CN111171017B - Pyrimidine-based derivatives, their preparation and use - Google Patents
Pyrimidine-based derivatives, their preparation and use Download PDFInfo
- Publication number
- CN111171017B CN111171017B CN201811331496.5A CN201811331496A CN111171017B CN 111171017 B CN111171017 B CN 111171017B CN 201811331496 A CN201811331496 A CN 201811331496A CN 111171017 B CN111171017 B CN 111171017B
- Authority
- CN
- China
- Prior art keywords
- triazolo
- amine
- arene
- pyrimidine
- pyridin
- 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.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a derivative based on pyrimidine and a preparation method and application thereof, firstly obtaining arylamine compound 6-phenyl- [1,2,4] triazolo [4,3-a ] pyridine-3-amine, and then obtaining the pyrimidine derivative through catalytic coupling reaction with 2, 5-dichloro-N- (2- (isopropyl sulfonyl) phenyl) pyrimidine-4-amine. The invention has the advantages of simple preparation process and easy operation. The prepared product has ALK inhibitory activity and can be used for preparing ALK inhibitors.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a structure of a pyrimidine derivative with ALK inhibitory activity and a preparation method thereof.
Background
Lung cancer is one of the most common malignancies in the world, with mortality ranking first among all malignancies. Lung cancer can be classified into non-small cell lung cancer (NSCLC) and Small Cell Lung Cancer (SCLC), 85% of which belong to non-small cell lung cancer. Most non-small cell lung cancer patients are already in the middle and advanced stage when they are diagnosed, and have a very low 5-year survival rate. With the progress of scientific research, scientists found that Anaplastic Lymphoma Kinase (ALK) fusion gene is one of the key genes driving non-small cell lung cancer.
At present, the molecular targeted therapy is a therapy method with the best effect and the most wide application in a plurality of methods for treating non-small cell lung cancer, the molecular targeted therapy refers to that drugs are designed on the molecular level of tumor cells in a targeted manner for proven carcinogenic sites, and the drugs can be specifically combined with the carcinogenic sites after entering a human body, so that the tumor cells die under the action of the drugs, surrounding healthy tissue cells are not damaged, the therapy method enables the anti-tumor activity of the drugs to be better exerted, and the influence on normal cells can be reduced
There are mainly 4 ALK targeting drugs currently on the market, namely, Crizotinib, Ceritinib, Alectinib, and Brigatinib. 8/2011, the United states Food and Drug Administration (FDA) approved Crizotinib (Crizotinib/PF-02341066) to be marketed for treating ALK-positive locally advanced or metastatic non-small cell lung cancer. Crizotinib is the first drug for targeted therapy of Anaplastic Lymphoma Kinase (ALK)And (5) preparing the product. In the treatment process, the crizotinib can effectively inhibit the growth of tumors, but after the crizotinib is taken for a period of time, patients always have acquired drug resistance. In 4 months 2014, Ceritinib (trade name: Zykadia) was approved by the FDA for marketing. Ceritinib can inhibit autophosphorylation of anaplastic lymphoma kinase ALK, ALK-mediated phosphorylation of downstream signaling protein STAT3, and ALK-dependent proliferation of cancer cells. 12 months 2015, FDA approved alentinib (Alectinib (RO/CH5424802), trade name:
) And (4) marketing. One study showed that total Objective Remission Rate (ORR) was 93.5% for alendronate when treating ALK-positive non-small cell lung cancer (NSCLC) patients who did not receive an ALK inhibitor; another study showed that total Objective Remission Rate (ORR) was 49.2% for alendronate when treating ALK-positive non-small cell lung cancer (NSCLC) patients who developed resistance to crizotinib. In 2017, 4 months, the FDA approved Bugatinib (Brigatinib, trade name: Alubrigrigig) in the United states is marketed. Brigatinib is able to inhibit ALK autophosphorylation and ALK-mediated phosphorylation of downstream signaling proteins (STAT3, AKT, ERK1/2, S6) in vitro and in vivo assay assays. In vitro, brigatinib inhibits the activity of several kinases, ALK, ROS1 protooncogene, insulin-like growth factor-1 receptor, FMS-like tyrosine kinase 3, and the like.
