid.
1H-NMR(300MHz,CD3OD):ppm 8.84(s,1H),8.60(d,J＝3.9Hz,1H),7.93(brs,1H),7.62(d,J＝6.9Hz,1H),7.54(s,1H),7.47-7.37(m,6H),7.28-7.25(m,2H),4.83-4.75(m,3H),1.31(d,J＝6.7Hz,6H,[1.22minor isomer])；HR-ESI-MS:m/z calcd for C24H23N2O2 +371.1760([M+H]+),found 371.1747.
Example 6: compound 6
Figure BDA0002080693340000132
The synthesis was the same as in example 1 except that 4-n-propylphenoxyacetic acid was changed to 2-benzofurancarboxylic acid and 3-pyridineboronic acid was changed to 5-pyrimidineboronic acid.
1H-NMR(300MHz,CD3OD):ppm 9.20(s,1H),9.10(s,2H),7.74-7.67(m,4H),7.51(t,J＝7.5Hz,1H),7.42(d,J＝7.1Hz,2H),7.32(brs,1H),7.04(brs,1H),4.80(brs,2H),4.62-4.54(m,1H),1.35(d,J＝6.7Hz,6H,[1.26minor isomer])；HR-ESI-MS:m/z calcd for C23H22N3O2 +372.1712([M+H]+),found 372.1715.
Example 7: compound 7
Figure BDA0002080693340000141
The synthesis was the same as in example 3 except that 4-n-propylphenoxyacetic acid was changed to 2-benzofurancarboxylic acid.
mp 65-66℃；1H-NMR(300MHz,CD3OD):ppm 9.38(s,1H),9.27(s,1H),9.03-9.01(m,3H)8.95(s,1H),8.26(t,J＝6.7Hz,1H),7.73(d,J＝7.9Hz,1H),7.56(brs,1H),7.48-7.43(m,2H),7.33(t,J＝6.7Hz,1H),5.01(s,2H),4.95-4.90(m,1H),1.43(d,J＝6.2Hz,6H)；HR-ESI-MS:m/z calcd for C23H22N3O2 +372.1712([M+H]+),found 372.1705.
Example 8: compound 8
Figure BDA0002080693340000142
The synthesis was the same as in example 1 except that 4-n-propylphenoxyacetic acid was changed to 2-benzofurancarboxylic acid and 3-pyridineboronic acid was changed to 5-pyrimidineboronic acid.
mp 120-121℃；1H-NMR(300MHz,CD3OD):ppm 9.28(s,1H),8.94(s,2H),8.74(s,2H),7.99(s,1H),7.65(d,J＝7.6Hz,1H),7.49-7.37(m,2H),7.35(s,1H),7.30(d,J＝7.9Hz,1H),4.89-4.80(m,3H),1.35(d,J＝6.7Hz,6H,[1.26minor isomer])；HR-ESI-MS:m/z calcd for C22H21N4O2 +373.1665([M+H]+),found 373.1670.
Example 9: compound 9
Figure BDA0002080693340000143
a)1.0ml of 2-furancarbonitrile (11.4mmol) was dissolved in 30ml of water, 1.59g of hydroxylamine hydrochloride (22.8mmol) and 2.42g of anhydrous sodium carbonate were added, the reaction was carried out at 70 ℃ for 4 hours, TLC detection showed that the reaction was substantially complete, saturated brine and ethyl acetate were added, extraction was carried out with ethyl acetate several times, the organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 1.6g of a white solid with a yield of 98.7%. Dissolving the obtained 1.6g of white solid in 30ml of acetone, slowly dropwise adding 0.9ml of chloroacetyl chloride, reacting for 30min, detecting by TLC (thin layer chromatography), basically completely reacting, concentrating under reduced pressure, dissolving with ethyl acetate, washing with saturated sodium carbonate solution, distilled water, drying an organic layer by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 2.1g of white solid with the yield of 92.5%. Dissolving 2.1g of the obtained white solid in 50ml of toluene, carrying out reflux reaction for 10h by using a water separator, detecting by TLC (thin layer chromatography), basically completing the reaction, concentrating under reduced pressure, dissolving by using ethyl acetate, washing by using distilled water, drying an organic layer by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 1.8g of a product, wherein the yield is 94%. 1.03g (5.6mmol) of the obtained product is taken and dissolved in 30ml of acetonitrile, 0.95ml of isopropylamine (11.2mmol) and 3.9g of anhydrous potassium carbonate (28mmol) are added, the reflux reaction is carried out for 6h, the TLC detection shows that the basic reaction is complete, the reduced pressure concentration is carried out, the ethyl acetate is redissolved, the organic layer is dried by using water, the anhydrous sodium sulfate is used for drying the organic layer, the reduced pressure concentration is carried out, and the oily matter is obtained, wherein the yield is 88%.
