Novel diketone compounds
阅读说明：本技术 一类新的二酮类化合物 (Novel diketone compounds ) 是由 许军 彭红 李永华 陶琳 刘成洪 张晓丽 夏龙军 赵岩 王晓霞 邝振英 于 2019-10-25 设计创作，主要内容包括：本发明涉及一类新的二酮类化合物。该化合物为式I化合物及其药学上可接受的盐、前药和溶剂合物,及包含所述化合物的药物组合物,并涉及其合成方法。此外,本发明涉及包含所述化合物的药物组合物,可用于抑制肿瘤相关性靶点蛋白或基因的活性。(The invention relates to a new diketone compound. The compounds are of formula I and pharmaceutically acceptable salts, prodrugs and solvates thereof, as well as pharmaceutical compositions comprising the compounds, and to methods of synthesizing the same. In addition, the invention relates to a pharmaceutical composition containing the compound, which can be used for inhibiting the activity of tumor-related target proteins or genes.)
1. A novel compound of formula (I):
including pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein:
a is selected fromH, wherein a1 is selected from aromatic phenyl ring groups and aromatic heterocyclic groups, a1 is optionally substituted with one or more, the same or different, R1;
b is selected fromH, wherein B1 is selected from aromatic benzene cyclyl and aromatic heterocyclyl, B1 is optionally substituted with one or more R1 which may be the same or different;
m is selected fromWherein M1 is selected from the group consisting of aromatic benzene cyclyl and aromatic heterocyclyl, M1 is optionally substituted with one or more, the same or different, R1;
r1 is H, OH, halogen, OR2, CN, NO2, COOH, CF3, C (O) NH2, OCOR2, SCOR2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, wherein C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl are optionally substituted by one OR more identical OR different R3;
r2 is H, C3-7 cycloalkyl, C5-7 aromatic cyclic group, C5-7 aromatic heterocyclic group, C7-11 aromatic bicyclic group, C7-11 aromatic heterobicyclic group, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, wherein the cyclic hydrocarbon group and the aliphatic hydrocarbon group are optionally substituted by one or more same or different R3;
r3 is H, CN, NO2, CF3, COOH, COOR4, CONHR4, CONR5R5 ', SONR6R 6', COR7, R8OH, halogen, benzene, C3-7 cycloalkyl, C5-7 aromatic heterocyclyl, C7-11 aromatic bicyclic group, C7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more identical or different R9; c1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, these aliphatic hydrocarbon groups being optionally substituted by one or more R10, which may be the same or different;
r4 is benzene, C3-7 cycloalkyl, C5-7 aromatic heterocyclyl, C7-11 aromatic bicyclic, C7-11 aromatic heterobicyclic, wherein these rings are optionally substituted with one or more R9, which may be the same or different;
R5R5 ' are each independently H, CN, NO2, CF3, COOH, COOR4, CONR5R5 ', SONR6R6 ', COR7, R8OH, halogen, benzene, C3-7 cycloalkyl, C5-7 aromatic heterocyclyl, C7-11 aromatic bicyclic, C7-11 aromatic heterobicyclic, wherein the rings are optionally substituted by one or more identical or different R9;
r6\ R6 ' are respectively H, CN, NO2, CF3, COOH, COOR4, CONR5R5 ', SONR6R6 ', COR7, R8OH and halogen; benzene, C3-7 cycloalkyl, C5-7 aromatic heterocyclyl, C7-11 aromatic bicyclic, C7-11 aromatic heterobicyclic, wherein the rings are optionally substituted with one or more R9, which may be the same or different;
r7 is H, CN, NO2, CF3, COOH, COOR4, CONR5R5 ', SONR6R 6', COR7, R8OH, halogen; benzene, C3-7 cycloalkyl, C5-7 aromatic heterocyclyl, C7-11 aromatic bicyclic, C7-11 aromatic heterobicyclic, wherein the rings are optionally substituted with one or more R9, which may be the same or different;
r8 is H, benzene, C3-7 cycloalkyl, C5-7 aromatic heterocyclyl, C7-11 aromatic bicyclic, C7-11 aromatic heterobicyclic, wherein these rings are optionally substituted with one or more, the same or different, R9;
r9 is H, CN, NO2, CF3, COOH, COOR4, CONR5R5 ', SONR6R 6', COR7, R8OH, halogen; benzene, C3-7 cycloalkyl, C5-7 aromatic heterocyclyl, C7-11 aromatic bicyclic, C7-11 aromatic heterobicyclic, wherein the rings are optionally substituted with one or more R10, which may be the same or different;
r10 is H, CN, NO2, CF3, COOH, COOR4, CONR5R5 ', SONR6R 6', COR7, R8OH, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl benzene, C3-7 cycloalkyl, C5-7 aromatic heterocyclic group, C7-11 aromatic bicyclic group, C7-11 aromatic heterobicyclic group;
2. the compound of claim 1, in various crystal forms including, but not limited to, crystalline, amorphous, and other various crystal forms.
3. A pharmaceutical composition comprising a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, optionally in combination with one or more other pharmaceutical compositions.
4. The pharmaceutical composition of claim 3, which can be prepared into pharmaceutical preparations and pharmaceutical dosage forms for injection or non-injection administration.
5. Use of a compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of diseases associated with STAT3, NF-kB, JAK2 and TNF- α proteins.
6. Use of the pharmaceutical composition of claim 3 for the preparation of a medicament for the treatment of diseases associated with STAT3, NF-kB, JAK2, and TNF- α proteins.
Technical Field
The invention relates to a diketone compound. The compounds are of formula (I) and pharmaceutically acceptable salts, prodrugs and solvates thereof, as well as pharmaceutical compositions comprising the compounds, and methods of synthesis thereof. In addition, the invention relates to a pharmaceutical composition containing the compound, which can be used for inhibiting the activity of tumor-related target proteins or genes.
Background
With the acceleration of modern life rhythm, cancer is becoming one of the leading causes of death of residents, and people speaking of cancer color change also become extremely important for the prevention and treatment of cancer. The rapid development of modern medical science provides power for the treatment and prevention of tumors, and scientists also provide new ideas and directions for the design of anti-cancer drugs while exploring and finding tumor targets. At present, the popular tumor target proteins include STAT3, JAK2, NF-kB, TNF-alpha and the like, and the STAT3, the JAK2, the NF-kB, the TNF-alpha and the like have non-negligible influence in the process of generating and developing tumors. On the basis of deeply researching the biological activity of target protein, the development of inhibitors or activators of the target protein is gradually a new favorite of academic research, curcumin is a main active ingredient of traditional Chinese medicine turmeric and has various pharmacological activities such as anti-tumor, anti-inflammatory and anti-oxidation, and the research finds that the curcumin is biologically linked with the target protein, so the research on the anti-cancer activity of the curcumin is hot day by day.
The STATs family consists of 7 members, STAT1, STAT2, STAT3, STAT4, STA5a, STAT5b and STAT6, respectively, where STAT3 is a cancer-dependent transcription factor and aberrant activation of the STAT3 signaling pathway is critical for carcinogenesis. The structure of the STAT3 gene is divided into an amino-terminal domain, a coiled-coil domain, an SH2 domain, a DNA domain and a linker domain and a C-terminal domain. When the internal environment changes, related cell growth factors influence the upstream JAKS protein, so that the domain change in the downstream STAT3 is caused, STAT3 is phosphorylated and abnormally activated, and finally, the tumor cells are immortalized and abnormally withered. Currently, there is temporarily no accurate approval for the STAT3 inhibitor to be marketed, so subsequent research and development on STAT3 inhibitors is a hotspot in drug research.
