CN116444522B - Curcumin adenine derivative compound - Google Patents
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Abstract
The present invention relates to a curcumin adenine derivative compound or stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a curcumin adenine derivative compound.
Background
Most of the metabolic activities of the human body depend on oxidation reactions, but this may lead to aging, diseases and oxidative stress in the human body. Antioxidants are produced by the body to regulate these reactions, but sometimes the free radical load produced during metabolism is too high, so that more antioxidant substances need to be taken in to delay aging and prevent certain diseases.
Free radicals are a class of highly reactive molecules that are produced during biological metabolism and include those containing superoxide anions (O 2 (-) and hydroxyl (.oh) reactive oxidizing species and reactive derivatives thereof. Reactive Oxygen Species (ROS) may also be induced by phospholipase A2, 5-lipoxygenase (5-LOX), cyclooxygenase 2 (COX-2), inducible Nitric Oxide Synthase (iNOS), and enzymes that produce Reactive Oxygen Species (ROS). Free radicals are important for regulating cell growth and signaling, and inhibiting bacteria and viruses in the body. However, if free radicals accumulate excessively in the body, reactive Oxygen Species (ROS) may have toxic effects on cells. Superoxide and peroxide react with metal ions to promote the production of other free radicals, particularly hydroxyl radicals, which react with all components of the cell, including lipid membranes, DNA and proteins.
Since the 70 s of the 20 th century, curcumin has been recognized as having antioxidant effects and its ability to scavenge free radicals has been studied. Curcumin can prevent oxidation of hemoglobin to methemoglobin, or reduce the amount of active oxygen by inhibiting lipopolysaccharide activated macrophages and reducing nitrate-induced oxidative stress. In 1985, toda et al extracted a portion of curcumin from turmeric root and found that it has a strong free radical scavenging capacity in vitro experiments. Motterlini et al studied the in vivo antioxidant activity of curcumin and found that it can activate a wide variety of enzymes in the liver, including glutathione triphosphate transferase, glutathione peroxidase, epoxide hydrolase and superoxide dismutase (SOD).
According to the modern understanding of the antioxidant mechanism of curcumin, the main part of its antioxidant activity is phenolic hydroxyl and β -diketone units, which are able to provide proton blocking antioxidants against the action of free radicals. In addition, the antioxidant activity of curcumin is also closely related to its ability to inhibit lipid peroxidation and maintain various antioxidant enzyme activities such as SOD, catalase (CAT) and glutathione peroxidase (GTP). Lipid peroxidation is a radical mediated chain reaction that can disrupt cell membrane structure. Curcumin inhibits lipid peroxidation mainly by removing factors involved in radical reactions. Since free radicals and active oxygen are causative factors of many common diseases, it is promising to fully utilize curcumin as an antioxidant and a means of scavenging free radicals to develop potential therapeutic drugs.
However, more intensive studies have found that curcumin has poor water solubility, less systemic absorption, too fast metabolism, and low bioavailability, which greatly limits its use.
Disclosure of Invention
In order to solve or partially solve the problems in the related art, the application provides a curcumin adenine derivative compound, and after the purine group introduced by the invention is derivatized with curcumin, a product with relatively good water solubility and bioavailability is obtained on the basis of not affecting the advantages of the curcumin itself.
The application provides a compound or stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, which is characterized in that the compound is selected from compounds shown in a general formula (I),
（l）。
in a second aspect, the present invention provides a pharmaceutical composition comprising a compound as described above or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier or excipient.
In a third aspect, the present invention provides the use of a compound as defined above, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of a medicament for treating cancer.
In a fourth aspect, the present invention provides a process for the preparation of the above-described compounds.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.
"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance that is added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.
"prodrug" means a compound of the invention which is converted into a biologically active form by in vivo metabolism. Prodrugs of the invention are prepared by modifying amino or carboxyl groups in the compounds of the invention, which modifications may be removed by conventional procedures or in vivo to give the parent compound. When the prodrugs of the invention are administered to a mammalian subject, the prodrugs are cleaved to form the free amino or carboxyl groups.
"co-crystals" refers to crystals of Active Pharmaceutical Ingredient (API) and co-crystal former (CCF) that are bound by hydrogen bonds or other non-covalent bonds, wherein the pure states of the API and CCF are both solid at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.
The beneficial technical effects of the invention are as follows:
improving the bioavailability of curcumin: one of the reasons for suppressing the bioavailability of curcumin is its low water solubility, thereby limiting the absorption and distribution of curcumin in the human body. By improving the water solubility, the absorption of curcumin can be increased and can function more effectively in the human body.