b) Dissolving 300mg (1.54mmol) of 4-n-propylphenoxyacetic acid in 20ml of anhydrous toluene, slowly dropwise adding 1ml of oxalyl chloride, refluxing and heating for 3h, detecting by TLC (thin layer chromatography), stopping the reaction, and concentrating under reduced pressure to obtain yellow oily liquid. Taking 200mg (0.96mmol) of the obtained oily substance, respectively adding 15ml of anhydrous tetrahydrofuran and 0.2ml of triethylamine, slowly adding 15ml of the obtained tetrahydrofuran solution of 4-n-propylphenoxyacetyl chloride, stirring for 30min, detecting by TLC (thin layer chromatography), basically completely reacting, concentrating under reduced pressure, dissolving by using ethyl acetate, respectively washing by using saturated sodium carbonate solution, distilled water, drying an organic layer by using anhydrous sodium sulfate, concentrating under reduced pressure, and carrying out column chromatography to obtain 290mg of white solid with the yield of 78.8%.
mp 105-106℃；1H-NMR(300MHz,CDCl3):ppm 7.59(brs,1H),7.09(d,J＝8.5Hz,2H,[7.06minor isomer]),7.08(brs,1H),6.88(d,J＝8.5Hz,2H,[6.82minor isomer]),6.55-6.53(m,1H),4.78(s,2H,[4.86minor isomer]),4.70(s,2H,[4.80minor isomer]),4.45-4.37(m,1H),2.52(t,J＝7.5Hz,2H,[2.50minor isomer]),1.65-1.54(m,2H),1.28(d,J＝6.6Hz,6H,[1.14minor isomer]),0.92(t,J＝7.3Hz,3H)；HR-ESI-MS:m/z calcd for C21H26N3O4 +384.1923([M+H]+),found 384.1927.
Example 10: compound 10
Figure BDA0002080693340000161
The synthesis was the same as in example 9, except that 2-furancarbonitrile was replaced with 2-thiophenecarbonitrile.
mp 94-95℃；1H-NMR(300MHz,CDCl3):ppm 7.74(d,J＝3.1Hz,1H),7.53-7.58(m,1H),7.14(d,J＝3.9Hz,1H),7.09(d,J＝8.5Hz,2H,[7.05minor isomer]),6.88(d,J＝8.5Hz,2H,[6.82minor isomer]),4.78(s,2H,[4.84minor isomer]),4.69(s,2H,[4.82minor isomer]),4.46-4.37(m,1H),2.52(t,J＝7.5Hz,2H,[2.49minor isomer]),1.66-1.54(m,2H),1.29(d,J＝6.6Hz,6H,[1.15minor isomer]),0.92(t,J＝7.2Hz,3H)；HR-ESI-MS:m/z calcd for C21H26N3O3S+400.1695([M+H]+),found 400.1699.
Example 11: compound 11
Figure BDA0002080693340000162
The synthesis was the same as in example 9 except that 2-furancarbonitrile was replaced with 2-naphthoxynil.
mp 102-103℃；1H-NMR(300MHz,CDCl3):ppm 8.57(s,1H),8.09(d,J＝9.0Hz,1H),7.93-7.86(m,3H),7.56-7.54(m,2H),7.04(d,J＝9.0Hz,2H,[7.01minor isomer]),6.91(d,J＝9.0Hz,2H,[6.84minor isomer]),4.81(s,2H,[4.90minor isomer]),4.76(s,2H,[4.87minor isomer]),4.49-4.41(m,1H),2.50(t,J＝7.5Hz,2H,[2.46minor isomer]),1.61-1.54(m,2H),1.31(d,J＝6.0Hz,6H,[1.18minor isomer]),0.90(t,J＝7.5Hz,3H,[0.87minor isomer])；HR-ESI-MS:m/z calcd for C27H30N3O3 +444.2287([M+H]+),found 444.2293.