The JAK (janus kinase) protein family is a non-transmembrane tyrosine kinase, consisting of JAK1, JAK2, JAK3 and TYK24 members, wherein JAK1 is mainly involved in binding cytokines to receptors, JAK2 is responsible for mediating signaling of extracellular ligands and receptors, JAK3 is functionally similar to JAK1, but JAK3 is only expressed in hematopoietic cells. The JAK/STAT3 axis is generally considered to be a classical signal path in cells and plays a key role in regulating multiple aspects of cell proliferation, apoptosis, angiogenesis and the like. The JAK/STAT3 signal channel is stimulated by extracellular signals to be activated, upstream JAK kinase is phosphorylated and aggregated, and then STAT3 protein is catalyzed to be phosphorylated to form a dimer, and the dimer enters into a cell nucleus to regulate the transcriptional activity of tumor genes. Compared with the study of STAT3 inhibitors, the study of JAK2 inhibitors is relatively mature, and at present, the JAK inhibitors which have been approved by FDA to be marketed are tofacitinib (tofacitinib) and ruxolitinib (ruxolitinib). The FDA approved letatinib (lestaurtinib) as a targeted inhibitor of JAKS in 2006, and the study of some tumors with letatinib is also in the clinical stage of research.
Research shows that the activation and transcription factor kappa B (NF-kB) is used as a nuclear transcription factor and is closely related to pathophysiological processes such as immune response, inflammatory response, cell proliferation, cell transformation and cell apoptosis. There are 5 members of the NF-kB family, RelA (p65), RelB, c-Rel, p50 (NF-. kappa.B 1) and p52 (NF-. kappa.B 2), of which p50 and RelA are the proteins that play a major physiological role. When cells are stimulated by inflammation or oxidation, NF-kB is activated and enters the cell nucleus, and is combined with a corresponding target sequence to regulate the expression of genes for coding cytokines, growth factors and cell adhesion molecules and influencing apoptosis, and mediate processes such as tumorigenesis development, angiogenesis, metastasis and the like. There are many studies on NF- κ B inhibitors, and currently, pyrrole dithio-carbamate (PDTC), dehydroepoxy methyl quinomycin (DHMEQ) and other inhibitors are approved for market, and more small molecule inhibitors are under development, for example: BAY11-7082 and the like
TNF-alpha is an important inflammatory cytokine, is mainly secreted by activated mononuclear macrophages, lymphocytes and the like, participates in processes of inflammatory reaction, immune homeostasis, host defense and the like of a human body, and has a series of biological effects of resisting tumors, regulating immunity, mediating inflammation, resisting cytotoxicity, carrying out apoptosis, damaging vascular endothelial cells and the like. Under physiological conditions, a proper amount of TNF-alpha can help the body resist pathogenic bacteria and prevent tumors, but when the amount of TNF-alpha exceeds a certain amount, the TNF-alpha can cause various pathological injuries and promote tumorigenesis, so the TNF-alpha is also considered to be a regulation and control correlator of cancer pathology. Currently, rhTNFR has been widely used in clinical applications as a TNF- α inhibitor and has good therapeutic effects, so that research on TNF- α inhibitors is extensive and thorough.
At present, a variety of novel anticancer drugs have been widely used in medicine, and curcumin is also spotlighted because of its superior antioxidant and anticancer activities. Curcumin is a micromolecular diphenol substance, is mainly extracted from curcuma plants, has multiple pharmacological effects of resisting infection, oxidation and coagulation, resisting inflammation, resisting tumor and the like, and is effective on cancers, autoimmune diseases, cardiovascular diseases, diabetes, atherosclerosis, stroke, metabolic diseases, neurodegenerative diseases and the like. Curcumin is a natural phenolic antioxidant, has anti-tumor activity, is often used as a pharmaceutical ingredient for treating and preventing different cancers, and STAT3 is a common intervention target for tumor treatment, so STAT3 also becomes one of the subjects of curcumin for researching a plurality of anti-cancer targets. The study at present finds that the function of curcumin is similar to that of a JAK/STAT signal pathway inhibitor AG490, and the curcumin can simultaneously or independently act on JAK2 and STAT3 by participating in the conduction of a JAK/STAT signal pathway, regulate the expression of STAT3, inhibit the activity of JAK2 and inhibit the phosphorylation of STAT3, so that the curcumin can inhibit the occurrence and development of some tumor diseases. The current research has proved that curcumin can inhibit proinflammatory cytokines and effectively inhibit inflammatory response by inhibiting the release of cytokines such as TNF-alpha, IL-6, IL-1 beta and the like through inhibiting the activation of NF-kB in the cytokines, so that curcumin has the potential of treating neuroinflammatory diseases, and is also tried to treat various chronic diseases and cancers related to the brain at present. Therefore, curcumin extracted from plants has wide, good and safe pharmacological activity, can play a role in cancer prevention through antioxidation or anti-inflammation, can increase the sensitivity of tumor target inhibitors currently researched or marketed, and has low solubility and low bioavailability but limits the application of curcumin.
On the basis of synthesized and discovered curcumin analogs, lipid solubility and stability of curcumin are improved by modifying groups such as ester groups, halogens, saturated alkyl groups and the like on the original structure of curcumin, water solubility of curcumin is improved by modifying groups such as hydroxyl groups, carboxyl groups, amino groups, carbonyl groups and the like to reduce toxicity of curcumin, and a series of structural modifications such as ether bonds and sulfydryl groups can enable diketone compounds to better pass through biological membranes and introduce sulfonic groups to improve water solubility of compounds are invented according to biomimetic synthesis.
Disclosure of Invention
The invention aims to: synthesizing a new diketone compound.
The invention also aims to provide a synthetic method of the novel diketone compound.
Another object of the present invention is the use of a new class of diketones for the treatment of tumors.
The structure of the novel diketone compound of the invention is as follows: a novel compound of formula (I):
including pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein:
a is selected fromH, wherein a1 is selected from aromatic phenyl ring groups and aromatic heterocyclic groups, a1 is optionally substituted with one or more, the same or different, R1;
b is selected fromH, wherein B1 is selected from aromatic benzene cyclyl and aromatic heterocyclyl, B1 is optionally substituted with one or more R1 which may be the same or different;
m is selected fromWherein M1 is selected from the group consisting of aromatic benzene cyclyl and aromatic heterocyclyl, M1 is optionally substituted with one or more, the same or different, R1;
r1 is H, OH, halogen, OR2, CN, NO2, COOH, CF3, C (O) NH2, OCOR2, SCOR2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, wherein C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl are optionally substituted by one OR more identical OR different R3;
r2 is H, C3-7 cycloalkyl, C5-7 aromatic cyclic group, C5-7 aromatic heterocyclic group, C7-11 aromatic bicyclic group, C7-11 aromatic heterobicyclic group, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, wherein the cyclic hydrocarbon group and the aliphatic hydrocarbon group are optionally substituted by one or more same or different R3;
r3 is H, CN, NO2, CF3, COOH, COOR4, CONHR4, CONR5R5 ', SONR6R 6', COR7, R8OH, halogen, benzene, C3-7 cycloalkyl, C5-7 aromatic heterocyclyl, C7-11 aromatic bicyclic group, C7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more identical or different R9; c1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, these aliphatic hydrocarbon groups being optionally substituted by one or more R10, which may be the same or different;
r4 is benzene, C3-7 cycloalkyl, C5-7 aromatic heterocyclyl, C7-11 aromatic bicyclic, C7-11 aromatic heterobicyclic, wherein these rings are optionally substituted with one or more R9, which may be the same or different;
R5R5 ' are each independently H, CN, NO2, CF3, COOH, COOR4, CONR5R5 ', SONR6R6 ', COR7, R8OH, halogen, benzene, C3-7 cycloalkyl, C5-7 aromatic heterocyclyl, C7-11 aromatic bicyclic group, C7-11 aromatic heterobicyclic group, wherein the rings are optionally substituted by one or more identical or different R9;
r6\ R6 ' are respectively H, CN, NO2, CF3, COOH, COOR4, CONR5R5 ', SONR6R6 ', COR7, R8OH and halogen; benzene, C3-7 cycloalkyl, C5-7 aromatic heterocyclyl, C7-11 aromatic bicyclic, C7-11 aromatic heterobicyclic, wherein the rings are optionally substituted with one or more R9, which may be the same or different;
r7 is H, CN, NO2, CF3, COOH, COOR4, CONR5R5 ', SONR6R 6', COR7, R8OH, halogen; benzene, C3-7 cycloalkyl, C5-7 aromatic heterocyclyl, C7-11 aromatic bicyclic, C7-11 aromatic heterobicyclic, wherein the rings are optionally substituted with one or more R9, which may be the same or different;
r8 is H, benzene, C3-7 cycloalkyl, C5-7 aromatic heterocyclyl, C7-11 aromatic bicyclic, C7-11 aromatic heterobicyclic, wherein these rings are optionally substituted with one or more, the same or different, R9;
r9 is H, CN, NO2, CF3, COOH, COOR4, CONR5R5 ', SONR6R 6', COR7, R8OH, halogen; benzene, C3-7 cycloalkyl, C5-7 aromatic heterocyclyl, C7-11 aromatic bicyclic, C7-11 aromatic heterobicyclic, wherein the rings are optionally substituted with one or more R10, which may be the same or different;
r10 is H, CN, NO2, CF3, COOH, COOR4, CONR5R5 ', SONR6R 6', COR7, R8OH, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl benzene, C3-7 cycloalkyl, C5-7 aromatic heterocyclic group, C7-11 aromatic bicyclic group, C7-11 aromatic hetero bicyclic group.