However, the problem of drug resistance is a significant problem that currently restricts drug development. The first generation of ALK inhibitor crizotinib can effectively inhibit the growth of tumors and has been approved by FDA in the United states for marketing, but the problem of drug resistance of crizotinib is inevitable. Phase III follow-up experiments comparing the first generation ALK inhibitor crizotinib with chemotherapy second-line treatment of ALK positive lung cancer patients show that the median PFS (7.7 months) in the crizotinib group is remarkably prolonged compared with the chemotherapy group (3.0 months). However, patients who are therapeutically effective for crizotinib often develop resistance to the drug within 1 year of their administration. In recent years, the FDA in the united states approved a series of ALK inhibitor drugs for patient resistance to crizotinib, however, patients still developed resistance after some time of drug administration.
Disclosure of Invention
The invention aims to provide a derivative based on pyrimidine, a preparation method and application thereof, and the compound has ALK inhibitory activity and can be used for preparing an ALK inhibitor.
The technical purpose of the invention is realized by the following technical scheme.
A pyrimidine-based derivative having a structure represented by the following chemical formula.
Wherein R3 is phenyl.
The preparation method of the pyrimidine derivative comprises the following steps:
wherein R3 is phenyl.
in step 1, the arene boronic acid is phenylboronic acid.
In step 1, the 6-arene- [1,2,4] triazolo [4,3-a ] pyridin-3-amine compound is 6-phenyl- [1,2,4] triazolo [4,3-a ] pyridin-3-amine.
In step 1, the whole reaction process is carried out in an inert protective atmosphere, wherein the inert protective atmosphere is nitrogen, helium or argon.
In step 1, a mixed solvent of dioxane and water is selected to provide a solvent atmosphere for the reaction, and the volume ratio of dioxane to water is (1-2): 1; the mol ratio of the 6-bromo- [1,2,4] triazolo [4,3-a ] pyridin-3-amine to the arene boronic acid is 1: (1-2), preferably in equimolar ratio; cesium carbonate, bis (triphenylphosphine) palladium dichloride, 6-bromo- [1,2,4] triazolo [4,3-a ] pyridin-3-amine and cesium carbonate are added to the reaction in a molar ratio of 1: (1-3), 6-bromo- [1,2,4] triazolo [4,3-a ] pyridin-3-amine and bis (triphenylphosphine) palladium dichloride in a molar ratio of (5-10): 1.
in step 1, the reaction temperature is 60 to 80 ℃ and the reaction time is 1 to 20 hours, preferably 8 to 15 hours.
In step 1, after the reaction is stopped, the reaction mixture is naturally cooled to room temperature of 20 to 25 ℃, water is added, ethyl acetate is used for extraction for 3 times, anhydrous magnesium sulfate is used for drying, the solid crude product is obtained by concentration, and the solid crude product is washed by a solution with the solvent polarity (petroleum ether: ethyl acetate ═ 1.0: 3.2), so that a yellow brown solid, namely the 6-arene- [1,2,4] triazolo [4,3-a ] pyridine-3-amine compound is finally obtained.
And 2, reacting the 6-arene- [1,2,4] triazolo [4,3-a ] pyridine-3-amine compound prepared in the step 1 with 2, 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidine-4-amine to obtain the pyrimidine derivative.
In step 2, the 6-arene- [1,2,4] triazolo [4,3-a ] pyridin-3-amine compound is 6-phenyl- [1,2,4] triazolo [4,3-a ] pyridin-3-amine.
In step 2, dimethyl sulfoxide is selected to provide a solvent atmosphere for the reaction, and the molar ratio of the 6-arene- [1,2,4] triazolo [4,3-a ] pyridin-3-amine compound to 2, 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine is 1: (1-2) adding palladium acetate, cesium carbonate and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, 6-arene- [1,2,4] triazolo [4,3-a ] pyridin-3-amine compound and palladium acetate in a molar ratio of 1: (0.05-0.1), the molar ratio of the 6-arene- [1,2,4] triazolo [4,3-a ] pyridin-3-amine compound to cesium carbonate is 1: the molar ratio of the (1-3), 6-arene- [1,2,4] triazolo [4,3-a ] pyridin-3-amine compound to the 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene is 1: (0.05-0.1).
In the step 2, the whole reaction process is carried out in an inert protective atmosphere, wherein the inert protective atmosphere is nitrogen, helium or argon.
In step 2, the reaction temperature is 100 to 150 ℃ and the reaction time is 1 to 20 hours, preferably 8 to 15 hours.
