CN111808081A - 2, 8-disubstituted quinazoline derivatives, preparation method thereof and application thereof in antitumor drugs - Google Patents
2, 8-disubstituted quinazoline derivatives, preparation method thereof and application thereof in antitumor drugs Download PDFInfo
- Publication number
- CN111808081A CN111808081A CN202010742612.3A CN202010742612A CN111808081A CN 111808081 A CN111808081 A CN 111808081A CN 202010742612 A CN202010742612 A CN 202010742612A CN 111808081 A CN111808081 A CN 111808081A
- Authority
- CN
- China
- Prior art keywords
- substituted
- derivatives
- alkyl
- disubstituted quinazoline
- quinazoline derivatives
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and provides a 2, 8-disubstituted quinazoline derivative shown as a formula I and a preparation method thereof.
Description
Technical Field
The invention belongs to the field of drug synthesis, and relates to 2, 8-disubstituted quinazoline derivatives, pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the compounds, preparation methods of the derivatives and the pharmaceutically acceptable salts, hydrates, solvates or prodrugs, and applications of the derivatives as therapeutic agents, especially ALK inhibitors.
Background
Tumors are new organisms formed by local tissue cell proliferation under the action of various tumorigenic factors, and can be divided into two major types, namely benign tumors and malignant tumors according to the cell characteristics and the degree of harm to the organisms. Benign tumor refers to tumor without infiltration and metastasis ability, most of which will not be malignant, and is easy to be excised and grow slowly during operation, and has little influence on the body. The malignant tumor has the characteristics of abnormal cell differentiation and proliferation, uncontrolled growth, infiltrability, transferability and the like, has extremely strong destructive power to normal tissues of a human body, becomes the first killer of human in the new century, seriously threatens the health of human and is one of the biggest public health problems in the world.
Anaplastic Lymphoma Kinase (ALK) is a tyrosine protein kinase closely related to malignant tumors, can be activated by fusing with other genes, and regulates the growth, differentiation and migration of tumors through a series of downstream cell signal pathways. Therefore, ALK is now an important drug target for designing and developing antitumor drugs.
The first generation of ALK inhibitor Crizotinib (Crizotinib) is the current first-line clinical drug for ALK-positive non-small cell lung cancer, but the Crizotinib has two main problems of drug-resistant mutation and tumor brain metastasis. Second-generation ALK inhibitors, namely, erlotinib (Alectinib), Ceritinib (Ceritinib), Brigatinib (Brigatinib), and the like, have been developed to solve the problem of drug resistance, but new drug-resistant mutations have been developed. At present, the third-generation ALK inhibitor Lauratinib (Lorlatinib) is obtained by structural modification of researchers on the basis of crizotinib, but the problem of continuous drug resistance cannot be solved at present.
Therefore, research and development of novel ALK inhibitors can improve the binding affinity of drugs and target proteins and improve the inhibitory activity on drug-resistant tumor cells, and have important scientific significance.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a 2, 8-disubstituted quinazoline derivative, a geometric isomer or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and an application thereof as an ALK inhibitor.
In order to achieve the purpose, the 2, 8-disubstituted quinazoline derivatives provided by the invention have the following structural general formula:
wherein R is1Selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy, N-alkylamido, formyl;
R2selected from hydrogen, C1-C6Alkyl, C substituted by halogen1-C6Alkyl or C1-C6An alkoxy group.
Preferably, R1Is selected from C1-C6Alkoxy, N-alkylamido, formyl; r2Selected from hydrogen, C1-C6Alkyl, C substituted by halogen1-C6Alkyl radical, C3-C6A cycloalkyl group.
The 2, 8-disubstituted quinazoline derivatives, geometric isomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof are selected from:
in addition, some of the compounds of formula (I) of the present invention have basic groups and may form pharmaceutically acceptable salts with acids according to conventional methods in the art to which the present invention pertains. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like. Most preferred is hydrochloric acid.
The "hydrate" of the present invention means an association of solvent molecules with water.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
The invention also includes prodrugs of the derivatives of the invention. Prodrugs of the derivatives of the invention are derivatives of formula (I) which may themselves have weak or even no activity, but which, upon administration, are converted under physiological conditions (e.g. by metabolism, solvolysis or otherwise) to the corresponding biologically active form.
The compounds of formula (I) may be in unsolvated form as well as solvated forms containing pharmaceutically acceptable solvents such as water, ethanol, and the like. The compounds of formula (I) may contain asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. All stereoisomeric forms of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof (e.g., racemic mixtures), are included within the scope of the present invention.