The compound of formula (I) is selected from:
(1)1- (4-methoxy-phenyl) -7-p-tolyl-hepta-1, 6-diene-3, 5-dione
(2)1- (4-allylphenyl) -7- (4-cyclohexyloxy-phenyl) -hepta-1, 6-diene-3, 5-dione
(3) 1', 1- ((1E, 6E) -3, 5-dioxohepta-1, 6-diene-1, 7-diyl) bis (2-methoxy-4, 1-phenylene)) 1, 1' -bis (4-fluorophenyl) bis (cyclopropane-1, 1-dicarboxylate)
(4) Acetic acid-4- [3, 5-dioxo-7- (4-pent-4-ynyl-phenyl) -hept-1, 6-dienyl ] -phenyl ester
(5) Cyclohexanecarboxylic acid 4- (7- { 2-bromo-4- [1- (3-methyl-butyryl) -cyclopropanecarbonyloxy ] -phenyl } -3, 5-dioxo-hept-1, 6-dienyl) -2-ethyl-phenyl ester
(6)4- ((1E, 6E) -7- (4- ((1- (chlorocarbonyl) cyclopropane-1-carbonyl) oxy) -2-methylphenyl) -3, 5-dioxo-1, 6-dien-1-yl) phenyl 1- (cyclohexylcarbamoyl) cyclopropane-1-carboxylate
(7)4- ((1E, 6E) -7- (4- ((1- (chlorocarbonyl) tert-butyl-1-carbonyl) oxy) -2-methylphenyl) -3, 5-dioxo-1, 6-dien-1-yl) phenyl 1- (formyl) cyclopropane-1-carboxylate
(8)4- ((1E, 6E) -7- (4- ((1- ((4-chlorophenyl) carbamoyl) cyclopropane-1-carbonyl) oxy) phenyl) -3, 5-dioxo-1, 6-diene-1- -) -methylphenyl-1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate
(9)1- (6-methoxy-pyridin-3-yl) -7- (6-methyl-pyridin-3-yl) -hepta-1, 6-diene-3, 5-dione
(10)1- (6-methyl-pyridin-3-yl) -7- (4-phenoxy-phenyl) -hepta-1, 6-diene-3, 5-dione
(11)5- (1E, 6E) -1- (5- (pent-4-yn-1-yl) pyridin-2-yl) -7- (tetrahydro-2H-pyran-4-yl) hepta-1, 6-diene-3, 5-dione
(12)5- ((1E, 6E) -7- (5- ((3, 3-dimethylbutyryl) thio) tetrahydro-2H-pyran-3-yl) -3, 5-dioxo-1, 6-dien-1-yl) pyridin-2-yl 1- (3, 3-dimethylbutyl) cyclopropane-1-carboxylate
(13)6- ((1E, 6E) -7- (3-bromo-5- ((1- (3-methylbutyryl) cyclopropane-1-carbonyl) oxy) pyridin-2-yl) -3, 5-dioxo-1, 6-dien-1-yl) -4-ethylpyridin-3-yl 1- (3-methylbutyryl) cyclopropane-1-carboxylate
(14)6- ((1E, 6E) -7- (4- ((1-carbamoylcyclopropane-1-carbonyl) oxy) phenyl) -3, 5-dioxo-1, 6-dien-1-yl) -5-methyl-4H-pyran-3-yl-1- (4, 4-dimethylpentanoyl) cyclopropane-1-carboxylate
(15)6- ((1E, 6E) -7- (5- ((1- ((4-chlorophenyl) carbamoyl) cyclopropane-1-carbonyl) oxy) -3, 4-dimethyl-4H-thiopyran-2-yl) -3, 5-dioxohept-1, 6-dien-1-yl) -4, 5-dimethyl-4H-thiopyran-3-yl 1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate
(16)6- ((1E, 6E) -7- (5- ((1- ((4-chlorophenyl) carbamoyl) cyclopropane-1-carbonyl) oxy) -3, 4-dimethyl-4H-pyran-2-yl) -3, 5-dioxohept-1, 6-dien-1-yl) -4, 5-dimethyl-4H-thiopyran-3-yl 1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate
(17)4- (1- - (((6- ((1E, 6E) -7- (4- ((1- ((4-cyclohexylphenyl) carbamoyl) cyclopropane-1-carbonyl) oxy) -2-methylphenyl) -3, 5-dioxohept-1, 6-dien-1-yl) -4H-pyran-3-yl) oxy) carbonyl) cyclopropane-1-carboxamido) benzoic acid
(18)3- (2- ((1- ((4-butyl) carbamoyl) cyclopropane-1-carbonyl) oxy) -5- ((1E, 6E) -7- (2-chloro-4- ((1- ((4- ((2E, 4E) -6- (dimethylamino) -6-oxohexane-2, 4-dien-2-yl) phenyl) carbamoyl) cyclopropane-1-carbonyl) oxy) -3-ethylphenyl) -3, 5-dioxo-1, 6-dien-1-yl) phenyl) propanoic acid
(19)3- (2- ((1- ((4-butyl) carbamoyl) cyclopropane-1-carbonyl) oxy) -5- ((1E, 6E) -7- (2-chloro-3-ethyl-4- ((1- ((4- (2-isopropyl-4, 5-dimethylcyclohexyl) phenyl) carbamoyl) cyclopropane-1-carbonyl) oxy) phenyl) -3, 5-dioxo-1, 6-dien-1-yl) phenyl) propanoic acid
(20)4- (1- ((4- ((1E, 6E) -7- (3- (cyanomethyl) -4- ((1- ((4-cyclohexylphenyl) carbamoyl) cyclopropane-1-carbonyl) oxy-2-cyclohexylethyl) phenyl) -3, 5-dioxo-1, 6-dien-1-yl) phenoxy) carbonyl) cyclopropane-1-carboxamido) benzoic acid methyl ester
(21) (1E, 6E) -1, 7-bis (6-bromopyridin-2-yl) hepta-1, 6-diene-3, 5-dione
(22) (1E, 6E) -1, 7-bis (5-bromopyridin-3-yl) hepta-1, 6-diene-3, 5-dione
(23) ((1E, 6E) -3, 5-dioxaheptyl-1, 6-diene-1, 7-diyl) bis (2-methoxy-4, 1-phenylene) bis (1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate)
(24) (1E, 6E) -1- (6-bromopyridin-2-yl) -7-phenyl-1, 6-diene-3, 5-dione
(25) (1E, 6E) -1- (5-bromopyridin-3-yl) -7-phenyl-1, 6-diene-3, 5-dione
(26) (1E, 6E) -1- (6-bromopyridin-2-yl) -7- (4-hydroxy-3-methoxyphenyl) hepta-1, 6-diene-3, 5-dione
(27) (1E, 6E) -1- (5-bromopyridin-3-yl) -7- (4-hydroxy-3-methoxyphenyl) hepta-1, 6-diene-3, 5-dione
(28) 3-benzylidene-pentane-2, 4-dione
(29)3- (3-hydroxy-4-methoxybenzylidene) pentane-2, 4-dione
(30)1- (5- (2-acetyl-3-oxobut-1-en-1-yl) -2-methoxyphenyl) 1- (4-fluorophenyl) cyclopropane-1, 1-dicarboxylate
Detailed Description
Example 1 was carried out.
