CN116986985A - Chalcone derivative and application thereof - Google Patents
Chalcone derivative and application thereof Download PDFInfo
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- CN116986985A CN116986985A CN202310949941.9A CN202310949941A CN116986985A CN 116986985 A CN116986985 A CN 116986985A CN 202310949941 A CN202310949941 A CN 202310949941A CN 116986985 A CN116986985 A CN 116986985A
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- GVSPXQVUXHMUMA-MDWZMJQESA-N (e)-3-(3,5-ditert-butyl-4-hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)\C=C\C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 GVSPXQVUXHMUMA-MDWZMJQESA-N 0.000 title claims description 16
- 102000000874 Pyrin Domain-Containing 3 Protein NLR Family Human genes 0.000 claims abstract description 42
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- 150000003839 salts Chemical class 0.000 claims abstract description 17
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 150000001788 chalcone derivatives Chemical class 0.000 claims abstract description 12
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- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 208000027866 inflammatory disease Diseases 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000005619 boric acid group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
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- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 134
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 104
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 62
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 39
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 1
- 229960001350 tofacitinib Drugs 0.000 description 1
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Abstract
The invention discloses chalcone derivatives with a structure shown in a formula (I), pharmaceutically acceptable salts or stereoisomers thereof and application of the chalcone derivatives as active ingredients in preparation of NLRP3 inflammation small-body inhibitors and/or STATs pathway inhibitors. The compounds can selectively inhibit activation of NLRP3 inflammatory corpuscles and inhibit STATs pathway, so that diseases related to NLRP3 inflammatory corpuscles and/or STATs pathway can be treated or improved, for example: acute peritonitis and colitis, and thus can be used for preparing therapeutic drugs for diseases related to NLRP3 inflammatory bodies and/or STATs pathway.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to chalcone derivatives and application thereof.
Background
NLRP3 inflammatory corpuscles are NOD-like receptors, consisting of three parts, namely an inflammatory corpuscle sensor molecule (NLRP 3 protein), a linker protein ASC, and an effector molecule caspase-1 precursor protein (Pro-caspase-1), and are a multiprotein complex present in the cytosol. After activation of NLRP3 inflammatory corpuscles, pro-caspase-1 self-cleaves into active caspase-1, further cleavage of Pro-IL-1β and Pro-IL-18 into active interleukin-1β (IL-1β) and interleukin-18 (IL-18), ultimately leading to inflammatory response and apoptosis. Much evidence suggests that many human diseases, such as Alzheimer's disease, gout, multiple sclerosis, type II diabetes, inflammatory bowel disease, etc., are closely associated with NLRP3 inflammatory corpuscles. To date, a variety of NLRP3 inflammatory body inhibitors have been found, but none are clinically useful.
In addition, the JAK/STAT pathway is also a critical pro-inflammatory signal that can mediate the biological effects of a variety of cytokines in inflammatory diseases. Interference with JAK and STAT families is a new approach for some patients that do not respond to current therapies. For example, tofacitinib is a non-specific inhibitor of JAK, affecting a variety of pro-inflammatory cytokine-dependent and STAT-mediated pathways, and is useful in treating patients who fail or are intolerant to conventional or biological therapies, such as rheumatoid arthritis, ulcerative colitis, psoriasis, and other various inflammation-related diseases. Research on the effects of STAT proteins on uncontrolled inflammatory pathology has become an active area.
Thus, the discovery of novel dual inhibitors of the NLRP3 inflammatory body/STAT pathway is of great interest in the treatment of inflammation-related disorders.
Disclosure of Invention
In view of the above problems, the present invention provides chalcone derivatives, which can inhibit activation of NLRP3 inflammatory bodies and inhibit STAT pathway, so that diseases related to NLRP3 inflammatory bodies and/or STAT pathway can be treated or ameliorated, for example: acute peritonitis and colitis.
The invention comprises the following technical scheme:
chalcone derivatives with a structure shown in a formula (I) or pharmaceutically acceptable salts or stereoisomers thereof,
Wherein R is 1 And R is 2 Each independently selected from: H. -C (=o) OR 3 、-C(=O)N(R 4 ) 2 、-N(R 5 )-C(=O)R 6 ;
R 3 Selected from: H. c (C) 1 -C 6 An alkyl group;
each R is 4 Each independently selected from: H. one or more R 7 Substituted C 1 -C 6 Alkyl, one or more R 7 Substituted C 3 -C 6 Cycloalkyl;
R 5 selected from: H. c (C) 1 -C 6 An alkyl group;
R 6 selected from: one or more R 7 Substituted C 1 -C 6 Alkyl, one or more R 7 Substituted C 3 -C 6 Cycloalkyl;
each R is 7 Each independently selected from: H. -C (=o) OR 3 、C 6 -C 10 Aryl, C 6 -C 10 Arylmethyl, -C (=O) N (R) 8 ) 2 ;
Each R is 8 Each independently selected from: H. c (C) 1 -C 6 Alkyl, C 6 -C 10 Aryl, boric acid group substituted C 1 -C 8 An alkyl group;
alternatively, R 1 、R 2 And the carbon atoms to which they are attached together form a 5-10 membered heterocyclic group.
In some of these embodiments, R 1 And R is 2 Each independently selected from: H. -C (=o) OR 3 、-C(=O)N(R 4 ) 2 、-N(R 5 )-C(=O)R 6 ;
R 3 Selected from: H. c (C) 1 -C 3 An alkyl group;
each R is 4 Each independently selected from: H. one or more R 7 Substituted C 1 -C 3 An alkyl group;
R 5 selected from: H. c (C) 1 -C 3 An alkyl group;
R 6 selected from: one or more R 7 A substituted cyclopropyl group;
each R is 7 Each independently selected from: H. -C (=o) OR 3 Phenyl, benzyl, -C (=o) N (R) 8 ) 2 ;
Each R is 8 Each independently selected from: H. c (C) 1 -C 3 Alkyl, phenyl, boric acid group substituted C 3 -C 6 An alkyl group;
alternatively, R 1 、R 2 And the carbon atoms to which they are attached together form an 8-10 membered heterocyclic group.
In some of these embodiments, R 1 And R is 2 Each independently selected from: H. -C (=o) OR 3 、-C(=O)N(R 4 ) 2 、-N(R 5 )-C(=O)R 6 ;
R 3 Selected from: methyl, ethyl;
each R is 4 Each independently selected from: H. one or more R 7 Substituted methyl;
R 5 selected from: h is formed;
R 6 selected from: one or more R 7 A substituted cyclopropyl group;
each R is 7 Each independently selected from: H. -C (=o) OR 3 Carboxyl, benzyl, -C (=O) N (R) 8 ) 2 ;
Each R is 8 Each independently selected from: H. methyl, ethyl, boric acid group substituted isopentyl;
alternatively, R 1 、R 2 And the carbon atoms to which they are attached together form an 8-membered heterocyclic group.
In some of these embodiments, R 4 One of which is H and the other is not H.
In some of these embodiments, there is one R 7 In the case of carboxyl, R 7 Is 2 and another R 7 Selected from: -C (=o) OR 3 Benzyl, -C (=o) N (R) 8 ) 2 。
In some of these embodiments, R 2 Is H and R 1 Is not H.
The invention also provides application of the chalcone derivative or pharmaceutically acceptable salt or stereoisomer thereof, which comprises the following technical scheme:
the chalcone derivative or the pharmaceutically acceptable salt or the stereoisomer thereof is applied to the preparation of NLRP3 inflammation small body inhibitor and/or STAT channel inhibitor.
The chalcone derivative or the pharmaceutically acceptable salt or the stereoisomer thereof is applied to the preparation of medicaments for preventing and/or treating diseases related to NLRP3 inflammatory corpuscles and/or STAT paths.
In some of these embodiments, the disease associated with NLRP3 inflammatory bodies and/or STAT pathways is an inflammatory disease, alzheimer's disease, gout, multiple sclerosis, type II diabetes.
In some embodiments, the inflammatory disease is inflammatory bowel disease, rheumatoid arthritis, psoriasis.
In some of these embodiments, the inflammatory disease is peritonitis and colitis.
In some embodiments, the peritonitis is acute peritonitis.
The invention also provides a pharmaceutical composition for preventing and treating inflammatory diseases, which comprises the following technical scheme:
a pharmaceutical composition for preventing and treating inflammatory diseases is prepared from active ingredients and pharmaceutically acceptable auxiliary materials, wherein the active ingredients comprise chalcone derivatives or pharmaceutically acceptable salts or stereoisomers thereof.
The chalcone derivative or the pharmaceutically acceptable salt thereof provided by the invention can selectively inhibit the activation of NLRP3 inflammatory corpuscles and inhibit STAT channels, so that diseases related to the NLRP3 inflammatory corpuscles and/or the STAT channels can be treated or improved, for example: acute peritonitis and colitis, and thus can be used for preparing therapeutic drugs for diseases related to NLRP3 inflammatory bodies and/or STAT pathways.