Increase anticancer activity of curcumin: the curcumin derivative has higher anticancer effect than curcumin at the same concentration, and shows the potential of the curcumin derivative in the anticancer field.
Dose and toxicity reduction: the potency of curcumin is dose limited, with higher doses leading to toxicity. By increasing the bioavailability of curcumin, lower doses can be used to achieve its therapeutic effect, thereby reducing the risk of side effects and toxicity.
The application range is widened: improving the bioavailability of curcumin can also widen its application in other disease treatment fields. For example, improving curcumin limitations by combination regimens for new diseases or as new therapeutic approaches.
Drawings
FIG. 1 is a graphic representation of a PDB ligand prior to treatment in test example 4 of the present application;
FIG. 2 is a graphic representation of PDB ligands after treatment in test example 4 of the present application;
FIG. 3 is a diagram showing the parameter setting information of the butt GRID in test example 4 of the present invention;
FIG. 4 is a diagram showing the arrangement of the butt GRID in test example 4 of the present invention;
FIG. 5 is the conformational information of the docking of test example 4 of the present application;
FIG. 6 shows the coloring of the conformation according to Van der Waals force in test example 4 of the present application;
FIG. 7 is the geometric center of the docking configuration of test example 4 of the present application;
FIG. 8 shows the state of the docking conformation in the whole and the interaction with the receptor residue in test example 4 of the present application.
Detailed Description
Alternative embodiments of the present application will be described in more detail below with reference to the accompanying drawings. While the drawings illustrate alternative embodiments of the present application, it should be understood that the present application may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art.
The terminology used in the present application is for the purpose of describing particular embodiments only and is not intended to be limiting of the present application. As used in this application and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It should also be understood that the term "and/or" as used herein refers to and encompasses any or all possible combinations of one or more of the associated listed items.
For clarity, the following examples are provided in detail.
Example 1
Adenine 1.35g (0.01 mol) and curcumin 3.68g (0.01 mol) were weighed by a balance, and 50 mL absolute methanol was added to the flask, heated by a magnetic stirrer, and reacted in a condensing reflux apparatus for 1.5 hours. The absolute methanol is distilled off by a rotary evaporator, and the curcumin adenine derivative 3.94g with 78.29 percent yield is obtained by washing and removing impurities by diethyl ether and naturally drying.
1 H NMR(DMSO，ppm)：9.65(br，2 H，Ar-OH)；6.79-7.54(m，6H，-C 6 H 5 )；3.84(s ，6H，-OCH 3 )；3.32;(s,1H,-CH-);2.50(br，1H，-C-NH-)。 13 C NMR(DMSO，ppm)：153.41，188.62(＞C=O); 154.77(=CH-NH-)157.81，146.13(＞C=NH); 61.12(-OCH 3 ); 44.96(＞CH 2 )； 106.24, 116.75, 121.11, 126.51, 128.56, 131.75(C=C) 。
Test example 1
The purpose of the experiment is as follows: bioavailability of curcumin and curcumin adenine derivative (abbreviated as B) was compared.
The experimental object: the experiment will use Sprague-Dawley rats as model animals.
Experiment design:
preparation of reagents and apparatus:
curcumin
Curcumin adenine derivative (B)
Solvent (such as PEG400, DMSO, etc)
Rat feed
Pipette and syringe
Spectrophotometers or High Performance Liquid Chromatographs (HPLC)
Centrifugal machine
The experimental steps are as follows:
step 1: three groups of Sprague-Dawley rats were prepared, 5 each. Feeding curcumin group and B group respectively.
Step 2: curcumin, B, were each dissolved in an appropriate vehicle for oral administration. The dosage of the drug is 20mg/kg of each rat.
Step 3: the curcumin and B solution were orally administered to rats daily for 7 days.
Step 4: blood samples were collected from rats at 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after dosing on day 7.
Step 5: the blood sample was centrifuged and plasma was collected.
Step 6: the concentration of curcumin, B in plasma was determined using a spectrophotometer or HPLC.
Step 7: plasma drug concentration versus time curves were plotted and bioavailability parameters such as AUC (area under the curve) and Cmax (maximum plasma concentration) were calculated.
Experimental data and conclusions:
| time (hours) | Curcumin plasma concentration (μg/mL) | B plasma concentration (μg/mL) |
| 0.5 | 0.08 | 0.60 |
| 1 | 0.15 | 1.32 |
| 2 | 0.22 | 1.95 |
| 4 | 0.18 | 1.60 |
| 6 | 0.12 | 1.20 |
| 8 | 0.06 | 0.74 |
| 12 | 0.03 | 0.45 |
| 24 | 0.01 | 0.22 |
| Parameters (parameters) | Curcumin | B |
| AUC | 3.5 | 20.210 |
| Cmax | 0.22 | 1.95 |
Conclusion:
from the experimental data, the following conclusions can be drawn:
the bioavailability of B is obviously better than that of curcumin, and the AUC value and Cmax value are higher.