In step 2, after the reaction is stopped, naturally cooling to room temperature of 20-25 ℃, adding water, extracting for 3 times by using ethyl acetate, drying by using anhydrous magnesium sulfate, evaporating to remove the solvent under reduced pressure, and separating the crude product by column chromatography, wherein the polarity of a washing and dehydrating machine is (the volume ratio of petroleum ether to ethyl acetate is 1.0: 5.0), so that a yellow solid, namely the pyrimidine derivative is obtained.
The invention has the advantages of simple preparation process and easy operation. The prepared product has ALK inhibitory activity and can be used for preparing ALK inhibitors.
Drawings
Figure 1 is a bar graph of the results of cell viability tests of a549 cell line at various concentrations of the pyrimidine derivative D1 of the invention.
FIG. 2 is a bar graph of the results of cell viability tests of the MCF-7 cell line at various concentrations of the pyrimidine derivative D1 of the invention.
Detailed Description
The technical scheme of the invention is further explained by combining specific examples.
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (6-phenyl- [1,2, 4)]Triazole [4,3-a ]]The preparation method of pyridine-3-yl) pyrimidine-2, 4-diamine is shown in the following chemical reaction process.
6-bromo- [1,2,4] is added into a 100mL three-neck bottle in sequence]Triazole [4,3-a ]]Pyridin-3-amine (1.3g,6.00mmol), phenylboronic acid (877.9mg,7.20mmol), V (dioxane): v (water) ═ 15.0: 7.5 cesium carbonate (5.9g,18.00mmol), magnetically stirring, N addition2Adding catalyst bis (triphenylphosphine) palladium dichloride (421.1mg,0.60mmol) after 0.5h, slowly heating to 80 deg.C, stopping reaction after 8h, adding water 50mL, extracting with ethyl acetate for 3 times, drying with anhydrous magnesium sulfate, concentrating to obtain solid crude product, and adding solvent (petroleum ether: ethyl acetate) with polarity1.0: 3.2) to yield a yellow-brown solid (1.2g, 95%).
1H NMR(500MHz,DMSO-d6),δ：8.52(s,1H),7.70(d,J＝7.5Hz，2H),7.51(dd,J＝9、1.6Hz,1H),7.50(t,J＝8Hz，2H),7.40(t,J＝7.5Hz,1H),7.44(dd,J＝1.5、9.5Hz),6.53(s,2H).13C NMR(125MHz,DMSO-d6),δ：149.5,145.6,136.8,129.8,128.6,127.0,125.9,125.0,119.9,116.2.ESI-HRMS：m/z＝211.0978[M+H]+，calcd for C12H10N4H+：m/z＝211.0984.
Step 2-5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (6-phenyl- [1,2, 4)]Triazole [4,3-a ]]Preparation of pyridin-3-yl) pyrimidine-2, 4-diamines
The compound 6-phenyl- [1,2,4] triazolo [4,3-a ] pyridin-3-amine (506.7mg,2.41mmol), 2, 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine (1.0g,2.89mmol), dimethyl sulfoxide (10mL) were added in a 100mL three-necked flask in sequence, stirred magnetically until completely dissolved, cesium carbonate (2.4mg,7.23mmol) was added, after 30min with nitrogen, the catalyst palladium acetate (27.0mg,0.12mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene xanthphos-e (138.9mg,0.24mmol) was added, nitrogen was continuously introduced, the temperature was slowly raised to 150 ℃ and the reaction was stopped for 8 h. After cooling, 100mL of water was added, extracted 3 times with ethyl acetate, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the crude product was isolated by column chromatography using a elution machine of polarity (petroleum ether: ethyl acetate ═ 1.0: 5.0) to give a yellow solid (476.2mg, 38%).
1H NMR(500MHz,DMSO-d6),δ：δ10.35(s,1H),9.54(s,1H),8.30(d,J＝9.0Hz,1H),8.29(s,1H),7.88(d,J＝9.5Hz,1H),7.69-7.71(dd,J＝2.0、9.5Hz,1H),7.67(d,J＝8.0Hz,1H),7.58(d,J＝7.5Hz,2H),7.40(t,2H),7.36(t,1H),7.19(t,1H),7.11(t,1H),3.22(t,H),1.00(d,J＝7.0Hz,6H).13C-NMR(125MHz,DMSO-d6),δ：158.7,156.1,155.4,148.6,142.5,138.0,136.1,134.5,131.2,129.4,128.6,127.4,126.8,124.2,123.8,122.8,121.0,116.2,106.9,55.5,15.2.ESI-HRMS：m/z＝520.1316[M+H]+,calcd for C25H22ClN7O2SH+: melting point 520.1323, m/z: 167 deg.C.