The compounds of formula (I) may exist in different tautomeric forms, all of which are included within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are mutually converted via a low energy barrier.
"alkyl" in the context of the present invention means a straight or branched chain alkyl group, wherein C1-C6By a group is meant a moiety having 1 to 6 carbon atoms, i.e. the group contains 1, 2, 3, 4, 5 or 6 carbon atoms.
The "alkoxy group" in the present invention means an alkyl ether group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
The term "cycloalkyl" in the present invention refers to an optionally substituted monovalent saturated hydrocarbon ring containing 3 to 6 ring-forming carbon atoms and may also include other non-ring-forming atoms as substituents (e.g., methylcyclopropyl).
The "halogen" as used herein means fluorine, chlorine, bromine or iodo.
The invention can contain the derivatives of the general formula (I) and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof as active ingredients, and the derivatives, the pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof are mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and prepare a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipients refer to any diluents, auxiliary agents and/or carriers which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
The derivatives of the invention comprising formula (I) may be synthesized by methods well known in the art including chemistry, particularly in accordance with the teachings of the present invention. The preparation method of the derivative can be synthesized according to the method of the route 1, 8-bromo-2-chloroquinazoline is taken as a raw material to perform a coupling reaction with different substituted phenylboronic acids under the catalysis of palladium to obtain an intermediate 2, and then the intermediate 2 and 1-methyl/ethyl/isopropyl-5-amino-3-methylpyrazole are subjected to a coupling reaction under the catalysis of palladium acetate to obtain a target compound.
The synthetic route is as follows.
Reagents and conditions in the route: (a) corresponding boric acid, Pd (dppf) Cl2,Na2CO3,1,4-dioxane/H2O,90℃；(b)Pd(AcO)2,X-phos,Cs2CO3,dioxane,90℃。
The anti-tumor agent is lung cancer, gastric cancer and glioma.
In the course of therapy or prophylaxis with the compounds of the invention, if divided doses are required, they will generally be administered so that a daily dose in the range 0.1mg/kg to 50mg/kg is obtained. Lower doses will be administered when the parenteral route is employed. For example, for intravenous or intraperitoneal administration, a dosage of 0.1mg/kg to 30mg/kg is generally used. Also, for administration by inhalation, a dose of 0.05mg/kg to 20mg/kg will be employed. Oral administration is also suitable, particularly in the form of tablets. Typically, a unit dosage form will contain from about 0.5mg to 0.5g of a compound of the invention and the unit dosage form may be administered once, twice, three or four times daily or, if desired, more frequently.
The invention has obvious technical effect.
The inventor designs and synthesizes a series of 2, 8-disubstituted quinazoline derivatives by means of a computer-aided drug design method on the basis of literature research. The compound has obvious ALK inhibitory activity and novel skeleton, and can obviously inhibit the growth of tumor cells. The experimental result shows that the 2, 8-disubstituted quinazoline derivative synthesized in the laboratory has the advantage of stronger antitumor activity, can be used for preparing antitumor drugs, and has the prospect of clinical development of antitumor drugs.
The method is implemented.
The following examples are intended to illustrate but not limit the scope of the invention. The nuclear magnetic resonance hydrogen spectrum of the compound is measured by BrukeraRx-400, and the mass spectrum is measured by Agilent 1100 LC/MS; all reagents used were analytically or chemically pure.
Example 1.
Step 1 Synthesis of intermediate 2
8-bromo-2-chloroquinazoline (1.00g,4.11mmol), 2- (methylcarbamoyl) phenylboronic acid (0.88g,4.93mmol) and sodium carbonate (1.74g,16.43mmol) were dissolved in 30mL1, 4-dioxane/water (10:1) under argon, followed by addition of Pd (dppf) Cl2(0.15g,0.21mmol), after the addition, the temperature was raised to 90 ℃ to react for 12 hours. TLC detection reaction is completed, the reaction temperature is reduced to room temperature, the solvent is removed by concentration under reduced pressure, then 100mL of ethyl acetate is added for extraction, and the organic layer is washed with water and saturated brine respectively, and Na2SO4Dry overnight. The drying agent was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 0.951g of a white solid with a yield of 77.69%.