Compound name: 1- (4-methoxy-phenyl) -7-p-tolyl-hepta-1, 6-diene-3, 5-dione
The structure of the compound is as follows:
the synthetic route is as follows:
the synthesis method comprises the following steps:
1.0g of acetylacetone and 0.35 g of boron trioxide are initially introduced into a 250mL three-necked flask with 30mL of ethyl acetate and introduced into a microwave reactor, and the reflux apparatus is switched on. Starting a microwave reaction furnace, starting a program, starting heating, reacting for 10min at 50 ℃, then adding 3.0g of p-anisaldehyde and 9.2g of tributyl borate, stirring for 1min, dropwise adding 0.5g of triethylamine diluted in 20mL of ethyl acetate into the reaction solution within 9min, automatically carrying out the next step after complete dropwise addition, heating to 80 ℃, reacting for 15min, adding 49mL of 1mol/LHCl, continuing to react for 5min, and stopping the reaction. And taking out the reaction three-necked bottle, adding a certain amount of ethyl acetate and sufficient water into the reaction liquid for extraction, taking out an organic layer, dehydrating by using anhydrous sodium sulfate, evaporating under reduced pressure to remove the solvent, recrystallizing by using methanol to obtain orange yellow needle crystals, drying at 40 ℃ for 6 hours to obtain an intermediate 1, weighing, and calculating the yield.
1.0g of intermediate 1 and 0.35 g of boron trioxide were initially charged in a 250mL three-necked flask with 30mL of ethyl acetate and charged into a microwave reactor, and the reflux apparatus was started. Starting a microwave reaction furnace, starting a program, starting heating, reacting for 10min at 50 ℃, then adding 3.0g of p-tolualdehyde and 9.2g of tributyl borate, stirring for 1min, dropwise adding 0.5g of triethylamine diluted in 20mL of ethyl acetate into the reaction solution within 9min, automatically carrying out the next step after dropwise adding, heating to 80 ℃, reacting for 15min, adding 49mL of 1mol/LHCl, continuing to react for 5min, and stopping the reaction. Taking out the reaction three-neck flask, adding a certain amount of ethyl acetate and sufficient water into the reaction solution for extraction, taking out an organic layer, dehydrating with anhydrous sodium sulfate, evaporating under reduced pressure to remove the solvent, recrystallizing with methanol to obtain orange yellow needle crystals, drying at 40 ℃ for 6h to obtain the target compound, weighing, and calculating the yield.
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ4.59(2H)，δ7.19(1H)，δ7.38(1H)，δ7.38(1H)，δ7.19(1H)，δ7.13(1H)，δ6.68(1H)，δ6.68(1H)，δ7.13(1H)，δ5.0(1-OH)，δ6.67(1H)，δ6.67(1H)，δ7.54(1H)，δ7.54(1H)
Example 2 was carried out.
Compound name: 1- (4-allylphenyl) -7- (4-cyclohexyloxy-phenyl) -hepta-1, 6-diene-3, 5-dione
The structure of the compound is as follows:
synthesis method reference example 1
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ4.59(2H)，δ7.18(1H)，δ7.01(1H)，δ7.01(1H)，δ7.18(1H)，δ3.22(2H)，δ7.19(1H)，δ6.72(1H)，δ6.72(1H)，δ7.19(1H)，δ3.64(1H)，δ1.82(2H)，δ1.44(2H)，δ1.44(2H)，δ1.44(2H)，δ1.82(2H)，δ6.67(1H)，δ6.67(1H)，δ7.54(1H)，δ7.54(1H)
Example 3 was carried out.
Compound name: 1', 1- (((1E, 6E) -3, 5-dioxohept-1, 6-diene-1, 7-diyl) bis (2-methoxy-4, 1-phenylene)) 1, 1' -bis (4-fluorophenyl) bis (cyclopropane-1, 1-dicarboxylate)
The structure of the compound is as follows:
the synthetic route is as follows:
the synthesis method comprises the following steps:
weighing 2.16mmol of 1- ((4-fluorophenoxy) carbonyl) cyclopropane-1-carboxylic acid, 2.16mmol of EDCI and 2.16mmol of DMAP into a 100ml round-bottom flask, adding 25ml of anhydrous dichloromethane, magnetically stirring for 1h, then adding 2.16mmol of curcumin, stirring for 12h at normal temperature, detecting the reaction degree by TLC, stopping the reaction after the belt raw material basically disappears, concentrating under reduced pressure, adding 3.3g of silica gel for sample mixing, evaporating to dryness under reduced pressure, loading on a silica gel column, eluting with petroleum ether-acetone, and recrystallizing with acetone to obtain the compound.
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ7.18(1H)，δ7.18(1H)，δ7.23(1H)，δ7.23(1H)，δ7.10(1H)，δ7.10(1H)，δ7.17(1H)，δ7.17(1H)，δ7.30(1H)，δ7.30(1H)，δ7.17(1H)，δ7.17(1H)，δ7.18(1H)，δ7.18(1H)，δ3.87(3H)，δ3.87(3H)，δ4.59(2H)，δ7.60(H)，δ7.60(H)，δ6.91(H)，δ6.91(H)
Example 4 was carried out.
Compound name: 1- (3, 3-dimethyl-butyl) -cyclopropanecarboxylic acid 4- {7- [4- (3, 3-dimethyl-butyryloxy) -phenyl ] -3, 5-dioxo-hept-1, 6-dienyl } -phenyl ester
The structure of the compound is as follows:
synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ4.59(2H)，δ7.27(1H)，δ7.02(1H)，δ7.02(1H)，δ7.27(1H)，δ7.27(1H)，δ7.02(1H)，δ7.02(1H)，δ7.27(1H)，δ2.15(2H)，δ1.06(3H)，δ1.06(3H)，δ1.48(2H)，δ0.41(2H)，δ0.41(2H)，δ1.21(2H)，δ1.06(3H)，δ1.06(3H)，δ1.06(3H)，δ6.67(1H)，δ6.67(1H)，δ7.54(1H)，δ7.54(1H)
Example 5 was carried out.
Compound name: acetic acid-4- [3, 5-dioxo-7- (4-pent-4-ynyl-phenyl) -hept-1, 6-dienyl ] -phenyl ester
The structure of the compound is as follows:
synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ4.59(2H)，δ7.25(1H)，δ7.07(1H)，δ7.07(1H)，δ7.25(1H)，δ2.55(2H)，δ7.27(1H)，δ7.02(1H)，δ7.02(1H)，δ7.27(1H)，δ1.79(2H)，δ2.03(2H)，δ1.82(1H)，δ2.08(3H)，δ6.67(1H)，δ6.67(1H)，δ7.54(1H)，δ7.54(1H)
Example 6 was carried out.