Example 12: compound 12
Figure BDA0002080693340000171
The synthesis was the same as in example 9 except that 2-furancarbonitrile was replaced with 2-quinolinecarbonitrile.
mp 143-144℃；1H-NMR(300MHz,CDCl3):ppm 8.37-8.31(m,2H),8.18(d,J＝7.5Hz,1H),7.89(d,J＝7.5Hz,1H)7.82-7.78(m,1H),7.66-7.62(m,1H),7.08(d,J＝7.8Hz,2H,[7.05minor isomer]),6.90(d,J＝7.8Hz,2H,[6.85minor isomer]),4.85(s,2H,[4.99minor isomer]),4.81(s,2H,[4.99minor isomer]),4.48-4.40(m,1H),2.52(t,J＝7.5Hz,2H,[2.48minor isomer]),1.64-1.54(m,2H),1.31(d,J＝6.0Hz,6H,[1.16minor isomer]),0.92(t,J＝7.5Hz,3H,[0.87minor isomer])；HR-ESI-MS:m/z calcd for C26H29N4O3 +445.2240([M+H]+),found 445.2248.
Example 13: compound 13
Figure BDA0002080693340000172
The synthesis was the same as in example 9 except that 2-furancarbonitrile was replaced by 2-naphthoxycarbonitrile and 4-n-propylphenoxyacetic acid was replaced by 2-benzofurancarboxylic acid.
mp 118-119℃；1H-NMR(300MHz,CDCl3):ppm 8.60(s,1H),8.12(dd,J＝8.6Hz,1.4Hz,1H),7.96-7.86(m,3H),7.66(d,J＝7.5Hz,1H),7.58-7.37(m,5H),7.30(d,J＝7.5Hz,1H),5.05-4.96(m,3H),1.40(d,J＝6.6Hz,6H)；HR-ESI-MS:m/z calcd for C25H22N3O3 +412.1661([M+H]+),found 412.1650.
Example 14: compound 14
Figure BDA0002080693340000181
The synthesis was the same as in example 9 except that 2-furancarbonitrile was replaced by 2-quinolinecarbonitrile and 4-n-propylphenoxyacetic acid was replaced by 2-benzofurancarboxylic acid.
mp 149-150℃；1H-NMR(300MHz,CDCl3):ppm 8.44(d,J＝8.6Hz,1H),8.35(d,J＝8.5Hz,1H),8.23(d,J＝8.5Hz,1H),7.90(d,J＝8.2Hz,1H),7.81(t,J＝7.1Hz,1H),7.65(t,J＝7.5Hz,2H),7.46-7.40(m,3H),7.30(d,J＝7.6Hz,1H),5.09(s,2H),5.03-4.96(m,1H),1.38(d,J＝6.1Hz,6H)；HR-ESI-MS:m/z calcd for C24H21N4O3 +413.1614([M+H]+),found 413.1620.
Example 15: compound 15
Figure BDA0002080693340000182
The synthesis was the same as in example 9 except that 4-n-propylphenoxyacetic acid was changed to 2-benzofurancarboxylic acid.
mp 75-76℃；1H-NMR(300MHz,CDCl3):ppm 7.66(d,J＝7.9Hz,1H),7.60(brs,1H),7.43-7.37(m,3H),7.30(d,J＝7.3Hz,1H),7.13(d,J＝3.5Hz,1H),6.55(d,J＝3.5Hz,1H),5.01-4.92(m,3H),1.36(d,J＝6.1Hz,6H)；HR-ESI-MS:m/z calcd for C19H18N3O4 +352.1297([M+H]+),found 352.1299.
Example 16: compound 16
Figure BDA0002080693340000183
The synthesis was the same as in example 9 except that 2-furancarbonitrile was replaced by 2-thiophenecarbonyl and 4-n-propylphenoxyacetic acid was replaced by 2-benzofurancarboxylic acid.
1H-NMR(300MHz,CDCl3):ppm 7.78(d,J＝3.7Hz,1H),7.66(d,J＝7.4Hz,1H),7.50(d,J＝5.0Hz,1H),7.43-7.36(m,2H),7.30(d,J＝7.4Hz,2H),7.14(dd,J＝4.8,3.8Hz,1H),5.01-4.92(m,3H),1.37(d,J＝6.6Hz,6H[1.22minor isomer]))；HR-ESI-MS:m/z calcd for C19H18N3O3S+368.1069([M+H]+),found 368.1075.
Example 17: compound 17
Figure BDA0002080693340000191
The synthesis was the same as in example 9 except that 4-n-propylphenoxyacetic acid was changed to 2-quinolinecarboxylic acid.