Drawings
FIG. 1 is a graph showing the results of compound 10v inhibiting activation of NLRP3 inflammasome in vitro; wherein A is a Western blot analysis result, B is a secretion result of IL-1 beta in a BMDMs cell model activated by NLRP3 inflammation bodies, C is a secretion result of IL-1 beta in a BMDMs cell model activated by NLRC4 inflammation bodies, and D is a secretion result of IL-1 beta in a BMDMs cell model activated by AIM2 inflammation bodies.
FIG. 2 is a graph showing the results of inhibition of NLRP3 inflammatory corpuscle assembly and STATs protein expression by compound 10 v.
Fig. 3 is a graph showing the results of compound 10v in improving Dextran Sodium Sulfate (DSS) induced colitis.
FIG. 4 shows the results of pathological sections of colon tissue of mice.
Detailed Description
In the compounds of the invention, when any variable (e.g., R 4 Etc.) occur more than once in any component, the definition of each occurrence is independent of the definition of each other occurrence. Also, combinations of substituents and variables are permissible provided that such combinations stabilize the compounds. The lines drawn from the substituents into the ring system indicate that the bond referred to may be attached to any substitutable ring atom. If the ring system is polycyclic, it means that such bonds are only attached to any suitable carbon atom adjacent to the ring. It is to be understood that substituents and substitution patterns of the compounds of this invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that may be readily synthesized from readily available starting materials by techniques in the art and methods set forth below. If the substituent itself is substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, as long as the structure is stabilized.
The term "alkyl" as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C 1 -C 6 Alkyl "medium" C 1 -C 6 The definition of "includes those having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangementAnd a group of atoms. For example, "C 1 -C 6 The alkyl group includes, in particular, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl.
The term "heterocyclyl" as used herein is a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent (including monocyclic, spiro, fused, bridged, etc.) wherein one or more ring atoms are selected from the group consisting of heteroatoms of N, O or S (O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
The starting materials in the following examples may be obtained commercially, or prepared by methods known in the art, or prepared according to the methods described herein.
The synthetic route of the compound of the invention is as follows:
the synthesis reaction conditions of chalcone derivatives include (a) DMAP, DIPEA, dichloromethane and room temperature; (b) sodium hydroxide, methanol, room temperature; (c) 1M aqueous hydrochloric acid, methanol, 60 ℃; (d) concentrated sulfuric acid, ethanol, 60 ℃; (e) Various amino acid methyl esters, DIPEA, HATU, dichloromethane, from 0 ℃ to room temperature; (f) lithium hydroxide, water, methanol, room temperature; (g) Various aminoacetamides, EDCI-HCl, HOBt, DIPEA, dichloromethane, from 0deg.C to room temperature; (h) trifluoroacetic acid, dichloromethane, room temperature; (i) Isobutyl boric acid, 1M aqueous hydrochloric acid, n-hexane/methanol.
The following are specific examples.
Example 1 (E) -Synthesis of 4- (3- (4-hydroxy-3, 5-dimethylphenyl) acryloyl) benzoic acid (5 a):
(1) 3, 5-dimethyl-p-hydroxybenzaldehyde (1) (1.0 equiv.) and DCM are mixed with each other, DIPEA (2.0 equiv.) and DAMP (0.03 equiv.) are added to the mixture, stirred uniformly, chloromethyl ether (2.0 equiv.) is then added dropwise under the condition of ice-water bath, the reaction is gradually restored to room temperature for 3h, and TLC detects the progress of the reaction. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give the product (2) (PE: ea=6:1).
(2) P-acetyl benzoic acid (3 a) (1.0 equiv.) and MeOH were mixed well, then NaOH saturated solution (2.0 equiv.) was added, stirring was performed, the product (2) obtained in step (1) was added dropwise to the solution after 10min, the reaction was performed for 24h at room temperature, and the progress of the reaction was checked by TLC. Subsequently, meOH in the solution was removed by evaporation under reduced pressure, and the pH of the remaining solution was adjusted to be acidic with 1M hydrochloric acid until a large amount of pale yellow solid was precipitated, and the residue was filtered and washed three times with water to give pale yellow solid (4 a).
(3) The product (4 a) from step (2) was mixed with MeOH, followed by dropwise addition of 1MHCl (2.0 equiv.) and reflux with heating in an oil bath at 60 ℃ for 1h, and the progress of the reaction was checked by TLC. After completion of the reaction, the solvent was removed by evaporation under reduced pressure, dried over anhydrous sodium sulfate, filtered, and the residue was isolated and purified by column chromatography (DCM: meoh=10:1) to give a yellow solid (5 a), yield: 58%. 1 HNMR(400MHz,DMSO-d 6 ) δ8.20-8.13 (m, 2H), 8.08-8.02 (m, 2H), 7.69 (d, j=15.5 hz, 1H), 7.61 (d, j=15.5 hz, 1H), 7.48 (s, 2H), 2.17 (s, 6H). HRMS (ESI) calculated: c (C) 18 H 16 O 4 [M+H] + 297.1082 experimental values: 297.1122.
example 2 synthesis of ethyl (E) -4- (3- (4-hydroxy-3, 5-dimethylphenyl) acryloyl) benzoate (5 b):
(1) 3, 5-dimethyl-p-hydroxybenzaldehyde (1) (1.0 equiv.) and DCM are mixed with each other, DIPEA (2.0 equiv.) and DAMP (0.03 equiv.) are added to the mixture, stirred uniformly, chloromethyl ether (2.0 equiv.) is then added dropwise under the condition of ice-water bath, the reaction is gradually restored to room temperature for 3h, and TLC detects the progress of the reaction. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give the product (2) (PE: ea=6:1).
(2) P-acetyl benzoic acid (3 a) (1.0 equiv.) and MeOH were mixed well, then NaOH saturated solution (2.0 equiv.) was added, stirring was performed, the product (2) obtained in step (1) was added dropwise to the solution after 10min, the reaction was performed for 24h at room temperature, and the progress of the reaction was checked by TLC. Subsequently, meOH in the solution was removed by evaporation under reduced pressure, and the pH of the remaining solution was adjusted to be acidic with 1M hydrochloric acid until a large amount of pale yellow solid was precipitated, and the residue was filtered and washed three times with water to give pale yellow solid (4 a).
(3) Mixing the carboxylic acid (4 a) obtained in the step (2) with ethanol uniformly, adding concentrated sulfuric acid (3.0 equiv), heating and refluxing in an oil bath at 60 ℃ for 4h, and detecting the reaction progress by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure, extracted with EA and water, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, and the obtained residue was isolated and purified by column chromatography to give white solid (5 b) (PE: ea=3:1) in 98% yield. 1 HNMR(400MHz,Methanol-d 4 ) δ8.12 (d, j=8.0 hz, 2H), 8.08 (d, j=8.0 hz, 2H), 7.68 (d, j=15.7 hz, 1H), 7.50 (d, j=15.6, 3.0hz, 1H), 7.34 (s, 2H), 4.37 (q, j=7.2 hz, 2H), 2.21 (s, 6H), 1.38 (t, j=7.1 hz, 3H); HRMS (ESI) calculated: c (C) 20 H 20 O 4 [M+H] + 325.1395 experimental values: 325.1432.
example 3: (E) Synthesis of (7) 3- (4-hydroxy-3, 5-dimethylphenyl) -1- (3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ] -5' -yl) prop-2-en-1-one:
(1) 3, 5-dimethyl-p-hydroxybenzaldehyde (1) (1.0 equiv.) and DCM are mixed with each other, DIPEA (2.0 equiv.) and DAMP (0.03 equiv.) are added to the mixture, stirred uniformly, chloromethyl ether (2.0 equiv.) is then added dropwise under the condition of ice-water bath, the reaction is gradually restored to room temperature for 3h, and TLC detects the progress of the reaction. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give the product (2) (PE: ea=6:1).
(2) Tert-butyl 5' -acetyl-3 ' h-spiro [ azetidine-3, 1' -isobenzofuran ] -1-carboxylate (6) (1.0 equiv.) is mixed with product (2) of step (1) in MeOH followed by addition of NaOH saturated solution (2.0 equiv.), stirring, reaction for 24h at room temperature and tlc detection of the progress of the reaction. MeOH in the solution was then removed by evaporation under reduced pressure and the resulting product (7 a) was purified by thin layer chromatography (DCM: meoh=10:1).