Compound name: cyclohexanecarboxylic acid 4- (7- { 2-bromo-4- [1- (3-methyl-butyryl) -cyclopropanecarbonyloxy ] -phenyl } -3, 5-dioxo-hept-1, 6-dienyl) -2-ethyl-phenyl ester
The structure of the compound is as follows:
synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ4.59(2H)，δ7.16(1H)，δ6.96(1H)，δ7.19(1H)，δ7.13(1H)，δ6.97(1H)，δ7.09(1H)，δ2.27(1H)，δ0.69(2H)，δ0.69(2H)，δ2.41(2H)，δ2.06(1H)，δ1.01(3H)，δ1.01(3H)，δ2.59(2H)，δ1.24(3H)，δ1.67(2H)，δ1.44(2H)，δ1.44(2H)，δ1.44(2H)，δ1.67(2H)，δ6.50(1H)，δ6.67(1H)，δ7.54(1H)，δ7.54(1H)
Example 7 was carried out.
Compound name: 4- ((1E, 6E) -7- (4- ((1- (chlorocarbonyl) cyclopropane-1-carbonyl) oxy) -2-methylphenyl) -3, 5-dioxo-1, 6-dien-1-yl) phenyl 1- (cyclohexylcarbamoyl) cyclopropane-1-carboxylate
The structure of the compound is as follows:
synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ4.59(2H)，δ7.15(1H)，δ6.83(1H)，δ6.82(1H)，δ7.27(1H)，δ7.02(1H)，δ7.02(1H)，δ7.27(1H)，δ0.74(2H)，δ0.74(2H)，δ2.35(3H)，δ8.0(1-NH)，δ0.69(2H)，δ0.69(2H)，δ3.54(1H)，δ1.66(2H)，δ1.44(2H)，δ1.44(2H)，δ1.66(2H)，δ6.50(1H)，δ6.67(1H)，δ7.81(1H)，δ7.54(1H)
Example 8 was carried out.
Compound name: 4- ((1E, 6E) -7- (4- ((1- (chlorocarbonyl) tert-butyl-1-carbonyl) oxy) -2-methylphenyl) -3, 5-dioxo-1, 6-dien-1-yl) phenyl 1- (formyl) cyclopropane-1-carboxylate
The structure of the compound is as follows:
synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ4.59(2H)，δ7.15(1H)，δ6.83(1H)，δ6.82(1H)，δ7.27(1H)，δ7.02(1H)，δ7.02(1H)，δ7.27(1H)，δ0.69(2H)，δ0.69(2H)，δ2.37(2H)，δ2.35(3H)，δ6.0(2-NH)，δ0.69(2H)，δ0.69(2H)，δ1.06(3H)，δ1.06(3H)，δ1.06(3H)，δ6.50(1H)，δ6.67(1H)，δ7.81(1H)，δ7.54(1H)
Example 9 was carried out.
Compound name: 4- ((1E, 6E) -7- (4- ((1- ((4-chlorophenyl) carbamoyl) cyclopropane-1-carbonyl) oxy) phenyl) -3, 5-dioxo-1, 6-diene-1- -) -methylphenyl-1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate
The structure of the compound is as follows:
synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ4.59(2H)，δ7.15(1H)，δ6.83(1H)，δ6.82(1H)，δ7.27(1H)，δ7.02(1H)，δ7.02(1H)，δ7.27(1H)，δ0.79(2H)，δ0.79(2H)，δ8.0(1-NH)，δ2.35(3H)，δ8.0(1-NH)，δ0.79(2H)，δ0.79(2H)，δ1.06(3H)，δ1.06(3H)，δ1.06(3H)，δ6.50(1H)，δ6.67(1H)，δ7.81(1H)，δ7.54(1H)
Example 10 was carried out.
Compound name: 1- (6-methoxy-pyridin-3-yl) -7- (6-methyl-pyridin-3-yl) -hepta-1, 6-diene-3, 5-dione
The structure of the compound is as follows:
synthesis method reference example 1
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ4.59(2H)，δ7.78(1H)，δ7.22(1H)，δ8.71(1H)，δ2.55(3H)，δ7.37(1H)，δ6.63(1H)，δ7.79(1H)，δ3.37(3H)，δ6.67(1H)，δ6.67(1H)，δ7.57(1H)，δ7.54(1H)
Example 11 was carried out.
Compound name: 1- (6-methyl-pyridin-3-yl) -7- (4-phenoxy-phenyl) -hepta-1, 6-diene-3, 5-dione
The structure of the compound is as follows:
synthesis method reference example 1
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ4.59(2H)，δ7.78(1H)，δ7.22(1H)，δ8.71(1H)，δ2.55(3H)，δ7.26(1H)，δ6.87(1H)，δ6.87(1H)，δ7.26(1H)，δ6.92(1H)，δ7.22(1H)，δ6.98(1H)，δ3.37(3H)，δ6.67(1H)，δ6.67(1H)，δ7.57(1H)，δ7.54(1H)
Example 12 was carried out.
Compound name: 5- (1E, 6E) -1- (5- (pent-4-yn-1-yl) pyridin-2-yl) -7- (tetrahydro-2H-pyran-4-yl) hepta-1, 6-diene-3, 5-dione
The structure of the compound is as follows:
synthesis method reference example 1
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ4.59(2H)，δ2.28(1H)，δ8.61(1H)，δδ7.55(1H)，δ7.40(1H)，δ2.55(2H)，δ1.60(2H)，δ3.60(2H)，δ3.60(2H)，δ1.60(2H)，δ1.79(2H)，δ2.30(2H)，δ1.82(1H)，δ7.82(1H)，δ6.13(1H)，δ7.75(1H)，δ6.82(1H)
Example 13 was carried out.
Compound name: 5- ((1E, 6E) -7- (5- ((3, 3-dimethylbutyryl) thio) tetrahydro-2H-pyran-3-yl) -3, 5-dioxo-1, 6-dien-1-yl) pyridin-2-yl 1- (3, 3-dimethylbutyl) cyclopropane-1-carboxylate
The structure of the compound is as follows:
synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ4.59(2H)，δ2.28(1H)，δ7.79(1H)，δ6.63(1H)，δ7.73(1H)，δ2.23(2H)，δ2.91(1H)，δ4.23(2H)，δ3.60(2H)，δ1.48(2H)，δ0.41(2H)，δ0.41(2H)，δ1.21(2H)，δ1.06(3H)，δ1.06(3H)，δ1.06(3H)，δ2.23(2H)，δ1.06(3H)，δ1.06(3H)，δ1.06(3H)，δ6.67(1H)，δ6.13(1H)，δ7.54(1H)，δ6.82(1H)
Example 14 was carried out.
Compound name: 6- ((1E, 6E) -7- (3-bromo-5- ((1- (3-methylbutyryl) cyclopropane-1-carbonyl) oxy) pyridin-2-yl) -3, 5-dioxo-1, 6-dien-1-yl) -4-ethylpyridin-3-yl 1- (3-methylbutyryl) cyclopropane-1-carboxylate
The structure of the compound is as follows:
synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ4.59(2H)，δ8.87(1H)，δ7.67(1H)，δ7.54(1H)，δ8.61(1H)，δ0.69(2H)，δ0.69(2H)，δ2.41(2H)，δ2.06(1H)，δ1.01(3H)，δ1.01(3H)，δ2.59(2H)，δ1.24(3H)，δ0.69(2H)，δ0.69(2H)，δ2.41(2H)，δ2.06(1H)，δ1.01(3H)，δ1.01(3H)，δ7.28(1H)，δ7.28(1H)，δ7.75(1H)，δ7.75(1H)
Example 15 was carried out.
Compound name: 6- ((1E, 6E) -7- (4- ((1-carbamoylcyclopropane-1-carbonyl) oxy) phenyl) -3, 5-dioxo-1, 6-dien-1-yl) -5-methyl-4H-pyran-3-yl-1- (4, 4-dimethylpentanoyl) cyclopropane-1-carboxylate
The structure of the compound is as follows:
synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ4.59(2H)，δ2.66(2H)，δ2.66(2H)，δ0.69(2H)，δ0.69(2H)，δ2.37(2H)，δ1.71(3H)，δ6.0(2-NH)，δ0.69(2H)，δ0.69(2H)，δ1.06(3H)，δ1.06(3H)，δ1.06(3H)，δ6.33(1H)，δ6.33(1H)，δ7.40(1H)，δ7.40(1H)，δ5.80(1H)，δ4.65(1H)，δ5.80(1H)
Example 16 was carried out.