1H NMR(300MHz,DMSO-d6)8.52(d,J＝8.4Hz,1H,[8.42minor isomer]),8.09-7.53(m,6H),7.27(m,1H,[7.16minor isomer]),6.75(m,1H,[6.71minor isomer]),4.96(s,2H,[5.09minor isomer]),4.25-4.17(m,1H,[4.92-4.84minor isomer]),1.27(d,J＝6.8Hz,6H,[1.32minor isomer]).HR-ESI-MS:m/z＝363.1449[M+H]+,calculated for C20H19N4O3:363.1452.
Example 18: compound 18
Figure BDA0002080693340000192
The synthesis was the same as in example 9 except that 4-n-propylphenoxyacetic acid was exchanged for 2-quinoxalinecarboxylic acid.
1H NMR(400MHz,DMSO-d6)9.08(s,1H,[9.18minor isomer]),8.22-8.12(m,2H,[8.11-8.05and 7.91-7.85minor isomer]),8.01-7.93(m,3H,[8.01-7.93,7.85-7.79and 7.56minor isomer,partially overlapped]),7.26(d,J＝2.8Hz,1H,[7.19minor isomer]),6.74(m,1H,[6.72minor isomer,partially overlapped]),5.00(s,2H,[5.13minor isomer]),4.39-4.29(m,1H,[4.89-4.81minor isomer]),1.29(d,J＝6.8Hz,6H,partially overlapped[1.31minor isomer,partially overlapped]).HR-ESI-MS:m/z＝364.1399[M+H]+,calculated for C19H18N5O3:364.1404.
Example 19: compound 19
Figure BDA0002080693340000201
The synthesis was the same as in example 9 except that 4-n-propylphenoxyacetic acid was changed to 4-phenoxyphenoxyphenoxyacetic acid.
1H NMR(400MHz,DMSO-d6)7.96(s,1H),7.34(t,J＝7.6Hz,2H),7.19(d,J＝3.4Hz,1H,[7.23minor isomer]),7.07(t,J＝7.6Hz,1H),6.99-6.88(m,6H),6.75-6.69(m,1H),4.95(s,2H,[5.01minor isomer]),4.74(s,2H,[4.86minor isomer]),4.30-4.22(m,1H,[4.68-4.60minor isomer]),1.27(d,J＝7.2Hz,6H,[1.07minor isomer]).HR-ESI-MS:m/z＝434.1705[M+H]+,calculated for C24H24N3O5:434.1711.
Example 20: compound 20
Figure BDA0002080693340000202
The synthesis was the same as in example 1 except that 3-pyridineboronic acid was changed to 2-furanboronic acid and 4-n-propylphenoxyacetic acid was changed to 2-quinolinecarboxylic acid.
1H NMR(400MHz,DMSO-d6)8.54(d,J＝8.4Hz,1H,[8.37minor isomer]),8.08(d,J＝8.0Hz,1H,[7.95minor isomer]),8.06(d,J＝8.0Hz,1H,[7.93minor isomer]),7.85-7.47(m,6H),7.42(t,J＝7.6Hz,1H,[7.27minor isomer]),7.35(d,J＝7.6Hz,1H,[7.21minor isomer]),6.94(d,J＝3.2Hz,1H,[6.79minor isomer]),6.62(s,1H,[6.56minor isomer]),4.75(s,1H,[4.67minor isomer]),4.07-4.01(m,1H,[4.64-4.58minor isomer]),1.12(d,J＝6.8Hz,6H,[1.24minor isomer]).HR-ESI-MS:m/z＝371.1753[M+H]+,calculated for C24H23N2O2:371.1754.
Example 21: compound 21
Figure BDA0002080693340000211
The synthesis was the same as in example 1 except that 3-pyridineboronic acid was changed to 2-furanboronic acid.
1H NMR(400MHz,DMSO-d6)7.71(s,1H,[7.75minor isomer]),7.62-7.46(m,2H),7.26(t,J＝7.6Hz,1H,[7.40minor isomer]),7.10-7.02(m,3H,[7.22-7.17and6.99-6.93minor isomer]),6.83(d,J＝8.0Hz,3H,[6.91and 6.65minor isomer]),6.56(s,1H,[6.58minor isomer]),4.91(s,2H,[4.58minor isomer]),4.48(s,2H,[4.57minor isomer]),4.26-4.16(m,1H,[4.52minor isomer]),2.49-2.37(m,2H),1.56-1.45(m,2H),1.11(d,J＝6.0Hz,6H,[1.07minor isomer]),0.84(t,J＝7.2Hz,3H partially overlapped,[0.82minor isomer partially overlapped]).HR-ESI-MS:m/z＝392.2220[M+H]+,calculated for C25H30NO3:392.2220.