(3) The product (7 a) obtained in step (2) was dissolved in DCM, trifluoroacetic acid (10 equiv) was added and reacted under stirring at room temperature for 4h, rotary evaporation, extraction with EA and water, the organic layers were combined, dried and the product was purified by thin layer chromatography to give pale yellow solid (7) in 63% yield. 1 HNMR(400MHz,CD 3 OD) δ8.13 (d, j=8.0 hz, 1H), 7.98 (s, 1H), 7.83 (d, j=7.9 hz, 1H), 7.69 (d, j=15.5 hz, 1H), 7.52 (d, j=15.5 hz, 1H), 7.35 (s, 2H), 5.21 (s, 2H), 4.50 (d, j=11.8 hz, 2H), 4.44 (d, j=11.9 hz, 2H), 2.22 (s, 6H); HRMS (ESI) calculated: c (C) 21 H 21 NO 3 [M+H] + 336.1555 experimental values: 336.1593.
example 4: synthesis of methyl (4- (3- (4-hydroxy-3, 5-dimethylphenyl) acryloyl) phenyl) carbamoyl) cyclopropane-1-carboxylate (5 d):
(1) 3, 5-dimethyl-p-hydroxybenzaldehyde (1) (1.0 equiv.) and DCM are mixed with each other, DIPEA (2.0 equiv.) and DAMP (0.03 equiv.) are added to the mixture, stirred uniformly, chloromethyl ether (2.0 equiv.) is then added dropwise under the condition of ice-water bath, the reaction is gradually restored to room temperature for 3h, and TLC detects the progress of the reaction. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give the product (2) (PE: ea=6:1).
(2) P-acetyl-benzyl amine (3 c) (1.0 equiv.) and MeOH were mixed well, then NaOH saturated solution (2.0 equiv.) was added, stirring was performed, the product obtained in step (1) was added dropwise to the solution after 10min, the reaction was performed for 24h at room temperature, and TLC was used to detect the progress of the reaction. Subsequently, meOH was removed from the solution by evaporation under reduced pressure, and the pH of the remaining solution was adjusted to be acidic with 1M hydrochloric acid until a large amount of pale yellow solid was precipitated, and the residue was filtered and washed three times with water to give pale yellow solid (4 c).
(3) Uniformly mixing 1, 1-cyclopropyl dicarboxylic acid monomethyl ester (1.0 equiv.) with HATU and DCM, stirring at room temperature for reaction for 30min, then adding the compound (4 c) (1.2 equiv.) obtained in step (2), reacting at room temperature for 10min, adding DIPEA (3.0 equiv.) and stirring at room temperature for reaction for 4h, and detecting the reaction progress by TLC. After completion of the reaction, the solvent was removed by evaporation under reduced pressure, redissolved with EA with 3% aqueous citric acid and saturated NaHCO, respectively 3 The aqueous solution and the mixture were extracted three times, respectively, the organic layer was retained, dried over anhydrous sodium sulfate, filtered, and the obtained residue was separated and purified by column chromatography to give a pale yellow solid (4 d).
(4) The product (4 d) from step (3) was mixed with MeOH, followed by dropwise addition of 1M HCl (2.0 equiv.) and reflux with heating in an oil bath at 60 ℃ for 1h, and the progress of the reaction was checked by TLC. After the completion of the reaction, the solvent was removed by evaporation under reduced pressure, dried over anhydrous sodium sulfate, filtered, and the residue was isolated and purified by column chromatography to give a dark yellow solid (5 d) in 85% yield. 1 HNMR(400MHz,DMSO-d 6 ) δ10.63 (s, 1H), 8.07 (dd, j=8.8, 2.0hz, 2H), 7.73 (dd, j=8.8, 2.0hz, 2H), 7.67 (d, j=15.5 hz, 1H), 7.54 (d, j=15.4 hz, 1H), 7.43 (s, 2H), 3.64 (s, 3H), 2.16 (s, 6H), 1.44-1.39 (m, 2H), 1.39-1.33 (m, 2H); HRMS (ESI) calculated: c (C) 23 H 23 NO 5 [M+H] + 394.1610 experimental values: 394.1647.
example 5: synthesis of methyl (4- (3- (4-hydroxy-3, 5-dimethylphenyl) acryloyl) benzoyl) glycinate (5 e):
(1) 3, 5-dimethyl-p-hydroxybenzaldehyde (1) (1.0 equiv.) and DCM are mixed with each other, DIPEA (2.0 equiv.) and DAMP (0.03 equiv.) are added to the mixture, stirred uniformly, chloromethyl ether (2.0 equiv.) is then added dropwise under the condition of ice-water bath, the reaction is gradually restored to room temperature for 3h, and TLC detects the progress of the reaction. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give the product (2) (PE: ea=6:1).
(2) P-acetyl benzoic acid (3 a) (1.0 equiv.) and MeOH were mixed well, then NaOH saturated solution (2.0 equiv.) was added, stirring was performed, the product obtained in step (1) was added dropwise to the solution after 10min, the reaction was performed for 24h at room temperature, and TLC was used to detect the progress of the reaction. Subsequently, meOH in the solution was removed by evaporation under reduced pressure, and the pH of the remaining solution was adjusted to be acidic with 1M hydrochloric acid until a large amount of pale yellow solid was precipitated, and the residue was filtered and washed three times with water to give pale yellow solid (4 a).
(3) The carboxylic acid (4 a) of step (2) was mixed with HATU, DCM and reacted under stirring at room temperature for 30min, followed by addition of glycine methyl ester hydrochloride (1.2 equiv.) and reaction at room temperature for 10min, followed by addition of DIPEA (3.0 equiv.) and reaction under stirring at room temperature for 4h, and tlc was used to detect the progress of the reaction. After completion of the reaction, the solvent was removed by evaporation under reduced pressure, redissolved with EA with 3% aqueous citric acid and saturated NaHCO, respectively 3 The aqueous solution and the mixture were extracted three times, respectively, the organic layer was retained, dried over anhydrous sodium sulfate, filtered, and the obtained residue was separated and purified by column chromatography to give pale yellow solid (4 e).
(4) The product (4 e) from step (3) was mixed with MeOH, followed by dropwise addition of 1M HCl (2.0 equiv.) and reflux in an oil bath at 60 ℃ for 1h, and the progress of the reaction was checked by TLC. After the completion of the reaction, the solvent was removed by evaporation under reduced pressure, dried over anhydrous sodium sulfate, filtered, and the residue was isolated and purified by column chromatography to give a yellow solid (5 e) in 65% yield. 1 HNMR(400MHz,CD 3 OD) δ9.17 (t, j=5.9 hz, 1H), 8.24-8.18 (m, 2H), 8.04-7.98 (m, 2H), 7.73 (d, j=15.4 hz, 1H), 7.65 (d, j=15.4 hz, 1H), 7.51 (s, 2H), 4.06 (d, j=5.7 hz, 2H), 3.67 (s, 3H), 2.21 (s, 6H); HRMS (ESI) calculated: c (C) 21 H 21 NO 5 [M+H] + 368.1453 experimental values: 368.1493.
example 6: (E) Synthesis of- (4- (3- (4-hydroxy-3, 5-dimethylphenyl) acryloyl) benzoyl) glycine (5 f):
(1) 3, 5-dimethyl-p-hydroxybenzaldehyde (1) (1.0 equiv.) and DCM are mixed with each other, DIPEA (2.0 equiv.) and DAMP (0.03 equiv.) are added to the mixture, stirred uniformly, chloromethyl ether (2.0 equiv.) is then added dropwise under the condition of ice-water bath, the reaction is gradually restored to room temperature for 3h, and TLC detects the progress of the reaction. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give the product (2) (PE: ea=6:1).
(2) P-acetyl benzoic acid (3 a) (1.0 equiv.) and MeOH were mixed well, then NaOH saturated solution (2.0 equiv.) was added, stirring was performed, the product (2) obtained in step (1) was added dropwise to the solution after 10min, the reaction was performed for 24h at room temperature, and the progress of the reaction was checked by TLC. Subsequently, meOH in the solution was removed by evaporation under reduced pressure, and the pH of the remaining solution was adjusted to be acidic with 1M hydrochloric acid until a large amount of pale yellow solid was precipitated, and the residue was filtered and washed three times with water to give pale yellow solid (4 a).
(3) The carboxylic acid (4 a) of step (2) was mixed with HATU, DCM and reacted under stirring at room temperature for 30min, followed by addition of glycine methyl ester hydrochloride (1.2 equiv.) and reaction at room temperature for 10min, followed by addition of DIPEA (3.0 equiv.) and reaction under stirring at room temperature for 4h, and tlc was used to detect the progress of the reaction. After completion of the reaction, the solvent was removed by evaporation under reduced pressure, redissolved with EA with 3% aqueous citric acid and saturated NaHCO, respectively 3 The aqueous solution and the mixture were extracted three times, respectively, the organic layer was retained, dried over anhydrous sodium sulfate, filtered, and the obtained residue was isolated and purified by column chromatography (DCM) to give pale yellow solid (4 e).