Compound name: 6- ((1E, 6E) -7- (5- ((1- ((4-chlorophenyl) carbamoyl) cyclopropane-1-carbonyl) oxy) -3, 4-dimethyl-4H-thiopyran-2-yl) -3, 5-dioxohept-1, 6-dien-1-yl) -4, 5-dimethyl-4H-thiopyran-3-yl 1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate
The structure of the compound is as follows:
synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ4.59(2H)，δ3.01(1H)，δ3.01(1H)，δ0.79(2H)，δ0.79(2H)，δ8.0(1-NH)，δ1.71(3H)，δ8.0(1-NH)，δ0.79(2H)，δ0.79(2H)，δ7.62(1H)，δ6.95(1H)，δ6.95(1H)，δ7.62(1H)，δ7.58(1H)，δ7.25(1H)，δ7.25(1H)，δ7.58(1H)，δ1.71(3H)，δ1.26(3H)，δ1.26(3H)，δ6.33(1H)，δ6.33(1H)，δ7.40(1H)，δ7.40(1H)，δ5.60(1H)，δ5.60(1H)
Example 17 was carried out.
Compound name: 6- ((1E, 6E) -7- (5- ((1- ((4-chlorophenyl) carbamoyl) cyclopropane-1-carbonyl) oxy) -3, 4-dimethyl-4H-pyran-2-yl) -3, 5-dioxohept-1, 6-dien-1-yl) -4, 5-dimethyl-4H-thiopyran-3-yl 1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate
The structure of the compound is as follows:
synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ4.59(2H)，δ3.01(1H)，δ2.83(1H)，δ0.79(2H)，δ0.79(2H)，δ8.0(1-NH)，δ1.71(3H)，δ8.0(1-NH)，δ0.79(2H)，δ0.79(2H)，δ7.62(1H)，δ6.95(1H)，δ6.95(1H)，δ7.62(1H)，δ7.58(1H)，δ7.25(1H)，δ7.25(1H)，δ7.58(1H)，δ1.71(3H)，δ1.26(3H)，δ1.26(3H)，δ6.33(1H)，δ6.33(1H)，δ7.40(1H)，δ7.40(1H)，δ5.60(1H)，δ5.60(1H)
Example 18 was carried out.
Compound name: 4- (1- - (((6- ((1E, 6E) -7- (4- ((1- ((4-cyclohexylphenyl) carbamoyl) cyclopropane-1-carbonyl) oxy) -2-methylphenyl) -3, 5-dioxohept-1, 6-dien-1-yl) -4H-pyran-3-yl) oxy) carbonyl) cyclopropane-1-carboxamido) benzoic acid
The structure of the compound is as follows:
synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ12.71(1-OH)，δ10.02(1-NH)，δ10.02(NH)，δ1.74(2H)，δ1.61(2H)，δ1.61(2H)，δ7.44(1H)，δ7.85(1H)，δ7.20(1H)，δ7.30(1H)，δ7.98(1H)，δ7.44(1H)，δ7.85(1H)，δ7.20(1H)，δ7.98(1H)，δ7.52(1H)，δ7.29(1H)，δ2.72(1H)，δ2.66(2H)，δ1.86(2H)，δ1.86(2H)，δ1.53(2H)，δ1.53(2H)，δ1.46(2H)，δ3.45(2H)，δ2.41(3H)，δ4.59(2H)，δ5.80(H)，δ4.65(H)，δ7.40(H)，δ7.97(H)，δ6.33(H)，δ6.74(H)
Example 19 was carried out.
Compound name: 3- (2- ((1- ((4-butyl) carbamoyl) cyclopropane-1-carbonyl) oxy) -5- ((1E, 6E) -7- (2-chloro-4- ((1- ((4- ((2E, 4E) -6- (dimethylamino) -6-oxohexane-2, 4-dien-2-yl) phenyl) carbamoyl) cyclopropane-1-carbonyl) oxy) -3-ethylphenyl) -3, 5-dioxo-1, 6-dien-1-yl) phenyl) propanoic acid
The structure of the compound is as follows:
synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ12.03(1-OH)，δ10.02(1-NH)，δ10.02(NH)，δ1.74(2H)，δ1.74(2H)，δ1.61(2H)，δ1.61(2H)，δ7.72(1H)，δ7.59(1H)，δ7.20(1H)，δ8.10(1H)，δ7.44(1H)，δ7.60(1H)，δ7.72(1H)，δ7.59(1H)，δ7.52(1H)，δ8.10(1H)，δ7.44(1H)，δ7.18(1H)，δ7.27(1H)，δ3.02(3H)，δ3.02(3H)，δ3.45(2H)，δ2.79(2H)，δ2.71(2H)，δ2.51(2H)，δ2.96(2H)，δ4.59(2H)，δ1.51(2H)，δ2.12(3H)，δ1.18(3H)，δ0.98(3H)，δ7.97(H)，δ6.57(H)，δ6.74(H)，δ6.91(H)，δ5.42(H)，δ7.36(H)
Example 20 was carried out.
Compound name: 3- (2- ((1- ((4-butyl) carbamoyl) cyclopropane-1-carbonyl) oxy) -5- ((1E, 6E) -7- (2-chloro-3-ethyl-4- ((1- ((4- (2-isopropyl-4, 5-dimethylcyclohexyl) phenyl) carbamoyl) cyclopropane-1-carbonyl) oxy) phenyl) -3, 5-dioxo-1, 6-dien-1-yl) phenyl) propanoic acid
Structure of compound
Synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ12.03(1-OH)，δ10.02(1-NH)，δ10.02(NH)，δ1.74(2H)，δ1.74(2H)，δ1.61(2H)，δ1.61(2H)，δ7.44(1H)，δ7.72(1H)，δ7.20(1H)，δ7.20(2H)，δ7.52(1H)，δ8.10(1H)，δ7.18(1H)，δ7.27(1H)，δ2.62(1H)，δ1.62(1H)，δ1.44(1H)，δ1.44(1H)，δ1.79(2H)，δ1.45(2H)，δ1.41(1H)，δ3.45(2H)，δ2.79(2H)，δ2.71(2H)，δ0.88(3H)，δ0.88(3H)，δ2.51(2H)，δ2.96(2H)，δ4.59(2H)，δ1.51(2H)，δ0.83(3H)，δ0.83(3H)，δ1.18(3H)，δ0.98(3H)，δ7.97(H)，δ7.60(H)，δ6.74(H)，δ6.91(H)
Example 21 was carried out.
Compound name: 4- (1- ((4- ((1E, 6E) -7- (3- (cyanomethyl) -4- ((1- ((4-cyclohexylphenyl) carbamoyl) cyclopropane-1-carbonyl) oxy-2-cyclohexylethyl) phenyl) -3, 5-dioxo-1, 6-dien-1-yl) phenoxy) carbonyl) cyclopropane-1-carboxamido) benzoic acid methyl ester
Structure of compound
Synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ10.02(1-NH)，δ10.02(NH)，δ1.74(2H)，δ1.74(2H)，δ1.61(2H)，δ1.61(2H)，δ7.28(1H)，δ7.44(1H)，δ7.75(1H)，δ7.20(1H)，δ7.16(2H)，δ7.83(1H)，δ7.62(1H)，δ7.28(1H)，δ7.44(1H)，δ7.75(1H)，δ7.20(1H)，δ7.62(1H)，δ7.83(1H)，δ7.34(1H)，δ7.54(1H)，δ2.72(1H)，δ1.50(1H)，δ1.86(2H)，δ1.86(2H)，δ1.63(2H)，δ1.63(2H)，δ1.53(2H)，δ1.53(2H)，δ1.53(2H)，δ1.53(2H)，δ1.46(2H)，δ1.46(2H)，δ4.49(2H)，δ3.45(2H)，δ4.33(2H)，δ1.70(2H)，δ4.59(2H)，δ7.60(H)，δ7.60(H)，δ6.91(H)，δ6.91(H)
Case 22 is implemented.