Step 2 Synthesis of the target Compound
Intermediate 2(500mg,1.68mmol), 5-amino-1, 3-dimethylpyrazole (205mg,1.85mmol), X-Phos (119mg,0.17mmol) and cesium carbonate (1.64g,5.04mmol) were dissolved in 25mL of 1, 4-dioxane under argon protection, followed by palladium acetate (38mg,0.16mmol), after which the temperature was raised to 90 ℃ and the reaction was completed by TLC after 8 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then extracted with 100mL of ethyl acetate, and the organic layer was washed with water and saturated brine, respectively, and Na2SO4Dry overnight. Filtering to remove desiccant, and vacuum evaporatingThe solvent and residue were purified by silica gel column chromatography to give 0.43g of a white solid in 68.75% yield.
1H-NMR(400MHz,DMSO-d6)9.63(s,1H),9.26(s,1H),8.73(d,J＝4.4Hz,1H),8.10(dd,J＝8.0,1.8Hz,1H),7.96-7.94(m,2H),7.77-7.74(m,2H),7.53(t,J＝8.4Hz,1H),6.95(dd,J＝7.8,2.4Hz,1H),6.02(s,1H),3.62(s,3H),2.83(d,J＝4.6Hz,3H),2.07(s,3H).ESI-MS m/z:373.2[M+H]+.
Examples 2-9 were prepared according to the procedure for example 1, starting with 8-bromo-2-chloroquinazoline, respectively, by first coupling with a substituted phenylboronic acid and then substitution with a substituted 5-amino-3-methylpyrazole.
Example 2.
1H-NMR(400MHz,DMSO-d6)9.64(s,1H),9.26(s,1H),8.14(dd,J＝8.0,1.8Hz,1H),7.86-7.79(m,3H),7.44(dd,J＝8.5,4.2Hz,1H),7.18(d,J＝8.1Hz,1H),7.10-7.08(m,1H),6.02(s,1H),3.79(s,3H),3.62(s,3H),2.06(s,3H).ESI-MS m/z:346.2[M+H]+.
Example 3.
1H-NMR(400MHz,DMSO-d6)9.65(s,1H),9.26(s,1H),8.16(dd,J＝8.1,2.0Hz,1H),7.93-7.89(m,2H),7.74-7.69(m,2H),7.58(t,J＝7.5Hz,1H),7.56(d,J＝7.4Hz,1H),6.02(s,1H),3.60(s,3H),2.37(s,3H),2.06(s,3H).ESI-MS m/z:358.2[M+H]+.
Example 4.
1H-NMR(400MHz,DMSO-d6)9.64(s,1H),9.26(s,1H),8.57(t,J＝1.4Hz,1H),8.31(d,J＝7.8Hz,1H),8.16(dd,J＝8.1,2.0Hz,1H),8.02-7.95(m,2H),7.74-7.69(m,2H),6.02(s,1H),3.62(s,3H),2.65(s,3H),2.05(s,3H).ESI-MS m/z:358.2[M+H]+.
Example 5.
1H-NMR(400MHz,DMSO-d6)9.63(s,1H),9.26(s,1H),8.16(dd,J＝8.1,2.0Hz,1H),7.96(dd,J＝8.4,2.1Hz,1H),7.81-7.77(m,2H),7.04(d,J＝7.8Hz,2H),6.02(s,1H),3.84(s,3H),3.61(s,3H),2.06(s,3H).ESI-MS m/z:346.2[M+H]+.
Example 6.
1H-NMR(400MHz,DMSO-d6)9.64(s,1H),9.26(s,1H),8.15(dd,J＝8.0,1.8Hz,1H),7.86-7.78(m,3H),7.44(dd,J＝8.4,4.1Hz,1H),7.18(d,J＝8.1Hz,1H),7.10-7.08(m,1H),6.01(s,1H),3.80(s,3H),3.97(q,J＝7.1Hz,2H),2.07(s,3H),1.26(t,J＝14.2Hz,3H).ESI-MS m/z:360.2[M+H]+.
Example 7.
1H-NMR(400MHz,DMSO-d6)9.64(s,1H),9.26(s,1H),8.72(d,J＝4.2Hz,1H),8.12(dd,J＝8.0,2.2Hz,1H),7.96-7.94(m,2H),7.77-7.74(m,2H),7.53(t,J＝8.4Hz,1H),6.96(dd,J＝7.8,2.2Hz,1H),6.02(s,1H),3.92–3.88(m,1H),2.83(d,J＝4.6Hz,3H),2.07(s,3H),1.32(t,J＝5.8Hz,6H).ESI-MS m/z:401.2[M+H]+.