(4) The methyl ester (4 e) synthesized in step (3) was mixed with MeOH and stirred well, an aqueous LiOH solution (2.0 equiv.) was added, the reaction was stirred at room temperature for 4h, and tlc detected the progress of the reaction. After completion of the reaction, the pH was adjusted to be acidic with 1M HCl, and a large amount of solid was precipitated and collected to give a yellow solid (4 f). Mixing the collected 4f with methanol, adding 1M HCl to make the solution acidic,reflux under heating at 60 ℃ for 1h, solvent was removed by evaporation under reduced pressure, the products were extracted with EA and water, the combined organic layers were dried over anhydrous sodium sulfate and obtained as a yellow solid (5 f) by thin layer chromatography (DCM: meoh=10:1) in 52% yield. 1 HNMR(400MHz,DMSO-d 6 ) δ9.00 (t, j=5.9 hz, 1H), 8.16 (d, j=8.2 hz, 2H), 7.97 (d, j=8.2 hz, 2H), 7.69 (d, j=15.5 hz, 1H), 7.60 (d, j=15.4 hz, 1H), 7.46 (s, 2H), 3.91 (d, j=4.9 hz, 2H), 2.16 (s, 6H); HRMS (ESI) calculated: c (C) 20 H 19 NO 5 [M+H] + 354.1297 experimental values: 354.1334.
example 7: synthesis of methyl (4- (3- (4-hydroxy-3, 5-dimethylphenyl) acryloyl) benzoyl) phenylalanine (5 g):
(1) 3, 5-dimethyl-p-hydroxybenzaldehyde (1) (1.0 equiv.) and DCM are mixed with each other, DIPEA (2.0 equiv.) and DAMP (0.03 equiv.) are added to the mixture, stirred uniformly, chloromethyl ether (2.0 equiv.) is then added dropwise under the condition of ice-water bath, the reaction is gradually restored to room temperature for 3h, and TLC detects the progress of the reaction. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give the product (2) (PE: ea=6:1).
(2) P-acetyl benzoic acid (3 a) (1.0 equiv.) and MeOH were mixed well, then NaOH saturated solution (2.0 equiv.) was added, stirring was performed, the product (2) obtained in step (1) was added dropwise to the solution after 10min, the reaction was performed for 24h at room temperature, and the progress of the reaction was checked by TLC. Subsequently, meOH in the solution was removed by evaporation under reduced pressure, and the pH of the remaining solution was adjusted to be acidic with 1M hydrochloric acid until a large amount of pale yellow solid was precipitated, and the residue was filtered and washed three times with water to give pale yellow solid (4 a).
(3) The carboxylic acid (4 a) of step (2) was mixed with HATU, DCM and reacted under stirring at room temperature for 30min, followed by addition of L-phenylalanine methyl ester hydrochloride (1.2 equiv.) and reaction at room temperature for 10min, addition of DIPEA (3.0 equiv.) and reaction stirred at room temperature for 4h, tlc detected the progress of the reaction. After the reaction is completed, the solvent is removed by reduced pressure evaporation,redissolving with EA with 3% aqueous citric acid and saturated NaHCO, respectively 3 The aqueous solution and the mixture were extracted three times, respectively, and the organic layer was retained, dried over anhydrous sodium sulfate, filtered, and the obtained residue was isolated and purified by column chromatography (DCM) to give a pale yellow solid (4 g).
(4) The product from step (3) (4 g) was mixed with MeOH, followed by dropwise addition of 1M HCl (2.0 equiv.) and reflux with heating in an oil bath at 60 ℃ for 1h, and the progress of the reaction was checked by TLC. After completion of the reaction, the solvent was removed by evaporation under reduced pressure, dried over anhydrous sodium sulfate, filtered, and the residue was isolated and purified by column chromatography to give a yellow solid (5 g) in 86% yield. 1 HNMR(400MHz,DMSO-d 6 ) δ9.04 (d, j=7.8 hz, 1H), 8.94 (s, 1H), 8.14 (d, j=8.0 hz, 2H), 7.89 (d, j=7.9 hz, 2H), 7.68 (j=15.4 hz, 1H), 7.60 j=15.4 hz, 1H), 7.47 (s, 2H), 7.31-7.20 (m, 5H), 7.19-7.13 (m, 1H), 4.70-4.60 (m, 1H), 3.61 (s, 3H), 2.17 (s, 6H); HRMS (ESI) calculated: c (C) 28 H 27 NO 5 [M+H] + 458.1923 experimental values: 458.1959.
example 8: (E) Synthesis of- (4- (3- (4-hydroxy-3, 5-dimethylphenyl) acryloyl) benzoyl) phenylalanine (5 h):
(1) 3, 5-dimethyl-p-hydroxybenzaldehyde (1) (1.0 equiv.) and DCM are mixed with each other, DIPEA (2.0 equiv.) and DAMP (0.03 equiv.) are added to the mixture, stirred uniformly, chloromethyl ether (2.0 equiv.) is then added dropwise under the condition of ice-water bath, the reaction is gradually restored to room temperature for 3h, and TLC detects the progress of the reaction. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give the product (2) (PE: ea=6:1).
(2) P-acetyl benzoic acid (3 a) (1.0 equiv.) and MeOH were mixed well, then NaOH saturated solution (2.0 equiv.) was added, stirring was performed, the product (2) obtained in step (1) was added dropwise to the solution after 10min, the reaction was performed for 24h at room temperature, and the progress of the reaction was checked by TLC. Subsequently, meOH in the solution was removed by evaporation under reduced pressure, and the pH of the remaining solution was adjusted to be acidic with 1M hydrochloric acid until a large amount of pale yellow solid was precipitated, and the residue was filtered and washed three times with water to give pale yellow solid (4 a).
(3) The carboxylic acid (4 a) of step (2) was mixed with HATU, DCM and reacted under stirring at room temperature for 30min, followed by addition of L-phenylalanine methyl ester hydrochloride (1.2 equiv.) and reaction at room temperature for 10min, addition of DIPEA (3.0 equiv.) and reaction stirred at room temperature for 4h, tlc detected the progress of the reaction. After completion of the reaction, the solvent was evaporated under reduced pressure, redissolved with EA, extracted three times with 3% aqueous citric acid and saturated aqueous NaHCO3, respectively, and the organic layer was retained, dried over anhydrous sodium sulfate, filtered, and the obtained residue was isolated and purified by column chromatography (DCM) to give pale yellow solid (4 g).
(4) Methyl ester (4 g) synthesized in step (3) was mixed with MeOH and stirred well, aqueous LiOH (2.0 equiv.) was added, the reaction was stirred at room temperature for 4h, and tlc detected the progress of the reaction. After the reaction was completed, the pH was adjusted to be acidic with 1M HCl, and a large amount of solid was precipitated and collected to give a yellow solid (4 h). The collected solid was mixed with methanol for 4h, 1M HCl was added to make the solution acidic, heated at 60 ℃ under reflux for 1h, the solvent was removed by evaporation under reduced pressure, the product was extracted with EA and water, the organic layers were combined, dried over anhydrous sodium sulfate, and the yellow solid (5 h) was obtained by thin layer chromatography (DCM: meoh=10:1) in 75% yield. 1 HNMR(400MHz,DMSO-d 6 ) Delta 8.99 (s, 1H), 8.92 (d, j=8.2 hz, 1H), 8.18-8.11 (m, 2H), 7.93-7.86 (m, 2H), 7.69 (d, j=15.4 hz, 1H), 7.60 (d, j=15.4 hz, 1H), 7.48 (s, 2H), 7.33-7.22 (m, 4H), 7.20-7.11 (m, 1H), 4.66-4.56 (m, 1H), 3.23-3.14 (m, 1H), 3.10-3.00 (m, 1H), 2.18 (s, 6H); HRMS (ESI) calculated: c (C) 27 H 25 NO 5 [M+H] + 444.1766 experimental values: 444.1805.
example 9: synthesis of 4- (3- (4-hydroxy-3, 5-dimethylphenyl) acryloyl) -N- (2-methylamino) -2-oxoethylbenzamide (5 i):
(1) 3, 5-dimethyl-p-hydroxybenzaldehyde (1) (1.0 equiv.) and DCM are mixed with each other, DIPEA (2.0 equiv.) and DAMP (0.03 equiv.) are added to the mixture, stirred uniformly, chloromethyl ether (2.0 equiv.) is then added dropwise under the condition of ice-water bath, the reaction is gradually restored to room temperature for 3h, and TLC detects the progress of the reaction. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give the product (2) (PE: ea=6:1).
(2) P-acetyl benzoic acid (3 a) (1.0 equiv.) and MeOH were mixed well, then NaOH saturated solution (2.0 equiv.) was added, stirring was performed, the product (2) obtained in step (1) was added dropwise to the solution after 10min, the reaction was performed for 24h at room temperature, and the progress of the reaction was checked by TLC. Subsequently, meOH in the solution was removed by evaporation under reduced pressure, and the pH of the remaining solution was adjusted to be acidic with 1M hydrochloric acid until a large amount of pale yellow solid was precipitated, and the residue was filtered and washed three times with water to give pale yellow solid (4 a).