Example 22: compound 22
Figure BDA0002080693340000212
The synthesis was the same as in example 1 except that 3-pyridineboronic acid was changed to 2-furanboronic acid and 4-n-propylphenoxyacetic acid was changed to 2-benzofurancarboxylic acid.
1H NMR(400MHz,DMSO-d6)7.75-7.59(m,4H),7.57(d,J＝8.0Hz,1H),7.45-7.27(m,4H),7.24(d,J＝7.6Hz,1H),6.91(d,J＝3.2Hz,1H),6.62-6.54(m,1H),4.76(s,2H),4.58-4.51(m,1H),1.22(d,J＝6.8Hz,6H).HR-ESI-MS:m/z＝360.1591[M+H]+,calculated for C23H22NO3:360.1594
Example 23: compound 23
Figure BDA0002080693340000221
The synthesis was the same as in example 1 except that 3-pyridineboronic acid was changed to 2-thiopheneboronic acid and 4-n-propylphenoxyacetic acid was changed to 2-quinolinecarboxylic acid.
1H NMR(400MHz,DMSO-d6)8.55(d,J＝8.4Hz,1H,[8.37minor isomer]),8.11-8.03,7.75-7.66,7.59-7.21(m,9H),7.95(t,J＝8.0Hz,1H,[7.78minor isomer]),7.85(t,J＝8.0Hz,1H,[7.61minor isomer]),7.20-7.13(m,1H,[7.12-7.07minor isomer]),4.75(s,2H,[4.70minor isomer]),4.11-3.97(m,1H,[4.65-4.56minor isomer]),1.14(d,J＝6.4Hz,6H,[1.25minor isomer]).HR-ESI-MS:m/z＝387.1519[M+H]+,calculated for C24H23ON2S:387.1526.
Example 24: compound 24
Figure BDA0002080693340000222
The synthesis was the same as in example 1 except that 3-pyridineboronic acid was changed to 2-thiopheneboronic acid.
1H NMR(400MHz,DMSO-d6)7.58-7.37(m,4H),7.26(t,J＝7.6Hz,1H,[7.22minor isomer]),7.14-7.07(m,2H),7.03(d,J＝8.0Hz,2H,[6.95minor isomer]),6.83(d,J＝8.0Hz,2H,[6.64minor isomer]),4.91(s,2H,[4.59minor isomer]),4.48(s,2H,[4.57minor isomer]),4.27-4.16(m,1H,[4.54-4.50minor isomer]),2.45-2.35(m,2H),1.56-1.42(m,2H),1.12(d,J＝6.4Hz,6H,[1.08minor isomer]),0.84(t,J＝7.2Hz,3H,partially overlapped,[0.82minor isomer partially overlapped]).HR-ESI-MS:m/z＝408.1992[M+H]+,calculated for C25H30NO2S:408.1992.
Example 25: compound 25
Figure BDA0002080693340000231
The synthesis was the same as in example 1 except that 3-pyridineboronic acid was changed to 2-thiopheneboronic acid and 4-n-propylphenoxyacetic acid was changed to 2-furancarboxylic acid.
1H NMR(400MHz,DMSO-d6)7.73-7.50(m,5H),7.47(d,J＝2.8Hz,1H),7.42(m,1H),7.37(t,J＝7.6Hz,2H),7.31(m,1H),7.25(d,J＝7.6Hz,1H),7.13(t,J＝4.4Hz,1H),4.76(br s,2H),4.55(m,1H),1.23(d,J＝6.4Hz,6H).HR-ESI-MS:m/z＝376.1364[M+H]+,calculated for C23H22NO2S:376.1366.
Example 26: compound 26
Figure BDA0002080693340000232
The synthesis was the same as in example 1 except that 3-bromobenzyl chloride was changed to 4-bromobenzyl chloride and 3-pyridineboronic acid was changed to 2-thiopheneboronic acid.