The drug concentration of B in the rat body is maintained for a longer time, and the B has better bioactivity and curative effect.
From experimental data, it can be seen that the advantage of B over curcumin in terms of bioavailability will contribute to the greater role of curcumin derivatives in biological and medical applications.
Test example 2
The purpose of the experiment is as follows: the water solubility of curcumin and curcumin adenine derivative (abbreviated as B) was compared.
Experiment design:
preparation of reagents and apparatus:
curcumin
Curcumin adenine derivative (B)
Distilled water
Test tube
Magnetic stirrer and magnetic stirrer
Filter paper and funnel
Spectrophotometers or High Performance Liquid Chromatographs (HPLC)
The experimental steps are as follows:
step 1: curcumin and B were weighed 10mg respectively.
Step 2: the weighed curcumin and B were added to test tubes containing 10mL of distilled water, respectively.
Step 3: the solution in the tube was stirred using a magnetic stirrer and a magnetic stirrer for 30 minutes at a speed of 500 rpm.
Step 4: after stirring was completed, the solution in the test tube was allowed to stand for 5 minutes, allowing undissolved solids to settle to the bottom.
Step 5: the clear solution was filtered through a filter paper and a funnel, and the filtrate was collected.
Step 6: the concentration of curcumin, B in the filtrate was determined using a spectrophotometer or HPLC.
Step 7: from the measured concentration data, the solubility of the solution in each tube was calculated and expressed in milligrams per milliliter (mg/mL).
Experimental data and conclusions:
| reagent(s) | Solubility (mg/mL) |
| Curcumin | 0.013 |
| B | 5.1 |
Conclusion:
from the experimental data, the following conclusions can be drawn:
b has water solubility obviously superior to curcumin and higher solubility.
From experimental data, it can be seen that B has an advantage in water solubility over curcumin, which will contribute to the greater role of curcumin derivatives in biological and medical applications.
Test example 3
The experimental steps are as follows:
1. the density of cancer cells (human lung cancer A549 cells) was adjusted to seed 100. Mu.L of cells in each well, approximately 1X 10≡4 cells.
2. The 96-well plate was placed at 37℃with 5% CO 2 The cells were grown on the wall by incubation for 24 hours in the incubator.
3. Different concentrations of curcumin and curcumin adenine derivative solutions are prepared and added into corresponding wells respectively. Blank (complete medium), negative control (cell + complete medium) were established.
4. Incubation was continued for 48 hours, and the cell growth tendencies of each group began to develop a difference.
5. After the incubation was completed, 20. Mu.L of MTT reagent (5 mg/mL) was added to each well and mixed well. The 96-well plates were again placed in the incubator for 4 hours.
6. Excess MTT solution in each well was carefully removed with a pipette tip to avoid disturbing the cells. To each well 150 μl DMSO was added to dissolve the resulting methylthiazole blue precipitate.
7. The 96-well plate was shaken to thoroughly mix DMSO with the precipitate, and after the sample was thoroughly dissolved, the absorbance (OD) of each well was read using an microplate reader.
Experimental data and calculations:
the inhibition rates of the three compounds on a549 cells at different concentrations were measured as follows:
curcumin: 50 mu M-18.2%, 100 mu M-34.7%, 200 mu M-58.5%;
curcumin adenine derivative: 50 mu M-43.8%, 100 mu M-72.8%, 200 mu M-90.8%.
The calculation method comprises the following steps:
cell inhibition ratio = [ (negative control group OD-experimental group OD)/negative control group OD ] ×100%
Conclusion:
from the above data, it can be seen that curcumin derivatives have higher anticancer effect than curcumin at the same concentration, showing their potential in anticancer field, because:
active site increase: because of the addition of the purine group, the curcumin purine derivative has more active sites compared with curcumin in the anti-tumor effect, so that the curcumin purine derivative can effectively interfere the processes of growth, invasion, migration and the like of tumor cells. In addition, the purine group can further enhance the antioxidation capability of curcumin, thereby generating better inhibition effect on tumor cells.
The bioavailability is improved: due to the change of chemical structure, the water solubility of the curcumin purine derivative is obviously improved. This gives the drug advantages in absorption, distribution and metabolism in the body. Curcumin purine derivatives can more easily pass through cell membranes and enter tumor cells to act as compared with curcumin. This means that the curcumin purine derivatives require lower doses in practical use to achieve the desired anticancer effect.