(3) Uniformly mixing the carboxylic acid (4 a) in the step (2) with HOBt and DCM, stirring in an ice water bath for 10min, then adding EDCI, continuously stirring under the ice water bath for 30min, further adding 2-amino-N-methylacetamide (1.2 equiv.), continuously stirring for 10min, finally adding DIPEA, stirring in the ice water bath for 1h, recovering to room temperature, reacting for 4h, and detecting the reaction progress by TLC. After completion of the reaction, the solvent was removed by evaporation under reduced pressure, redissolved with EA, and quenched with 3% aqueous citric acid and saturated NaHCO, respectively 3 The organic phase was dried over anhydrous sodium sulfate and filtered, and the residue was isolated and purified by thin layer chromatography (DCM: meoh=10:1) to give a pale yellow solid (4 i).
(4) The product obtained in step (3) was dissolved in MeOH, pH was adjusted to be acidic with 1M HCl, and the reaction was stirred at 60 ℃ for 1h, a large amount of solid was precipitated, and filtered to obtain yellow solid (5 i) in 63% yield. 1 HNMR(400MHz,DMSO-d 6 ) Delta 8.97-8.86 (m, 2H), 8.20-8.13 (m, 2H), 8.03-7.96 (m, 2H), 7.83 (d, j=4.6 hz, 1H), 7.71 (d, j=15.5 hz, 1H), 7.60 (d, j=15.5 hz, 1H), 7.48 (s, 2H), 3.81 (d, j=5.9 hz, 2H), 2.56 (d, j=4.5 hz, 3H), 2.17 (s, 6H); HRMS (ESI) calculated: c (C) 21 H 22 N 2 O 4 [M+Na] + 389.1477 experimental values: 389.1471.
example 10: (E) Synthesis of (5 j) N- (2-ethylamino) -2-oxoethyl) -4- (3- (4-hydroxy-3, 5-dimethylphenyl) acryloyl) benzamide:
(1) 3, 5-dimethyl-p-hydroxybenzaldehyde (1) (1.0 equiv.) and DCM are mixed with each other, DIPEA (2.0 equiv.) and DAMP (0.03 equiv.) are added to the mixture, stirred uniformly, chloromethyl ether (2.0 equiv.) is then added dropwise under the condition of ice-water bath, the reaction is gradually restored to room temperature for 3h, and TLC detects the progress of the reaction. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give the product (2) (PE: ea=6:1).
(2) P-acetyl benzoic acid (3 a) (1.0 equiv.) and MeOH were mixed well, then NaOH saturated solution (2.0 equiv.) was added, stirring was performed, the product (2) obtained in step (1) was added dropwise to the solution after 10min, the reaction was performed for 24h at room temperature, and the progress of the reaction was checked by TLC. Subsequently, meOH in the solution was removed by evaporation under reduced pressure, and the pH of the remaining solution was adjusted to be acidic with 1M hydrochloric acid until a large amount of pale yellow solid was precipitated, and the residue was filtered and washed three times with water to give pale yellow solid (4 a).
(3) The carboxylic acid (4 a) of step (2) was mixed with HATU, DCM and reacted under stirring at room temperature for 30min, followed by addition of glycine methyl ester hydrochloride (1.2 equiv.) and reaction at room temperature for 10min, followed by addition of DIPEA (3.0 equiv.) and reaction under stirring at room temperature for 4h, and tlc was used to detect the progress of the reaction. After completion of the reaction, the solvent was removed by evaporation under reduced pressure, redissolved with EA with 3% aqueous citric acid and saturated NaHCO, respectively 3 The aqueous solution and the mixture were extracted three times, respectively, the organic layer was retained, dried over anhydrous sodium sulfate, filtered, and the obtained residue was isolated and purified by column chromatography (DCM) to give pale yellow solid (4 e).
(4) The methyl ester (4 e) synthesized in step (3) was mixed with MeOH and stirred well, an aqueous LiOH solution (2.0 equiv.) was added, the reaction was stirred at room temperature for 4h, and tlc detected the progress of the reaction. After completion of the reaction, the pH was adjusted to neutral with 1M HCl, extracted three times with EA, the organic layers were combined and the solvent was evaporated to give a pale yellow solid (4 f).
(5) CollectingThe pale yellow solid (4 f) is obtained, evenly mixed with HOBt and DCM, stirred in an ice-water bath at 0 ℃ for 10min, then EDCI is added, stirring is continued for 30min under the ice-water bath, ethylamine hydrochloride is added, stirring is continued for 10min, DIPEA is added finally, stirring is carried out for 1h under the ice-water bath, the reaction is carried out for 4h at room temperature, and TLC detects the reaction progress. After completion of the reaction, the solvent was removed by evaporation under reduced pressure, redissolved with EA with 3% aqueous citric acid and saturated NaHCO, respectively 3 The mixture was extracted three times, the organic layer was retained, dried over anhydrous sodium sulfate and filtered, and the obtained residue was isolated and purified by thin layer chromatography (DCM: meoh=10:1) to give a pale yellow solid (4 j).
(6) The product (4 j) obtained in step (5) was dissolved in MeOH, pH was adjusted to be acidic with 1M HCl, and the reaction was stirred at 60 ℃ for 1h, a large amount of solid was precipitated, and the product was filtered to obtain a dark yellow solid (5 j) in 26% yield. 1 HNMR(400MHz,DMSO-d 6 ) Delta 8.97 (s, 1H), 8.91 (t, j=6.0 hz, 1H), 8.22-8.15 (m, 2H), 8.04-7.98 (m, 2H), 7.95 (t, j=5.6 hz, 1H), 7.73 (d, j=15.5 hz, 1H), 7.62 (d, j=15.4 hz, 1H), 7.50 (s, 2H), 3.83 (d, j=5.9 hz, 2H), 3.15-3.02 (m, 2H), 2.18 (s, 6H), 1.00 (t, j=7.2 hz, 3H). HRMS (ESI) calculated: c (C) 22 H 24 N 2 O 4 [M+Na] + 403.1667 experimental values: 403.1624.
example 11: synthesis of 2-dimethylamino-2-oxoethyl-4- (3- (4-hydroxy-3, 5-dimethylphenyl) acryloyl) benzamide (5 l):
(1) 3, 5-dimethyl-p-hydroxybenzaldehyde (1) (1.0 equiv.) and DCM are mixed with each other, DIPEA (2.0 equiv.) and DAMP (0.03 equiv.) are added to the mixture, stirred uniformly, chloromethyl ether (2.0 equiv.) is then added dropwise under the condition of ice-water bath, the reaction is gradually restored to room temperature for 3h, and TLC detects the progress of the reaction. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give the product (2) (PE: ea=6:1).
(2) P-acetyl benzoic acid (3 a) (1.0 equiv.) and MeOH were mixed well, then NaOH saturated solution (2.0 equiv.) was added, stirring was performed, the product (2) obtained in step (1) was added dropwise to the solution after 10min, the reaction was performed for 24h at room temperature, and the progress of the reaction was checked by TLC. Subsequently, meOH in the solution was removed by evaporation under reduced pressure, and the pH of the remaining solution was adjusted to be acidic with 1M hydrochloric acid until a large amount of pale yellow solid was precipitated, and the residue was filtered and washed three times with water to give pale yellow solid (4 a).
(3) The carboxylic acid (4 a) of step (2) was mixed with HATU, DCM and reacted under stirring at room temperature for 30min, followed by addition of glycine methyl ester hydrochloride (1.2 equiv.) and reaction at room temperature for 10min, followed by addition of DIPEA (3.0 equiv.) and reaction under stirring at room temperature for 4h, and tlc was used to detect the progress of the reaction. After completion of the reaction, the solvent was removed by evaporation under reduced pressure, redissolved with EA with 3% aqueous citric acid and saturated NaHCO, respectively 3 The aqueous solution and the mixture were extracted three times, respectively, the organic layer was retained, dried over anhydrous sodium sulfate, filtered, and the obtained residue was isolated and purified by column chromatography (DCM) to give pale yellow solid (4 e).
(4) The methyl ester (4 e) synthesized in step (3) was mixed with MeOH and stirred well, an aqueous LiOH solution (2.0 equiv.) was added, the reaction was stirred at room temperature for 4h, and tlc detected the progress of the reaction. After completion of the reaction, the pH was adjusted to neutral with 1M HCl, extracted with EA and water, the organic layers were combined, and the solvent was removed by rotary evaporation to give a pale yellow solid (4 f).