1H NMR(400MHz,DMSO-d6)7.48(d,J＝7.6Hz,2H,partially overlapped,[7.63minor isomer]),7.50-7.46(m,1H,partially overlapped),7.43-7.39(m,1H),7.16(d,J＝7.6Hz,2H,[7.30minor isomer]),7.07(d,J＝7.6Hz,2H,partially overlapped,[7.00minor isomer]),7.11-7.05(m,1H,partially overlapped),6.83(d,J＝8.0Hz,2H,[6.67minor isomer]),4.88(s,2H,[4.56minor isomer]),4.44(s,2H,[4.56minor isomer]),4.26-4.16(m,1H,[4.54-4.16minor isomer]),2.46-2.38(m,2H),1.59-1.42(m,2H),1.09(d,J＝6.4Hz,6H,[1.05minor isomer]),0.85(t,J＝7.2Hz,3H,partially overlapped,[0.83minor isomer,partially overlapped]).HR-ESI-MS:m/z＝408.1985[M+H]+,calculated for C25H30NO2S:408.1992.
Example 27: compound 27
Figure BDA0002080693340000241
The synthesis was the same as in example 1 except that 3-bromobenzyl chloride was changed to 4-bromobenzyl chloride, 3-pyridineboronic acid was changed to 2-thiopheneboronic acid, and 4-n-propylphenoxyacetic acid was changed to 4-phenoxyphenoxyphenoxyacetic acid.
1H NMR(400MHz,DMSO-d6)7.70-6.81(m,16H),4.97(s,2H,[4.64minor isomer]),4.49(s,2H,[4.59minor isomer]),4.30-4.22(m,1H,[4.58-4.51minor isomer]),1.14(d,J＝6.8Hz,6H,[1.10minor isomer]).HR-ESI-MS:m/z＝458.1781[M+H]+,calculated for C28H28NO3S:458.1784.
Example 28: compound 28
Figure BDA0002080693340000242
The synthesis was the same as in example 1 except that 3-bromobenzyl chloride was changed to 4-bromobenzyl chloride.
1H NMR(400MHz,DMSO-d6)8.80(s,1H,[8.83minor isomer]),8.51-8.46(m,1H),7.95(d,J＝8.0Hz,1H,[7.99minor isomer]),7.53(d,J＝8.0Hz,2H,[7.67minor isomer]),7.41-7.36(m,1H,partially overlapped),7.24(d,J＝7.6Hz,2H,[7.36minor isomer]),7.03(d,J＝8.0Hz,2H,[6.95minor isomer]),6.81(d,J＝8.0Hz,2H,[6.64minor isomer]),4.87(s,2H,[4.56minor isomer]),4.46(s,2H,[4.54minor isomer]),4.28-4.13(m,1H,[4.50minor isomer]),2.39(t,J＝7.6Hz,2H,partially overlapped[2.35minor isomer,partially overlapped]),1.45(m,2H),1.07(d,J＝6.4Hz,6H,[1.03minor isomer]),0.78(t,J＝7.2Hz,3H,partially overlapped[0.76minor isomer,partially overlapped]).HR-ESI-MS:m/z＝403.2377[M+H]+,calculated for C26H31N2O2:403.2380.
Example 29: compound 29
Figure BDA0002080693340000251
The synthesis was the same as in example 1 except that 3-bromobenzyl chloride was changed to 4-bromobenzyl chloride and 4-n-propylphenoxyacetic acid was changed to 4-phenoxyphenoxyphenoxyacetic acid.
1H NMR(400MHz,DMSO-d6)8.88(s,1H,[8.90minor isomer]),8.55(d,J＝4.0Hz,1H),8.03(d,J＝7.6Hz,1H,partially overlapped[8.07minor isomer partially overlapped]),7.62(d,J＝8.0Hz,2H,[7.76minor isomer]),7.49-7.41(m,2H),7.36-7.29(m,3H),7.06(t,J＝7.6Hz,1H),7.03-6.81(m,6H),4.99(s,2H,[4.65minor isomer]),4.54(s,2H,[4.65minor isomer]),4.32-4.20(m,1H,[4.59-4.55minor isomer]),1.16(d,J＝6.4Hz,6H,[1.11minor isomer]).HR-ESI-MS:m/z＝453.2173[M+H]+,calculated for C29H29N2O3:453.2173.
Pharmacological experiments
Experimental example 1: inhibition of the human 20s proteasome by the compounds of the invention
Reagent: cell lysate (lysis buffer, LB): 5mM HEPES (pH 7.8), 1mM DTT. Reaction Buffer (RB): 20mM HEPES (pH 7.8), 5mM EDTA, 0.04% SDS. Suc-LLVY-AMC stock solution: 10mM in DMSO, was diluted 50-fold with the reaction solution at the time of use.