Compound name: (1E, 6E) -1, 7-bis (6-bromopyridin-2-yl) hepta-1, 6-diene-3, 5-dione
The structure of the compound is as follows:
synthesis method reference example 1
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ7.41(1H)，δ7.62(1H)，δ7.41(1H)，δ7.62(1H)，δ7.69(1H)，δ7.69(1H)，δ7.75(H)，δ7.75(H)，δ7.52(H)，δ7.52(H)
Example 23 was carried out.
Compound name: (1E, 6E) -1, 7-bis (5-bromopyridin-3-yl) hepta-1, 6-diene-3, 5-dione
The structure of the compound is as follows:
synthesis method reference example 1
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ8.41(1H)，δ9.02(1H)，δ8.41(1H)，δ9.02(1H)，δ8.22(1H)，δ8.22(1H)，δ4.59(2H)，δ7.70(H)，δ7.70(H)，δ6.91(H)，δ6.91(H)
Example 24 was carried out.
Compound name: ((1E, 6E) -3, 5-dioxaheptyl-1, 6-dien-1, 7-diyl) bis (2-methoxy-4, 1-phenylene) bis (1- (((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate)
The structure of the compound is as follows:
synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ10.02(OH)，δ10.02(OH)，δ1.74(2H)，δ1.74(2H)，δ1.74(2H)，δ1.74(2H)，δ7.14(1H)，δ7.14(1H)，δ7.23(1H)，δ7.10(1H)，δ7.59(1H)，δ7.59(1H)，δ7.23(1H)，δ7.30(1H)，δ7.14(1H)，δ7.14(1H)，δ7.10(1H)，δ7.59(1H)，δ7.59(1H)，δ7.30(1H)，δ3.87(3H)，δ3.87(3H)，δ4.59(2H)，δ7.60(H)，δ7.60(H)，δ6.91(H)，δ6.91(H)
Example 25 was carried out.
Compound name: (1E, 6E) -1- (6-bromopyridin-2-yl) -7-phenyl-1, 6-diene-3, 5-dione
The structure of the compound is as follows:
synthesis method reference example 1
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ7.62(1H)，δ7.54(1H)，δ7.41(1H)，δ7.54(1H)，δ7.69(1H)，δ7.38(1H)，δ7.38(1H)，δ7.33(1H)，δ4.59(2H)，δ7.75(H)，δ7.60(H)，δ7.52(H)，δ6.91(H)
Example 26 was carried out.
Compound name: (1E, 6E) -1- (5-bromopyridin-3-yl) -7-phenyl-1, 6-diene-3, 5-dione
The structure of the compound is as follows:
synthesis method reference example 1
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ7.62(1H)，δ7.54(1H)，δ7.41(1H)，δ7.54(1H)，δ7.69(1H)，δ7.38(1H)，δ7.38(1H)，δ7.33(1H)，δ4.59(2H)，δ7.75(H)，δ7.60(H)，δ7.52(H)，δ6.91(H)
Example 27 was carried out.
Compound name: (1E, 6E) -1- (6-bromopyridin-2-yl) -7- (4-hydroxy-3-methoxyphenyl) hepta-1, 6-diene-3, 5-dione
The structure of the compound is as follows:
synthesis method reference example 1
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ9.55(OH)，δ7.62(1H)，δ7.11(1H)，δ7.41(1H)，δ6.99(1H)，δ6.79(1H)，δ7.69(1H)，δ3.83(3H)，δ4.59(2H)，δ7.75(H)，δ7.60(H)，δ7.52(H)，δ6.91(H)
Example 28 was carried out.
Compound name: (1E, 6E) -1- (5-bromopyridin-3-yl) -7- (4-hydroxy-3-methoxyphenyl) hepta-1, 6-diene-3, 5-dione
The structure of the compound is as follows:
synthesis method reference example 1
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ9.55(OH)，δ8.41(1H)，δ9.02(1H)，δ8.22(1H)，δ7.11(1H)，δ6.99(1H)，δ6.79(1H)，δ3.83(3H)，δ4.59(2H)，δ7.70(H)，δ7.60(H)，δ7.69(H)，δ6.91(H)
Example 29 was carried out.
Compound name: 3-benzylidene-pentane-2, 4-dione
The structure of the compound is as follows:
synthesis method reference example 1
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ7.54(1H)，δ7.54(1H)，δ7.18(1H)，δ7.54(1H)，δ7.54(1H)，δ7.18(1H)，δ7.38(1H)，δ7.38(1H)，δ7.19(1H)，δ7.38(1H)，δ7.38(1H)，δ7.19(1H)，δ7.33(1H)，δ7.33(1H)，δ7.08(1H)，δ4.50(1H)，δ7.60(H)，δ7.60(H)，δ6.91(H)，δ6.91(H)
Example 30 was carried out.
Compound name: 3- (3-hydroxy-4-methoxybenzylidene) pentane-2, 4-dione
The structure of the compound is as follows:
synthetic methods reference examples 1 and 3
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ9.42(OH)，δ6.98(1H)，δ6.67(1H)，δ6.71(1H)，δ3.86(3H)，δ4.50(1H)，δ2.43(3H)，δ2.43(3H)
Example 31 was carried out.
Compound name: 1- (5- (2-acetyl-3-oxobut-1-en-1-yl) -2-methoxyphenyl) 1- (4-fluorophenyl) cyclopropane-1, 1-dicarboxylate
The structure of the compound is as follows:
synthesis method reference example 1
1H-NMR(400MHZ，CDCl3，TMS，ppm):
δ1.91(2H)，δ7.18(1H)，δ7.32(1H)，δ6.84(1H)，δ7.17(1H)，δ7.10(1H)，δ7.18(1H)，δ7.17(1H)，δ3.83(1H)，δ4.50(1H)，δ2.43(3H)，δ2.43(3H)
Example 32: inhibition of STAT3 protein
The effect of the study compound on the activity of purified recombinant STAT3 was to investigate the inhibitory activity of the compound on STAT3 from an enzymatic level. The experimental principle is that a luminescence enzyme detection method is adopted for detecting the ADP content generated by the reaction of STAT3 and a substrate Poly (4:1Glu, Tyr) peptide: after ADP is converted into ATP, the ATP can be used as a substrate of the Ultra-Glo luciferase catalytic reaction to generate a light signal. The luminescence signal is positively correlated with the amount of ADP and the enzyme activity. Thus, the inhibitory effect of compounds on recombinant STAT3 was determined by observing the luminescent signal generated by the reaction of STAT3 with the substrate.
The experimental method comprises the following steps:
the basic process is as follows: the compound with 10 concentration units with the lowest concentration of 0.0001 and the increment of 8um is selected to be incubated with STAT3 for 1 hour at 37 ℃, then substrate and ATP are added for mixing, a certain amount of ADP-Glo is added for mixing for 2 minutes after the reaction is carried out for 1 hour at 37 ℃, and the reaction is carried out for 1 hour at room temperature. Then adding the detection reagent, incubating for 1 hour at room temperature, and detecting by a chemiluminescence apparatus. Observation of STAT3 inhibition by Compounds with IC50And (4) showing. The results are shown in Table 1.