(5) Uniformly mixing the carboxylic acid (4 f) in the step (4) with HOBt and DCM, stirring in an ice-water bath at 0 ℃ for 10min, then adding EDCI, continuously stirring in the ice-water bath for 30min, then adding N, N-dimethyl hydrochloride (1.2 equiv.), continuously stirring for 10min, finally adding DIPEA, stirring in the ice-water bath for 1h, recovering to room temperature, reacting for 4h, and detecting the reaction progress by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure, redissolved in EA, extracted three times with 3% aqueous citric acid and saturated NaHCO3 with the mixture, the organic layer was retained, dried over anhydrous sodium sulfate, filtered and the obtained residue was isolated and purified by thin layer chromatography (DCM: meoh=10:1) to give a pale yellow solid (4 l).
(5) Dissolving the product (4 l) obtained in the step (4) with MeOH, adjusting the pH to be acidic with 1M HCl, stirring and reacting for 1h at 60 ℃ to precipitate a large amount of solid, and filtering to obtain dark yellowYield of coloured solid (5 l) 23%. 1 HNMR(400MHz,DMSO-d 6 ) Delta 8.93 (s, 1H), 8.72 (t, j=5.6 hz, 1H), 8.16 (d, j=8.1 hz, 2H), 7.98 (d, j=8.2 hz, 2H), 7.70 (d, j=15.5 hz, 1H), 7.60 (d, j=15.4 hz, 1H), 7.48 (s, 2H), 4.09 (d, j=5.6 hz, 2H), 2.99 (s, 3H), 2.82 (s, 3H), 2.17 (s, 6H); HRMS (ESI) calculated: c (C) 22 H 24 N 2 O 4 [M+Na] + 403.1634 experimental values: 403.1628.
example 12: (E) Synthesis of (5 m) N- (2- (diethylamino) -2-oxoethyl) -4- (3- (4-hydroxy-3, 5-dimethylphenyl) acryloyl) benzamide:
(1) 3, 5-dimethyl-p-hydroxybenzaldehyde (1) (1.0 equiv.) and DCM are mixed with each other, DIPEA (2.0 equiv.) and DAMP (0.03 equiv.) are added to the mixture, stirred uniformly, chloromethyl ether (2.0 equiv.) is then added dropwise under the condition of ice-water bath, the reaction is gradually restored to room temperature for 3h, and TLC detects the progress of the reaction. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give the product (2) (PE: ea=6:1).
(2) P-acetyl benzoic acid (3 a) (1.0 equiv.) and MeOH were mixed well, then NaOH saturated solution (2.0 equiv.) was added, stirring was performed, the product (2) obtained in step (1) was added dropwise to the solution after 10min, the reaction was performed for 24h at room temperature, and the progress of the reaction was checked by TLC. Subsequently, meOH in the solution was removed by evaporation under reduced pressure, and the pH of the remaining solution was adjusted to be acidic with 1M hydrochloric acid until a large amount of pale yellow solid was precipitated, and the residue was filtered and washed three times with water to give pale yellow solid (4 a).
(3) Uniformly mixing the carboxylic acid (4 a) in the step (2) with HOBt and DCM, stirring in an ice-water bath at 0 ℃ for 10min, then adding EDCI, continuing stirring in the ice-water bath for 30min, then adding 2-amino-N, N-diethyl acetamide hydrochloride (1.2 equiv.), continuing stirring for 10min, finally adding DIPEA, stirring in the ice-water bath for 1h, returning to room temperature for 4h, and detecting the reaction progress by TLC. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, redissolved with EA and dissolved in 3% citric acid water, respectively Liquid and saturated NaHCO 3 The organic layer was washed three times, dried over anhydrous sodium sulfate, filtered, and the resulting residue was isolated and purified by thin layer chromatography (DCM: meoh=10:1) to give a pale yellow solid (4 m).
(5) The product (4M) obtained in step (4) was dissolved in MeOH, pH was adjusted to acidic with 1M HCl, stirred at 60 ℃ for 1h, a large amount of solid was precipitated, and filtered to give a dark yellow solid (5M) in 76% yield. 1 HNMR(400MHz,DMSO-d 6 ) Delta 8.93 (s, 1H), 8.72 (t, j=5.6 hz, 1H), 8.16 (d, j=8.1 hz, 2H), 7.98 (d, j=8.2 hz, 2H), 7.70 (d, j=15.5 hz, 1H), 7.60 (d, j=15.4 hz, 1H), 7.48 (s, 2H), 4.09 (d, j=5.6 hz, 2H), 2.99 (s, 3H), 2.82 (s, 3H), 2.17 (s, 6H); HRMS (ESI) calculated: c (C) 22 H 24 N 2 O 4 [M+Na] + 403.1634 experimental values: 403.1628.
example 13: (E) Synthesis of (5 k) 4- (3- (4-hydroxy-3, 5-dimethylphenyl) acryloyl) -N- (2-oxo-2-phenylamino) ethylbenzamide
(1) 3, 5-dimethyl-p-hydroxybenzaldehyde (1) (1.0 equiv.) and DCM are mixed with each other, DIPEA (2.0 equiv.) and DAMP (0.03 equiv.) are added to the mixture, stirred uniformly, chloromethyl ether (2.0 equiv.) is then added dropwise under the condition of ice-water bath, the reaction is gradually restored to room temperature for 3h, and TLC detects the progress of the reaction. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give the product (2) (PE: ea=6:1).
(2) P-acetyl benzoic acid (3 a) (1.0 equiv.) and MeOH were mixed well, then NaOH saturated solution (2.0 equiv.) was added, stirring was performed, the product (2) obtained in step (1) was added dropwise to the solution after 10min, the reaction was performed for 24h at room temperature, and the progress of the reaction was checked by TLC. Subsequently, meOH in the solution was removed by evaporation under reduced pressure, and the pH of the remaining solution was adjusted to be acidic with 1M hydrochloric acid until a large amount of pale yellow solid was precipitated, and the residue was filtered and washed three times with water to give pale yellow solid (4 a).
(3) The carboxylic acid (4) of step (2)a) Uniformly mixed with HATU and DCM, stirred at room temperature for 30min, then added glycine methyl ester hydrochloride (1.2 equiv.) and reacted at room temperature for 10min, added DIPEA (3.0 equiv.) and stirred at room temperature for 4h, and TLC was used to check the progress of the reaction. After completion of the reaction, the solvent was removed by evaporation under reduced pressure, redissolved with EA with 3% aqueous citric acid and saturated NaHCO, respectively 3 The aqueous solution and the mixture were extracted three times, respectively, the organic layer was retained, dried over anhydrous sodium sulfate, filtered, and the obtained residue was isolated and purified by column chromatography (DCM) to give pale yellow solid (4 e).
(4) The methyl ester (4 e) synthesized in step (3) was mixed with MeOH and stirred well, an aqueous LiOH solution (2.0 equiv.) was added, the reaction was stirred at room temperature for 4h, and tlc detected the progress of the reaction. After completion of the reaction, the pH was adjusted to neutral with 1M HCl, extracted with EA and water, the organic layers were combined, and the solvent was removed by rotary evaporation to give a pale yellow solid (4 f).
(5) Collecting pale yellow solid (4 f), mixing with HOBt and DCM, stirring in ice water bath at 0deg.C for 10min, adding EDCI, stirring in ice water bath for 30min, adding aniline (1.2 equiv.), stirring for 10min, adding DIPEA, stirring in ice water bath for 1 hr, recovering to room temperature, and performing TLC detection. After completion of the reaction, the solvent was removed by evaporation under reduced pressure, redissolved with EA with 3% aqueous citric acid and saturated NaHCO, respectively 3 The mixture was extracted three times, the organic layer was kept, dried over anhydrous sodium sulfate, filtered, and the obtained residue was separated and purified by column chromatography to obtain pale yellow solid (4 k).
(6) The product (4 k) obtained in step (5) was stirred with MeOH, the pH was adjusted to acidic with 1M HCl, reacted for 1h at 60 ℃ and a large amount of solid was precipitated, filtered to obtain yellow solid (5 k), purified by thin layer chromatography and yield 38%. 1 HNMR(400MHz,DMSO-d 6 ) δ10.10 (s, 1H), 9.06 (t, j=5.9 hz, 1H), 9.01 (s, 1H), 8.22-8.17 (m, 2H), 8.05-8.01 (m, 2H), 7.73 (d, j=15.4 hz, 1H), 7.63 (d, j=15.4 hz, 1H), 7.60-7.56 (m, 2H), 7.50 (s, 2H), 7.32-7.25 (m, 2H), 7.06-6.99 (m, 1H), 4.07 (d, j=5.8 hz, 2H), 2.18 (s, 6H); HRMS (ESI) calculated: c (C) 26 H 24 N 2 O 4 [M+H] + 429.1770 Experimental values:429.1809.