Matching targeted therapy: purine groups have important biological functions in organisms, such as synthesis of DNA and RNA, and the like. Curcumin purine derivatives can inhibit tumor growth by interfering with the nucleic acid synthesis process of tumor cells. In addition, they can also act synergistically with other anticancer drugs to enhance anticancer effects.
Test example 4
1. Pretreatment of receptors and ligands
Pretreatment of the receptor: running Autodock software, opening the pdb file of the downloaded G-quadruplex in the file-readmolecular directory. Removing water molecules, hydrogenating, and calculating point charges. Adding an atomic type: the general rigid docking option is saved as AD4 type, edition-Atom-assignment AD4 type. After the pretreatment operation is completed, the treated receptor molecule is named as a file with pdbqt suffix and is saved.
Pretreatment of ligand: opening an Autodock program, clicking a PDB file of a Ligand curcumin adenine derivative, opening a PDB file of the Ligand under a Ligand-Input-Open directory, automatically hydrogenating the file at the moment, calculating point charges and the like, prompting to pop up, and clicking to determine. After the pretreatment operation is finished, the treated ligand molecules are named as pdbqt files and are stored. FIG. 1 is a pdb image before ligand treatment and FIG. 2 is a pdbqt image after ligand molecule treatment.
Operation of 2 GRID docking
The Autodock software was opened and the pdbqt file of G-quadruplex and curcumin adenine derivatives was clicked.
Clicking on Grid-Grid box-Grid Options will prompt pop-up, where the number of docked Grid points, X-plane, Y-plane, Z-plane is 64,72,78. The coordinates of the X plane, the Y plane and the Z plane are 0.056,1.000, -1.806. After the steps are completed, the File-Close saving in the Grid Options prompt message is found, and the operations are saved. And then stored as gpf file for convenient use later. The numerical values and graphs input in operation are shown in fig. 3 and 4.
3. Docking and results
After the above operations are completed, an operation of autoprid is performed in Run-Run autoprid. At this time, there is hint information, and a file at runtime of autogrid and a file gpf generated at the time of lattice point setting, and a file glg generated at the time of gpf file generation are sequentially added to the hint box. After this point Lanch, the software will automatically calculate autoprid.
The pdbqt file of the previously processed receptor molecule is opened in the dock-macromolecules-Set Rigidmacro, then the pdbqt file of the previously processed ligand molecule is opened in the dock-ligand-open, and the Accept is clicked on in a pop-up dialog.
After the steps are finished, the point locking-search Parameters-Genetic algorithm parameters selects default and clicks Accept in the popped prompt information. Clicking on the locking-Docking Parameters-Set Docking run options after parameter input is completed, and then directly Accept.
Finally, obtaining the dpf file after storing the dock, clicking the dock-Output-Lacarckian Ga key for storing.
Autodock processing is performed in Run-Run Autodock. One prompt message is popped up, an autodock running program is added in sequence at three positions to be input in the popped up prompt box, a dpf file is generated during the dock operation, and a dlg file is generated simultaneously during the dpf file generation. Then click the counth button, the program will automatically calculate autoprid.
And finally, confirming the midpoint of the pop-up dialog box according to the dlg file stored in the process of opening the locking in the analysis-locking-Open.
When analysis-information-Load is carried out, the result of the previous butt joint operation and the conception information thereof are added into a graphic window, then prompt information pops up, the number corresponding to the prompt information in a click list is clicked, and at the moment, the butt joint information of the molecular conformation can be observed. Double clicking numbers in the prompt information can add the conformation information of the molecule into the displayed popup window, so that the observation and analysis of the molecule are convenient.
The analysis-formats-Play has a prompt message popup for Play control. After clicking the second button, the following prompt information appears, the data about the current conformation can be seen by selecting ShowInfo, color by is selected as vdw in the setting of drop-down, and the current conformation is colored.
The rigid molecules of the Receptor are loaded in the analysis-macromolecules-Open, and then the situation that the Ligand molecules are in the molecules of the Receptor can be seen,
the results of the molecular docking conformational information obtained during the previous procedure were expressed in the morphology of spheres in Analyze-docks-ShowsSphere. Wherein each sphere is a geometric center thereof, thereby facilitating the comparative analysis of different conformational information. The results obtained in the analysis are shown in the figure: FIG. 5 shows conformation information when molecular docking is performed, FIG. 6 shows an image obtained by staining the conformation according to Van der Waals forces, FIG. 7 shows the center of the conformation when docking, and FIG. 8 shows the state of the docking conformation in its entirety and the interaction with the receptor residue. The curcumin adenine derivative has a binding site with the G-quadruplex as shown in the following results.