TABLE 1 STAT3 activation test results
Compound (I)
Inhibition of STAT3 IC50(μM)
Compounds of the invention example 1
<35
Compounds of the invention example 2
<29
Compounds of the invention example 3
<30
Compounds of the invention example 4
<28
Compounds of the invention example 5
<35
Compounds of the invention example 6
<34
Compounds of the invention example 7
<34
Compounds of the invention example 8
<32
Compounds of the invention in example 9
<35
Compounds of the invention example 10
<34
Compounds of the invention example 11
<35
Compounds of the invention example 12
<35
Compounds of the invention example 13
<31
Compounds of the invention example 14
<32
Compounds of the invention example 15
<34
Compounds of the invention example 16
<32
Compounds of the invention example 17
<31
Compounds of the invention example 18
<34
Compounds of the invention of example 19
<29
Compounds of the invention example 20
<28
Compounds of the invention example 21
<26
Compounds of the invention example 22
<34
Compounds of the invention example 23
<35
Compounds of the invention example 24
<26
Compounds of the invention example 25
<29
Compounds of the invention example 26
<31
Compounds of the invention example 27
<26
Compounds of the invention example 28
<35
Compounds of the invention example 29
<29
Compounds of the invention example 30
<27
Example 33: inhibition of NF-kB proteins
The effect of the compound on the activity of the purified recombinant NF-kB is studied from the enzymatic level of the inhibitory activity of the compound on NF-kB. The experimental principle is that a luminescence enzyme detection method is adopted for detecting the ADP content generated by the reaction of NF-kappa B and a substrate Poly (4:1Glu, Tyr) peptide: after ADP is converted into ATP, the ATP can be used as a substrate of the Ultra-Glo luciferase catalytic reaction to generate a light signal. The luminescence signal is positively correlated with the amount of ADP and the enzyme activity. Thus, the inhibitory effect of a compound on recombinant NF-. kappa.B was determined by observing the luminescent signal produced by the reaction of NF-. kappa.B with the substrate.
The experimental method comprises the following steps:
the basic process is as follows: the compound with 10 concentration units with the lowest concentration of 0.0001 increasing to 8um is selected to be incubated with NF-kappa B for 1 hour at 37 ℃, then substrate and ATP are added for mixing, a certain amount of ADP-Glo is added for mixing for 2 minutes after the reaction at 37 ℃ for 1 hour, and the reaction is carried out for 1 hour at room temperature. Then adding the detection reagent, incubating for 1 hour at room temperature, and detecting by a chemiluminescence apparatus. Observation of NF- κ B inhibition by Compounds with IC50And (4) showing. The results are shown in Table 2.
TABLE 2NF- κ B activation test results
Example 34: inhibition of NF-kB proteins
The effect of the compound on the activity of the purified recombinant NF-kB is studied from the enzymatic level of the inhibitory activity of the compound on NF-kB. The experimental principle is that a luminescence enzyme detection method is adopted for detecting the ADP content generated by the reaction of NF-kappa B and a substrate Poly (4:1Glu, Tyr) peptide: after ADP is converted into ATP, the ATP can be used as a substrate of the Ultra-Glo luciferase catalytic reaction to generate a light signal. The luminescence signal is positively correlated with the amount of ADP and the enzyme activity. Thus, the inhibitory effect of a compound on recombinant NF-. kappa.B was determined by observing the luminescent signal produced by the reaction of NF-. kappa.B with the substrate.
The experimental method comprises the following steps:
the basic process is as follows: the compound with 10 concentration units with the lowest concentration of 0.0001 increasing to 8um is selected to be incubated with NF-kappa B for 1 hour at 37 ℃, then substrate and ATP are added for mixing, a certain amount of ADP-Glo is added for mixing for 2 minutes after the reaction at 37 ℃ for 1 hour, and the reaction is carried out for 1 hour at room temperature. Then adding the detection reagent, incubating for 1 hour at room temperature, and detecting by a chemiluminescence apparatus. Observation of NF- κ B inhibition by Compounds with IC50And (4) showing. The results are shown in Table 3.
TABLE 3 NF- κ B activation test results
Example 35: inhibition of JAK2 protein
The effect of the compounds on the activity of purified recombinant JAK2 was investigated from the enzymatic level for the inhibitory activity of the compounds on JAK 2. The experimental principle is that a luminescence enzyme detection method is adopted for detecting the ADP content generated by the reaction of JAK2 and a substrate Poly (4:1Glu, Tyr) peptide: after ADP is converted into ATP, the ATP can be used as a substrate of the Ultra-Glo luciferase catalytic reaction to generate a light signal. The luminescence signal is positively correlated with the amount of ADP and the enzyme activity. Therefore, the inhibitory effect of compounds on recombinant JAK2 was determined by observing the luminescent signal generated by reaction of JAK2 with a substrate.
The experimental method comprises the following steps:
the basic process is as follows: the compound with 10 concentration units with the lowest concentration of 0.0001 increasing to 8um is selected to be incubated with JAK2 for 1 hour at 37 ℃, then substrate and ATP are added for mixing, a certain amount of ADP-Glo is added for mixing for 2 minutes after the reaction at 37 ℃ for 1 hour, and the reaction is carried out for 1 hour at room temperature. Then adding the detection reagent, incubating for 1 hour at room temperature, and detecting by a chemiluminescence apparatus. Observation of JAK2 inhibition by Compounds with IC50And (4) showing. The results are shown in Table 4.
TABLE 4 JAK2 activation test results
Compound (I)
Inhibitory effect IC on JAK250(μM)
Compounds of the invention example 1
<26
Compounds of the invention example 2
<35
Compounds of the invention example 3
<35
Compounds of the invention example 4
<33
Compounds of the invention example 5
<29
Compounds of the invention example 6
<23
Compounds of the invention example 7
<35
Compounds of the invention example 8
<21
Compounds of the invention in example 9
<35
Compounds of the invention example 10
<35
Compounds of the invention example 11
<34
Compounds of the invention example 12
<35
Compounds of the invention example 13
<28
Compounds of the invention example 14
<35
Compounds of the invention example 15
<35
Compounds of the invention example 16
<35
Compounds of the invention example 17
<28
Compounds of the invention example 18
<29
Compounds of the invention of example 19
<28
Compounds of the invention example 20
<35
Compounds of the invention example 21
<34
Compounds of the invention example 22
<33
Compounds of the invention example 23
<29
Compounds of the invention example 24
<24
Compounds of the invention example 25
<25
Compounds of the invention example 26
<28
Compounds of the invention example 27
<29
Compounds of the invention example 28
<31
Compounds of the invention example 29
<32
Compounds of the invention example 30
<31
Example 36: inhibition of TNF-alpha protein
The effect of the compounds on the activity of purified recombinant TNF-. alpha.was investigated from the enzymatic level for the TNF-. alpha.inhibitory activity of the compounds. The experimental principle is that a luminescence enzyme detection method is adopted for detecting the ADP content generated by the reaction of TNF-alpha and substrate Poly (4:1Glu, Tyr) peptide: after ADP is converted into ATP, the ATP can be used as a substrate of the Ultra-Glo luciferase catalytic reaction to generate a light signal. The luminescence signal is positively correlated with the amount of ADP and the enzyme activity. Thus, the inhibitory effect of a compound on recombinant TNF- α was determined by observing the luminescent signal produced by the reaction of TNF- α with the substrate.
The experimental method comprises the following steps:
the basic process is as follows: the compound with 10 concentration units with the lowest concentration of 0.0001 and the increment of 8um is selected to be incubated with TNF-alpha for 1 hour at 37 ℃, then substrate and ATP are added for mixing, a certain amount of ADP-Glo is added for mixing for 2 minutes after the reaction at 37 ℃ for 1 hour, and the reaction is carried out for 1 hour at room temperature. Then adding the detection reagent, incubating for 1 hour at room temperature, and detecting by a chemiluminescence apparatus. Observation of TNF-alpha inhibition by Compounds, with IC50And (4) showing. The results are shown in Table 5.
TABLE 5 TNF-alpha activation test results
Example 37: acute toxicity test in mice
Taking the compound, observing the acute toxicity of the single oral gavage administration of the mice, and calculating LD50. The results are shown in Table 6.
TABLE 6 acute toxicity test results of single oral gavage administration in mice