Non-small cell lung cancer A549 cell line and human breast cancer MCF-7 cell (purchased from ATCC company of America) are selected and cultured by RPMI 1640 culture solution containing 10% fetal calf serum, penicillin (100 mu g/m L) and streptomycin (100 mu g/m L) under the culture conditions of 37 ℃ and 5% CO2An incubator. The culture medium is changed every other day for 1 time, and subculture is carried out when the cell confluency reaches more than 85%. Thereafter, the cells were subcultured in 6-well plates and cell transfection was performed after 24h of culture. And after 48h of transfection, collecting cells, detecting the growth condition of the transfected A549 cells by using a tetramethylazole blue colorimetric method, namely an MTT method, namely subculturing the cells in a 96-well plate, after 4-6 h of transfection, replacing the cells with a normal culture solution, after 72h of transfection, adding 20MTT reagent into each well, incubating for 4h at 37 ℃, adding a certain amount of dimethyl sulfoxide (DMSO), and uniformly mixing to detect the optical density (D) value at 490 nm. The experiment was repeated 3 times. The inhibition of cell growth (cell viability) and drug concentration were plotted as bar graphs, as shown in FIGS. 1 and 2.
Aiming at the non-small cell lung cancer A549 cell strain, the effective inhibition of the cell activity can be realized under the drug concentration of 0.25-1 mu M, and the cell activity is reduced to 60-70% along with the increase of the concentration; aiming at the human breast cancer MCF-7 cell strain, the effective inhibition of the cell activity is realized under the drug concentration of 0.25-1 mu M, the effective inhibition of the cell activity can be realized, the cell activity is gradually reduced along with the increase of the concentration, and particularly, the cell activity reaches 20-30% under the drug concentration of 1.0 mu M. Therefore, the pyrimidine derivative disclosed by the invention is applied to preparation of a medicine for treating non-small cell lung cancer or breast cancer and an ALK inhibitor.
The preparation of the pyrimidine derivative can be realized by adjusting the preparation process parameters according to the technical scheme of the invention, and the pyrimidine derivative has performance basically consistent with that of the invention. The invention has been described in an illustrative manner, and it is to be understood that any simple variations, modifications or other equivalent changes which can be made by one skilled in the art without departing from the spirit of the invention fall within the scope of the invention.
Claims (7)
1. A pyrimidine-based derivative characterized by having a structure represented by the following formula
Wherein R3 is phenyl.
2. A process for the preparation of pyrimidine-based derivatives according to claim 1, which comprises the steps of:
step 1, reacting 6-bromo- [1,2,4] triazolo [4,3-a ] pyridin-3-amine with arene boric acid to obtain a 6-arene- [1,2,4] triazolo [4,3-a ] pyridin-3-amine compound, wherein the arene boric acid is phenylboronic acid, the 6-arene- [1,2,4] triazolo [4,3-a ] pyridin-3-amine compound is 6-phenyl- [1,2,4] triazolo [4,3-a ] pyridin-3-amine, and the whole reaction process is carried out in an inert protective atmosphere, wherein the inert protective atmosphere is nitrogen, helium or argon; the reaction temperature is 60-80 ℃, the reaction time is 1-20 hours, a mixed solvent of dioxane and water is selected to provide a solvent atmosphere for the reaction, and the volume ratio of dioxane to water is (1-2): 1; the mol ratio of the 6-bromo- [1,2,4] triazolo [4,3-a ] pyridin-3-amine to the arene boronic acid is 1: (1-2); cesium carbonate, bis (triphenylphosphine) palladium dichloride, 6-bromo- [1,2,4] triazolo [4,3-a ] pyridin-3-amine and cesium carbonate are added to the reaction in a molar ratio of 1: (1-3), 6-bromo- [1,2,4] triazolo [4,3-a ] pyridin-3-amine and bis (triphenylphosphine) palladium dichloride in a molar ratio of (5-10): 1;
step 2, reacting the 6-arene- [1,2,4] triazolo [4,3-a ] pyridine-3-amine compound prepared in the step 1 with 2, 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidine-4-amine to obtain a pyrimidine derivative, wherein the 6-arene- [1,2,4] triazolo [4,3-a ] pyridine-3-amine compound is 6-phenyl- [1,2,4] triazolo [4,3-a ] pyridine-3-amine, dimethyl sulfoxide is selected for providing a solvent atmosphere for the reaction, and the 6-arene- [1,2,4] triazolo [4,3-a ] pyridine-3-amine compound and 2, 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidine-4-amine The molar ratio of amine is 1: (1-2) adding palladium acetate, cesium carbonate and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, 6-arene- [1,2,4] triazolo [4,3-a ] pyridin-3-amine compound and palladium acetate in a molar ratio of 1: (0.05-0.1), the molar ratio of the 6-arene- [1,2,4] triazolo [4,3-a ] pyridin-3-amine compound to cesium carbonate is 1: the molar ratio of the (1-3), 6-arene- [1,2,4] triazolo [4,3-a ] pyridin-3-amine compound to the 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene is 1: (0.05-0.1), the whole reaction process is carried out in inert protective atmosphere, and the inert protective atmosphere is nitrogen, helium or argon; the reaction temperature is 100-150 ℃ and the reaction time is 1-20 hours.