Example 14: synthesis of (R) -1- (S) -2- (4-hydroxy-3, 5-dimethylphenyl) acryloyl) benzamide) -3-phenylpropionamido) -3-methylbutyrate (10 v):
(1) 3, 5-dimethyl-p-hydroxybenzaldehyde (1) (1.0 equiv.) and DCM are mixed with each other, DIPEA (2.0 equiv.) and DAMP (0.03 equiv.) are added to the mixture, stirred uniformly, chloromethyl ether (2.0 equiv.) is then added dropwise under the condition of ice-water bath, the reaction is gradually restored to room temperature for 3h, and TLC detects the progress of the reaction. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give the product (2) (PE: ea=6:1).
(2) P-acetyl benzoic acid (3 a) (1.0 equiv.) and MeOH were mixed well, then NaOH saturated solution (2.0 equiv.) was added, stirring was performed, the product (2) obtained in step (1) was added dropwise to the solution after 10min, the reaction was performed for 24h at room temperature, and the progress of the reaction was checked by TLC. Subsequently, meOH in the solution was removed by evaporation under reduced pressure, and the pH of the remaining solution was adjusted to be acidic with 1M hydrochloric acid until a large amount of pale yellow solid was precipitated, and the residue was filtered and washed three times with water to give pale yellow solid (4 a).
(3) Uniformly mixing the product 4a (1.0 equiv.) obtained in the step (2) with HOBt and DCM, stirring in an ice-water bath at 0 ℃ for 10min, adding EDCI, continuing stirring in the ice-water bath for 30min, adding (alpha S) -alpha-amino-N- [ (1R) -1- [ (3 aS,4S,6S,7 aR) -hexahydro-3 a, 5-trimethyl-4, 6-methyl bridge-1, 3, 2-benzodioxan-2-yl ] -3-methylbutyl ] benzamide hydrochloride (8, 1.2 equiv.) again, stirring for 10min, adding DIPEA, stirring in the ice-water bath for 1h, recovering to room temperature for 4h, and detecting the reaction progress by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure, redissolved in EA, extracted three times with 3% aqueous citric acid and saturated NaHCO3 with the mixture, the organic layer was retained, dried over anhydrous sodium sulfate, filtered and the obtained residue was isolated and purified by thin layer chromatography (DCM: meoh=10:1) to give a pale yellow solid (9 v).
(6) The borate (9 v) synthesized in step (5) was dissolved in MeOH, isobutyl boric acid (2.0 equiv.) and n-hexane (2.0 equiv.) were added, the solution was made acidic with 1M HCl, stirred overnight at room temperature, and the reaction was detected by TLC. After completion of the reaction, the MeOH phase was collected, the solvent was removed by evaporation under reduced pressure, dissolved in DCM, extracted twice with water, dried over anhydrous sodium sulfate, filtered and the residue was isolated and taken up by column chromatography to give a yellow solid (10 v) (DCM: meoh=20:1) in 68% yield. 1 HNMR(400MHz,CD 3 OD) δ8.08 (d, j=8.1 hz, 2H), 7.89 (d, j=7.9 hz, 2H), 7.68 (d, j=15.7, 3.1hz, 1H), 7.51 (d, j=15.5, 3.1hz, 1H), 7.34 (s, 2H), 7.29 (d, j=4.4 hz, 4H), 7.25-7.20 (m, 1H), 4.96 (t, j=8.1 hz, 1H), 3.21 (dd, j=7.9, 2.6hz, 2H), 2.64 (t, j=7.7 hz, 1H), 2.22 (s, 6H), 1.36-1.23 (m, 2H), 1.12 (t, j=7.5 hz, 2H), 0.84-0.78 (m, 6H); HRMS (ESI) calculated: C32H237 BN2O6[ M+Na ]]+579.2642 experimental values: 579.2639.
EXAMPLE 15 in vitro study of the inhibition of NLRP3 inflammatory corpuscles by chalcone derivatives
J774a.1 cells were plated onto 96-well plates, each well approximately 5×10 5 Cells were plated overnight, the supernatant was discarded, 100. Mu.L of DMEM medium containing bacterial lipopolysaccharide (LPS, 1. Mu.g/ml) containing 10% serum was added to each well, then chalcone derivatives (20. Mu.M, 10. Mu.M, 5. Mu.M, 1. Mu.M, 500nM, 250nM, 125nM, 62.5 nM) were added to treat for 1 hour, nigericin (Nigericin, 10. Mu.M) was added to treat for 1 hour, and then cell supernatant was collected, and IL-1. Beta. Content was measured using Mouse IL-1. Beta. ELISA kit to calculate the inhibition of NLRP3 inflammatory bodies by the compounds of the present invention.
The results are shown in Table 1: the chalcone derivative provided by the invention has good inhibitory activity on NLRP3 inflammatory corpuscles.
Table 1: inhibition of NLRP3/IL-1 beta by chalcone derivatives on J774A.1 cells
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EXAMPLE 16 specific inhibition of activation of NLRP3 inflammatory corpuscles by Compound 10v in vitro
1. NLRP3 inflammatory body activation and IL-1 beta detection: j774a.1 cells or mouse Bone Marrow Derived Macrophages (BMDMs) were plated onto 96-well plates, 5×10 each 5 Cells were plated overnight, the supernatant was discarded, 100. Mu.L of DMEM medium containing bacterial Lipopolysaccharide (LPS) (1. Mu.g/ml) containing 10% serum was added to each well, then treated with different concentrations of compound 10v (200 nM, 100nM, 50 nM) for 1h, then with Nigericin (10. Mu.M) for 1h, after which the cell supernatant was collected and assayed for IL-1β content using the Mouse IL-1β ELISA kit.
2. Western blot analysis: the j774a.1 cell samples treated in step 1 were lysed in RIPA lysis buffer with protease inhibitors at 4 ℃ for 30min. Proteins in the lysate or supernatant were separated with a 12% SDS-polyacrylamide gel, transferred to PVDF membrane, and subjected to Western blotting with anti-murine IL-1. Beta. Antibody, anti-ASC antibody, anti-casease-1 antibody, anti-NLRP 3 antibody, anti-beta-actin antibody.
3. NLRC4 and AIM2 inflammatory body activation and IL-1β detection for NLRC4 or AIM2 inflammatory body activation, BMDMs cells were stimulated with 1. Mu.g/mL LPS for 5h, then treated with different concentrations (50 nM, 100nM, 200 nM) of compound 10v for 1h, then cells were infected with bacterial flagellin (FLA-ST Ultrapure) (2.5. Mu.g/mL) or with poly (dA: dT) (0.25. Mu.g/mL) for 4h, after which cell supernatants were collected and IL-1β content was determined using the Mouse IL-1β ELISA kit.
The results are shown in FIG. 1, and from the results of FIG. 1, compound 10v can inhibit IL-1β secretion in both NLRP3 inflammatory somal activated J774A.1 and BMDMs cell models in a concentration-dependent manner (panels A and B in FIG. 1). Western blot experiments showed that the effect of compound 10v on inhibition of caspase-1p20 maturation and IL-1β secretion was dose dependent, but did not affect pro-IL-1β, pro-caspase-1, NLRP3 or ASC in cell lysates (panel A in FIG. 1). At the same time, compound 10v had no inhibitory effect on activation of NLRC4 inflammatory bodies (panel C in fig. 1) and slightly inhibitory effect on AIM2 inflammatory bodies (panel D in fig. 1). The above results indicate that 10v can selectively inhibit caspase-1 activation and IL-1 beta secretion that are dependent on NLRP3 inflammatory bodies.
Example 17: mechanism of inhibiting NLRP3 inflammatory body activation by compound 10v
NLRP3 inflammatory body assembly assay: treatment of J774A.1 cells in 6 well plates with LPS (1. Mu.g/mL) in CO 2 Incubate in incubator for 5h, incubate with corresponding concentrations of compound 10v for 1h, and finally incubate with Nigericin (10. Mu.M) for 1h. Cells treated with IP lysate containing proteasome and PMSF and the above steps were lysed on ice for 10min, then gently scraped off with a cell scraper, transferred to EP tubes and lysed for a further 30min. After completion of the lysis, the mixture was centrifuged at 12000rpm at 4℃for 10 minutes, the supernatant was removed, and 20. Mu.L of agar beads was added to each supernatant, and the mixture was left in a refrigerator at 4℃overnight with care of the homogenization before the addition. Removing supernatant, adding anti-NLRP 3 antibody into supernatant, shaking up and down, and incubating in refrigerator at 4deg.C for 6-8 hr. Then directly adding 20 mu L of agar gel beads after shaking uniformly, and placing in a refrigerator at 4 ℃ for cold storage and incubation for 6-8h. The supernatant was discarded and the bottom beads were retained. The beads were washed 5 times with pre-chilled D-PBS, added with a 2 Xloading Buffer, gently mixed, and cooked on a metal bath at 100deg.C for 10min. Proteins in the lysate or supernatant were separated on a 10% SDS-polyacrylamide gel, transferred to PVDF membrane, and subjected to Western blot analysis with anti-Ubiquitin antibody.