Example 8.
1H-NMR(400MHz,DMSO-d6)9.64(s,1H),9.27(s,1H),8.15(dd,J＝8.1,1.8Hz,1H),7.86-7.78(m,3H),7.44(dd,J＝8.4,4.1Hz,1H),7.19(d,J＝8.1Hz,1H),7.10-7.06(m,1H),6.02(s,1H),3.80(s,3H),3.94–3.89(m,1H),2.06(s,3H),1.33(t,J＝5.6Hz,6H).ESI-MSm/z:374.2[M+H]+.
Example 9.
1H-NMR(400MHz,DMSO-d6)9.64(s,1H),9.24(s,1H),8.16(dd,J＝8.0,2.1Hz,1H),7.97(dd,J＝8.4,2.1Hz,1H),7.81-7.77(m,2H),7.04(d,J＝7.8Hz,2H),6.02(s,1H),3.93–3.89(m,1H),3.84(s,3H),2.06(s,3H),1.31(t,J＝5.5Hz,6H).ESI-MS m/z:374.2[M+H]+.
And (4) testing the pharmacological activity.
First, in vitro ALK inhibitory activity assay.
HTRF homogeneous time-resolved fluorescence: kinase ALKWTAnd ALKL196MPurchased from Sigma Aldrich, test kit HTRF KinEASE-TK from Cisbio, and tested as per the instructions. Preparing the compound of the embodiment into a series of gradient concentrations, incubating the compound with kinase for 5min at room temperature, adding a proper amount of enzyme reaction substrate and ATP, starting an enzyme reaction process, adding a proper amount of reaction termination solution and detection solution into an enzyme reaction system after 30min, incubating for 1h, reading in an enzyme labeling instrument, and fitting IC (integrated circuit) simultaneously50The value is obtained. The test results are shown in Table 1.
Table 1 results of in vitro ALK inhibitory activity assay.
As shown in the table, the example compounds in the general formula (I) of the invention are shown to be ALK and ALKL196MHas obvious inhibiting activity.
Secondly, MTT method tests cell proliferation inhibition activity.
Cell lines: human non-small cell lung cancer NCI-H2228(EML4-ALK positive cell line), SK-N-BE2(ALIC gene amplification cell line), SH-SY5Y (ALK FI 174 mutant cell line) were purchased from the cell bank of Chinese academy of sciences.
The test method comprises the following steps:
inoculating the tumor cells into 96-well plate at 37 deg.C and 5% CO per well in 5000-2Culturing for 24h in a cell culture box, adding compounds to be detected with different concentrations, setting 3 multiple holes for each concentration, continuing culturing for 48h after adding, removing culture solution, and determining cell activity by using MTT reagent. Adding 15 mu L of the prepared MTT reaction solution into each hole, continuously culturing for 4h, sucking and removing the supernatant, adding DMSO into 100 mu L/hole to dissolve the reduction product, keeping away from light for 5min, reading the absorbance value at 490nm wavelength, and calculating the cell activity. IC (integrated circuit)50Refers to the concentration of inhibitor at which cell growth is inhibited by half. The results are shown in Table 2.
Table 2 MTT assay cell proliferation inhibition results.
The results show that: the compound synthesized by the invention has obvious inhibitory activity on three cancer cells NCI-H2228, SK-N-BE2 and SH-SY 5Y.
Claims (7)
1. A2, 8-disubstituted quinazoline derivative, a geometric isomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein the derivative has the following structural formula:
wherein R is1Selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy, N-alkylamido, formyl; r2Selected from hydrogen, C1-C6Alkyl, C substituted by halogen1-C6Alkyl or C1-C6An alkoxy group.
2. The 2, 8-disubstituted quinazoline derivatives of claim 1, wherein R is a geometric isomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof1Is selected from C1-C6Alkoxy, N-alkylamido, formyl; r2From hydrogen, C1-C6Alkyl, C substituted by halogen1-C6Alkyl radical, C3-C6A cycloalkyl group.
3. The substituted 2, 6-diaminopurine derivatives as claimed in claim 1, wherein said derivatives are selected from the group consisting of:
4. the process for preparing substituted 2, 8-disubstituted quinazoline derivatives as claimed in any one of claims 1 to 2, wherein the process comprises the following steps: 8-bromo-2-chloroquinazoline is used as a raw material to perform a coupling reaction with different substituted phenylboronic acids under the catalysis of palladium to obtain an intermediate 2, and then the intermediate 2 and 1-methyl/ethyl/isopropyl-5-amino-3-methylpyrazole are subjected to a coupling reaction under the catalysis of palladium acetate to obtain a target compound.