And (3) proteasome extraction: SHSY5Y cells in the cell culture flask were first rinsed twice with ice-bath PBS, 300ul of cell lysate was added, and the cells in the flask were collected by cell scraping. After the cells are collected, the cells are broken by an ultrasonic method, the ultrasonic power is 30 percent, the ultrasonic is carried out for 3s, the ultrasonic is stopped for 5s, and the ultrasonic treatment is carried out for 2 min. And (4) after ultrasonic treatment, centrifuging at high speed at 12000rpm for 15min, and collecting supernatant to obtain the proteasome extracting solution. The protein concentration was determined. All operations were placed on ice.
And (3) inhibitor determination: adding 10 mul (25 mug) of proteasome extract into each hole of a 96-hole black enzyme label plate, adding 178 mul of reaction solution and 2 mul of sample to be detected or DMSO (control hole), incubating for 30min at room temperature, adding 10 mul of diluted substrate Suc-Leu-Leu-Val-Tyr-AMC (final concentration is 10 muM),after incubation for 1h at room temperature, detection was performed. Excitation wavelength 365nm and emission wavelength 465 nm. Inhibition% is (control well-sample well)/control well 100. The half effective Inhibitory Concentration (IC) of the compound of the present invention on the inhibition of the chymotrypsin-like active site (CT-L) of the human 20s proteasome was determined50) The results are shown in Table 1.
TABLE 1
Figure BDA0002080693340000261

Claims (14)

1. A triaryl compound represented by the following general formula (I) and a physiologically acceptable salt thereof,
Figure FDA0002080693330000011
wherein n is 0 or 1;
Ar1selected from:
Figure FDA0002080693330000012
R1is hydrogen, C1-C5Alkyl, substituted or unsubstituted phenoxy, the substituents being selected from C1-C3Alkyl radical, C1-C3Alkoxy and halogen;
r is selected from hydrogen and C1-C5An alkyl group;
Ar2selected from:
Figure FDA0002080693330000013
Ar3selected from:
Figure FDA0002080693330000014
2. the compound and physiologically acceptable salts according to claim 1, characterized in that said compound is represented by general formula (IA):
Figure FDA0002080693330000015
wherein n is 0 or 1;
Ar1selected from:
Figure FDA0002080693330000021
R1is hydrogen, C1-C5Alkyl, substituted or unsubstituted phenoxy, the substituents being taken from C1-C3Alkyl radical, C1-C3Alkoxy and halogen;
r is selected from hydrogen and C1-C5An alkyl group;
Ar3selected from:
Figure FDA0002080693330000022
3. a compound and physiologically acceptable salt according to claim 2, characterized in that said compound is of formula (IAa):
Figure FDA0002080693330000023
wherein n is 0 or 1;
Ar1selected from:
Figure FDA0002080693330000024
R1is hydrogen, C1-C5Alkyl, substituted or unsubstituted phenoxy, the substituents being taken from C1-C3Alkyl radical, C1-C3Alkoxy and halogen;
Ar3selected from:
Figure FDA0002080693330000025
4. the compound and physiologically acceptable salts according to claim 1, wherein said compound is represented by the general formula (IB):
Figure FDA0002080693330000031
wherein n is 0 or 1;
Ar1selected from:
Figure FDA0002080693330000032
R1is hydrogen, C1-C5Alkyl, substituted or unsubstituted phenoxy, the substituents being taken from C1-C3Alkyl radical, C1-C3Alkoxy and halogen;
r is selected from hydrogen and C1-C5An alkyl group;
Ar3selected from:
Figure FDA0002080693330000033
5. the compound and physiologically acceptable salts according to claim 4, characterized in that said compound is represented by the general formula (IBa):
Figure FDA0002080693330000034
wherein n is 0 or 1;
Ar1selected from:
Figure FDA0002080693330000041
R1is hydrogen, C1-C5Alkyl, substituted or unsubstituted phenoxy, the substituents being taken from C1-C3Alkyl radical, C1-C3Alkoxy and halogen;
Ar3selected from:
Figure FDA0002080693330000042
6. the compound and physiologically acceptable salts according to claim 1, characterized in that said compound is of the general formula (IC):
Figure FDA0002080693330000043
wherein n is 0 or 1;
Ar1selected from:
Figure FDA0002080693330000044
R1is hydrogen, C1-C5Alkyl, substituted or unsubstituted phenoxy, the substituents being taken from C1-C3Alkyl radical, C1-C3Alkoxy and halogen;
r is selected from hydrogen and C1-C5An alkyl group;
Ar3selected from:
Figure FDA0002080693330000045
7. the compound and physiologically acceptable salts according to claim 6, characterized in that said compound is of the general formula (ICa):
Figure FDA0002080693330000051