As shown in a in fig. 2, the dosing group showed ubiquitinated NLRP3 protein compared to the model group, indicating that 10v promoted accumulation of NLRP3 ubiquitination. As shown in B in fig. 2, there was a clear interaction between NLRP3 and ASC in LPS and Nigericin treated j774a.1 cells, whereas compound 10v reduced this interaction, suggesting that compound 10v may inhibit assembly of NLPR3 inflammatory bodies by promoting ubiquitination of NLRP3, inhibiting binding of NLRP3 to ASC, and thus inhibiting release of IL-1β.
Example 18: compound 10v inhibits expression of STAT1 and STAT5
J774a.1 cells in large dishes were treated with compound 10v for 2h, the supernatant removed, and incubated with LPS (1 μg/mL) for an additional 6h. The J774A.1 cell samples treated in the above steps were lysed in RIPA lysis buffer with protease inhibitors at 4℃for 30min. Proteins in lysates or supernatants were separated with 10% SDS-polyacrylamide gel, transferred onto PVDF membrane, and subjected to western blot analysis with anti-rabbit STAT1 antibody, anti-STAT 3 antibody, anti-STAT 5 antibody, anti-pSTAT 1 antibody, anti-pSTAT 3 antibody, anti-pSTAT 5 antibody.
As shown in fig. 2, C-E, compound 10v did not affect STAT3 expression and phosphorylation process, but was able to reduce STAT1 and STAT5 expression, and reduce the extent of their phosphorylation, and was dose dependent. It was demonstrated that compound 10v could also inhibit immune-related STATs pathways.
Example 19: compound 10v improves Dextran Sodium Sulfate (DSS) induced colitis
1. Female C57BL/6 mice from 6 to 8 weeks were divided into 5 groups of 6 mice each, and the specific grouping treatment was as follows:
a first group: administering distilled water in the diet on days 1-10, while daily gavage of vehicle;
second group: distilled water was administered on the diet on days 1-3, and 2.5% dss in distilled water was administered daily on the diet starting on days 4-10, with daily gavage of vehicle;
third group: every third day the gastric lavage compound sulfasalazine (10 mg/kg), distilled water with 2.5% dss was administered daily in the diet starting on day four;
group IV, 10v (0.2 mg/kg) of the compound was intraperitoneally injected every three days, starting daily administration of 2.5% DSS in distilled water in the diet;
group five i were given 10v (0.6 mg/kg) of compound per three days i.p., and distilled water with 2.5% dss was given daily on the diet on day four;
2. the hematochezia and body weight of each group of mice were monitored daily starting from the day prior to DSS administration, and the colon of the mice was taken on day 11 for length measurement and IL-1 β content determination in the colon.
Results as shown in fig. 3, from the results of fig. 3, the severity of hematochezia in mice was increased and the colon length of mice was shortened after administration of 2.5% dss in diet, and the IL-1 beta in colon was significantly increased, and the intraperitoneal injection of compound 10v could improve hematochezia in mice, improve colon length shortening, and reduce IL-1 beta level in colon, in a dose-dependent manner.
3. The result of pathological section of the colon tissue of the mice is shown in fig. 4, the colonic mucosa structure of the DSS group is obviously damaged, the goblet cells completely disappear, the crypt structure is completely destroyed, the colonic surface basically presents a ulcer shape, and the inflammatory infiltration is serious. The colon of the mice treated by the compound 10v has good treatment effect, intact mucous membrane, good cup-shaped cell and crypt structure state, almost no ulcer surface and extremely low inflammatory infiltration degree, so the compound 10v can obviously improve the colitis induced by DSS.
The activity test result shows that the chalcone compound disclosed by the invention has the activity of inhibiting NLRP3 inflammatory corpuscles on a tested cell J774A.1. Meanwhile, the representative compound 10v can selectively inhibit activation of NLRP3 inflammatory corpuscles, inhibit immune related STATs channels and improve DSS-induced colonitis, and therefore, the chalcone compound has application in treating NLRP3 inflammatory corpuscles and/or STATs channels related diseases.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (13)
1. Chalcone derivatives with a structure shown in a formula (I) or pharmaceutically acceptable salts or stereoisomers thereof,
wherein R is 1 And R is 2 Each independently selected from: H. -C (=o) OR 3 、-C(=O)N(R 4 ) 2 、-N(R 5 )-C(=O)R 6 ;
R 3 Selected from: H. c (C) 1 -C 6 An alkyl group;
each R is 4 Each independently selected from: H. one or more R 7 Substituted C 1 -C 6 Alkyl, one or more R 7 Substituted C 3 -C 6 Cycloalkyl;
R 5 selected from: H. c (C) 1 -C 6 An alkyl group;
R 6 selected from: one or more R 7 Substituted C 1 -C 6 Alkyl, one or more R 7 Substituted C 3 -C 6 Cycloalkyl;
each R is 7 Each independently selected from: H. -C (=o) OR 3 、C 6 -C 10 Aryl, C 6 -C 10 Arylmethyl, -C (=O) N (R) 8 ) 2 ;
Each R is 8 Each independently selected from: H. c (C) 1 -C 6 Alkyl, C 6 -C 10 Aryl, boric acid group substituted C 1 -C 8 An alkyl group;
alternatively, R 1 、R 2 And the carbon atoms to which they are attached together form a 5-10 membered heterocyclic group.
2. Chalcone derivatives or pharmaceutically acceptable salts or thereof according to claim 1The stereoisomer is characterized in that R 1 And R is 2 Each independently selected from: H. -C (=o) OR 3 、-C(=O)N(R 4 ) 2 、-N(R 5 )-C(=O)R 6 ;
R 3 Selected from: H. c (C) 1 -C 3 An alkyl group;
each R is 4 Each independently selected from: H. one or more R 7 Substituted C 1 -C 3 An alkyl group;
R 5 selected from: H. c (C) 1 -C 3 An alkyl group;
R 6 selected from: one or more R 7 A substituted cyclopropyl group;
each R is 7 Each independently selected from: H. -C (=o) OR 3 Phenyl, benzyl, -C (=o) N (R) 8 ) 2 ;
Each R is 8 Each independently selected from: H. c (C) 1 -C 3 Alkyl, phenyl, boric acid group substituted C 3 -C 6 An alkyl group;
alternatively, R 1 、R 2 And the carbon atoms to which they are attached together form an 8-10 membered heterocyclic group.
3. Chalcone derivative or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein R 1 And R is 2 Each independently selected from: H. -C (=o) OR 3 、-C(=O)N(R 4 ) 2 、-N(R 5 )-C(=O)R 6 ;
R 3 Selected from: methyl, ethyl;
each R is 4 Each independently selected from: H. one or more R 7 Substituted methyl;
R 5 selected from: h is formed;
R 6 selected from: one or more R 7 A substituted cyclopropyl group;
each R is 7 Each independently selected from: H. -C (=o) OR 3 Carboxyl, benzyl, -C (=O) N (R) 8 ) 2 ;
Each R is 8 Each independently selected from: H. methyl, ethyl, boric acid group substituted isopentyl;
Alternatively, R 1 、R 2 And the carbon atoms to which they are attached together form an 8-membered spiroheterocyclic group.
4. Chalcone derivative or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein R 4 One of which is H and the other is not H.
5. A chalcone derivative or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 4, wherein there is one R 7 In the case of carboxyl, R 7 Is 2 and another R 7 Selected from: -C (=o) OR 3 Benzyl, -C (=o) N (R) 8 ) 2 。
6. Chalcone derivative or pharmaceutically acceptable salt thereof or stereoisomer thereof according to any one of claims 1 to 4, wherein R 2 Is H and R 1 Is not H.
7. Chalcone derivative or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein the chalcone derivative is selected from the group consisting of:
8. use of a chalcone derivative according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of an inhibitor of NLRP3 inflammatory bodies and/or inhibitors of stat pathway.
9. Use of a chalcone derivative according to any one of claims 1-7 or a pharmaceutically acceptable salt or stereoisomer thereof in the manufacture of a medicament for the prevention and/or treatment of diseases associated with NLRP3 inflammatory bodies and/or stat pathways.
10. The use according to claim 9, wherein the diseases associated with NLRP3 inflammatory bodies and/or stat pathways are inflammatory diseases, alzheimer's disease, gout, multiple sclerosis, type II diabetes.
11. The use according to claim 10, wherein the inflammatory disease is inflammatory bowel disease, rheumatoid arthritis, psoriasis.
12. The use according to claim 11, wherein the inflammatory diseases are peritonitis and colitis.
13. A pharmaceutical composition for preventing and treating inflammatory diseases, which is characterized by being prepared from an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises the chalcone derivative or the pharmaceutically acceptable salt or the stereoisomer thereof according to any one of claims 1 to 7.
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