5. The use of the substituted 2, 8-disubstituted quinazoline derivatives as claimed in any one of claims 1 to 2 in the preparation of an anti-tumour medicament.
6. Use of a compound according to any one of claims 1-3 in the manufacture of a medicament for inhibiting an ALK-mediated condition or disease.
7. The substituted 2, 8-disubstituted quinazoline derivatives as claimed in claim 5, wherein said antineoplastic agent is selected from lung cancer, gastric cancer or glioma.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010742612.3A CN111808081A (en) | 2020-07-29 | 2020-07-29 | 2, 8-disubstituted quinazoline derivatives, preparation method thereof and application thereof in antitumor drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010742612.3A CN111808081A (en) | 2020-07-29 | 2020-07-29 | 2, 8-disubstituted quinazoline derivatives, preparation method thereof and application thereof in antitumor drugs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111808081A true CN111808081A (en) | 2020-10-23 |
Family
ID=72863303
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010742612.3A Withdrawn CN111808081A (en) | 2020-07-29 | 2020-07-29 | 2, 8-disubstituted quinazoline derivatives, preparation method thereof and application thereof in antitumor drugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111808081A (en) |
-
2020
- 2020-07-29 CN CN202010742612.3A patent/CN111808081A/en not_active Withdrawn
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN115335379B (en) | Spirocyclic quinazoline compounds | |
| CN114929704B (en) | Spirocyclic quinazoline compounds | |
| CN105254615B (en) | Phenylaminopyrimidine derivatives and their use in preparation of drugs for resisting cancers | |
| CN115315427B (en) | HPK1 inhibitor and preparation method and application thereof | |
| CN107531678B (en) | EGFR inhibitor and pharmaceutically acceptable salts and polymorphs thereof and uses thereof | |
| CN109134586B (en) | Tripterine derivative and application thereof | |
| CN111511749A (en) | Compounds having macrocyclic molecular structures and uses thereof | |
| CN111909101B (en) | EGFR kinase inhibitor and application thereof in preparation of anti-cancer drugs | |
| JP2019526605A (en) | Crystal form and salt form of substituted 2-H-pyrazole derivative and method for producing the same | |
| CN116390728A (en) | Quinazoline derivative, preparation method and application thereof | |
| EP3284746B1 (en) | Preparation and use of kinase inhibitor | |
| CN112939979A (en) | 2-morpholine purine derivative, preparation method thereof and application thereof in antitumor drugs | |
| CN112010819A (en) | Benzamide-containing benzo-hexahydric heterocyclic derivative and application thereof in antitumor drugs | |
| US6821990B2 (en) | Ethanol solvate of (-)-cis-2-(2-chlorophenyl)-5, 7-dihydroxy-8 [4R-(3S-hydroxy-1-M ethyl) piperidinyl]-4H-1-benzopyran-4-one | |
| CN107892691B (en) | 2,8, 9-trisubstituted-9H-purine compound and salt and application thereof | |
| CN111808081A (en) | 2, 8-disubstituted quinazoline derivatives, preparation method thereof and application thereof in antitumor drugs | |
| CN115433207A (en) | Macrocyclic heterocyclic compound as EGFR inhibitor and application thereof | |
| CN116437915A (en) | Crystal form of pyrrolo-heterocyclic derivative and preparation method thereof | |
| CN111808108A (en) | Substituted 2, 6-diaminopurine derivatives, preparation method thereof and application thereof in antitumor drugs | |
| CN115073367A (en) | Anti-tumor compound used as AXL inhibitor and application thereof | |
| CN113416171A (en) | 4, 5-dihydronaphthoisoxazole derivatives and application thereof in antitumor drugs | |
| CN104119321B (en) | The 2-maleate and its polymorph of indolinone derivative | |
| CN112724124A (en) | 4-hydroxyquinoline derivatives, preparation method thereof and application thereof in antitumor drugs | |
| CN112004809A (en) | 5-chloro-2, 4-pyrimidine derivatives as antitumor agents | |
| CN111848585A (en) | 2, 4-disubstituted quinazoline derivative, preparation method thereof and application thereof in antitumor drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20201023 |