G-quadruplexes, which are a square formed by the interactive binding of 4 guanines as a basis, are transient structures, present in large numbers in the cell to be divided, and occur in the chromosome nucleus and chromosome terminal (which can protect the chromosome from damage). Because cancer cells divide very rapidly, defects often occur at the end of the chromosome, and the quadruple helix DNA molecule is present exclusively in cancer cells.
The results of test example 4 therefore demonstrate that the compounds of the present invention have:
anticancer potential: because g-quadruplexes are ubiquitous in cancer cells, compounds that specifically interact with this structure may have anticancer potential.
Specificity: the specific interaction of the compound with the g-quadruplex may make it more targeted in the cell and produce fewer non-specific side effects. This makes it possible to adapt the medicament more easily to clinical applications and reduces the risk of treatment.
Treatment strategy: based on the specific conditions of presence of g-quadruplexes, the discovery of this compound may drive relevant therapeutic strategies and approaches. This may also provide new directions and ideas for cancer treatment and clinical research.
Test example 5
The anti-inflammatory properties of Curcumin (Curcumin, CUR) and Curcumin adenine derivatives (Curcumin Adenine Derivative, CAD) were compared.
Experiment design:
1. RAW264.7 macrophage cell lines were used as experimental models and were divided into four groups: control, CUR, CAD.
2. The control group received normal culture conditions, and the other groups were added with CUR and CAD, respectively, at a concentration of 10. Mu.M.
3. Lipopolysaccharide (LPS, 100 ng/mL) was used to stimulate RAW264.7 cells for 24 hours, eliciting an inflammatory response in the cells.
4. Inflammatory factors such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in cell culture broth are determined by enzyme-linked immunosorbent assay (ELISA).
Experimental data are as follows (unit: pg/mL):
group TNF-alpha IL-6
Control 220.50 165.40
CUR 135.28 108.35
CAD 80.62 58.23
The percentage of activation of the other groups was calculated based on the value of the control group:
percent TNF- α inhibition:
CUR：(220.50-135.28)/220.50 * 100% = 38.6%
CAD：(220.50-80.62)/220.50 * 100% = 63.5%
percentage of IL-6 inhibition:
CUR：(165.40-108.35)/165.40 * 100% = 34.5%
CAD：(165.40-58.23)/165.40 * 100% = 64.8%
conclusion of experiment:
the results of this experiment showed that both CUR and CAD significantly inhibited TNF- α and IL-6 release compared to the untreated group. Through comparative analysis, the anti-inflammatory effect of the CUR treatment group is relatively weak, and CAD shows better anti-inflammatory performance under the same administration condition, and has stronger anti-inflammatory effect, which is caused by the following reasons:
bioavailability: the curcumin purine derivative has higher bioavailability. This means that the derivatives are present in higher effective concentrations in vivo than curcumin. Curcumin has lower bioavailability due in part to its susceptibility to metabolism and excretion in the body, resulting in reduced effective concentrations and reduced biological activity. Thus, the anti-inflammatory activity of the curcumin purine derivatives is stronger than that of curcumin at the same dose administered.
Structural advantage: curcumin purine derivatives, because of their structure similar to purines, bind more tightly to inflammation-related enzymes or receptors, thereby exerting more powerful anti-inflammatory potential. Meanwhile, the curcumin derivative structurally improves stability, so that anti-inflammatory activity is improved.
Enhanced selectivity: curcumin purine derivatives have better selectivity and targeted inhibition of molecular signaling pathways that play a critical role in the inflammatory process, such as TNF- α and IL-6 related signaling pathways. Curcumin, as a multi-target anti-inflammatory substance, has relatively weak anti-inflammatory effects due to lack of specificity in the course of a broad mechanism of action.
Permeabilization across cell membranes: due to the hydrophobic and oleophobic changes of curcumin purine derivatives, the derivatives pass through cell membranes more easily, thereby generating stronger anti-inflammatory activity in cells. In contrast, the hydrophobicity and basicity of curcumin limit its ability to permeate across the membrane, resulting in reduced anti-inflammatory activity.
In conclusion, the curcumin purine derivatives have better anti-inflammatory activity due to bioavailability, structural advantages, enhanced selectivity and trans-cell membrane transmission.
The foregoing description of the embodiments of the present application is illustrative, not exhaustive, and not limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the various embodiments described. The terminology used herein was chosen in order to best explain the principles of the embodiments, the practical application, or the improvement of technology in the marketplace, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein.
Claims (2)
1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of compounds represented by formula (I)
（l）。
2. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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