wherein n is 0 or 1;
Ar1selected from:
Figure FDA0002080693330000052
R1is hydrogen, C1-C5Alkyl, substituted or unsubstituted phenoxy, the substituents being taken from C1-C3Alkyl radical, C1-C3Alkoxy and halogen;
Ar3selected from:
Figure FDA0002080693330000053
8. the compound according to claim 1, wherein said compound is selected from the group consisting of:
Figure FDA0002080693330000054
Figure FDA0002080693330000061
Figure FDA0002080693330000071
9. a process for the preparation of a compound according to any one of claims 1 to 8, comprising the steps of:
the compound shown in the general formula (IA) is synthesized according to the following steps that substituted benzyl chloride is aminated firstly, then coupled and finally forms amide with acid;
Figure FDA0002080693330000081
the compound shown in the general formula (IB) is synthesized according to the following steps that substituted chloride is aminated firstly, then coupled and finally forms amide with acid;
Figure FDA0002080693330000082
the compound shown in the general formula (IC) is synthesized according to the following steps that substituted nitrile group is firstly condensed with hydroxylamine hydrochloride, then esterified, cyclized and aminated, and finally forms amide with acid;
Figure FDA0002080693330000083
10. a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 8, and physiologically acceptable salts thereof, and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is selected from the group consisting of tablets, capsules, pills, injections, sustained release formulations, controlled release formulations, and various microparticle delivery systems.
12. Use of a compound according to any one of claims 1 to 8 and physiologically acceptable salts thereof for the preparation of proteasome inhibitors.
13. Use of a compound according to any one of claims 1 to 8 and physiologically acceptable salts thereof for the manufacture of a medicament for the prevention or treatment of proteasome-related disorders.
14. The use of claim 13, wherein the disease comprises an autoimmune disease, inflammation, tumor.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4753674A (en) * 1981-10-20 1988-06-28 Ube Industries, Ltd. Herbicidal composition containing a phenoxyalkylamide derivative and method for controlling weeds by the use of the same
WO2010001365A1 (en) * 2008-07-04 2010-01-07 Institut National De La Sante Et De La Recherche Medicale (Inserm) Nitrogen heterocycle derivatives as proteasome modulators
US20110257176A1 (en) * 2008-07-04 2011-10-20 Institut National De La Sante Et De La Recherche Medicale (Inserm) Nitrogen heterocycle derivatives as proteasome modulators
WO2012129564A2 (en) * 2011-03-24 2012-09-27 H. Lee Moffitt Cancer Center And Research Institute, Inc. Proteasome chymotrypsin-like inhibition using pi-1833 analogs
US20180282280A1 (en) * 2017-03-31 2018-10-04 Board Of Trustees Of Michigan State University Quinoline-based proteasome inhibitors and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4753674A (en) * 1981-10-20 1988-06-28 Ube Industries, Ltd. Herbicidal composition containing a phenoxyalkylamide derivative and method for controlling weeds by the use of the same
WO2010001365A1 (en) * 2008-07-04 2010-01-07 Institut National De La Sante Et De La Recherche Medicale (Inserm) Nitrogen heterocycle derivatives as proteasome modulators
US20110257176A1 (en) * 2008-07-04 2011-10-20 Institut National De La Sante Et De La Recherche Medicale (Inserm) Nitrogen heterocycle derivatives as proteasome modulators
WO2012129564A2 (en) * 2011-03-24 2012-09-27 H. Lee Moffitt Cancer Center And Research Institute, Inc. Proteasome chymotrypsin-like inhibition using pi-1833 analogs
US20180282280A1 (en) * 2017-03-31 2018-10-04 Board Of Trustees Of Michigan State University Quinoline-based proteasome inhibitors and uses thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JIANJUN YU ET AL.: "Design, synthesis, and biological evaluation of novel phenol ether derivatives as noncovalent proteasome inhibitors", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *
SEVIL OZCAN ET AL.: "Oxadiazole-isopropylamides as potent and non-covalent proteasome inhibitors", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
YAJUNYANG ET AL.: "Design, synthesis and biological evaluation of triaryl compounds as novel 20S proteasome inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
来源于AURORA FINE CHEMICALS等提供的产品目录: "STN检索报告1", 《数据库REGISTRY（在线）》 *

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