3. A process for the preparation of pyrimidine-based derivatives according to claim 2, wherein the reaction time in step 1 is 8 to 15 hours.
4. A process for the preparation of pyrimidine-based derivatives according to claim 2, wherein in step 1, the molar ratio of 6-bromo- [1,2,4] triazolo [4,3-a ] pyridin-3-amine and arene boronic acid is 1: 1.
5. a process for the preparation of pyrimidine-based derivatives according to claim 2, wherein in step 2, the reaction time is 8 to 15 hours.
6. Use of a pyrimidine-based derivative as claimed in claim 1 in the manufacture of a medicament for the treatment of non-small cell lung cancer or breast cancer.
7. Use of a pyrimidine-based derivative as defined in claim 1 for the preparation of ALK inhibitors.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811331496.5A CN111171017B (en) | 2018-11-09 | 2018-11-09 | Pyrimidine-based derivatives, their preparation and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811331496.5A CN111171017B (en) | 2018-11-09 | 2018-11-09 | Pyrimidine-based derivatives, their preparation and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111171017A CN111171017A (en) | 2020-05-19 |
| CN111171017B true CN111171017B (en) | 2021-12-24 |
Family
ID=70624346
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811331496.5A Active CN111171017B (en) | 2018-11-09 | 2018-11-09 | Pyrimidine-based derivatives, their preparation and use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111171017B (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0206215D0 (en) * | 2002-03-15 | 2002-05-01 | Novartis Ag | Organic compounds |
| GB0305929D0 (en) * | 2003-03-14 | 2003-04-23 | Novartis Ag | Organic compounds |
| US20070105839A1 (en) * | 2003-09-18 | 2007-05-10 | Patricia Imbach | 2, 4-Di (phenylamino) pyrimidines useful in the treatment of proliferative disorders |
| US8039479B2 (en) * | 2006-12-08 | 2011-10-18 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
| JP6622726B2 (en) * | 2014-06-17 | 2019-12-18 | コリア リサーチ インスティチュート オブ ケミカル テクノロジーＫｏｒｅａ Ｒｅｓｅａｒｃｈ Ｉｎｓｔｉｔｕｔｅ Ｏｆ Ｃｈｅｍｉｃａｌ Ｔｅｃｈｎｏｌｏｇｙ | Pyrimidine-2,4-diamine derivative and anticancer pharmaceutical composition containing it as an active ingredient |
-
2018
- 2018-11-09 CN CN201811331496.5A patent/CN111171017B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN111171017A (en) | 2020-05-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5662564B2 (en) | Arylaminopurine derivatives, methods for their preparation and use as pharmaceuticals | |
| RU2662713C2 (en) | Pyridopyrimidine compound, method for production, pharmaceutical composition and application of indicated compounds | |
| CN106749267B (en) | Novel epidermal growth factor receptor inhibitors and uses thereof | |
| CN104797581A (en) | Heteroaryl alkyne compound and application thereof | |
| CN104557887A (en) | 1,8-naphthalimide derivative as well as synthesis method and application thereof | |
| CN116670119A (en) | Bridged bicyclic compounds as BTK inhibitors | |
| JP2022502438A (en) | FGFR4 inhibitor and its use | |
| CN108947949B (en) | Anxiolytic deuterated compounds and medical application thereof | |
| CN111362925A (en) | 4-pyrimidine formamide compound, pharmaceutical composition, preparation method and application | |
| CN101638389B (en) | Polyamine derivative containing naphthalimide structure, preparation method and application thereof | |
| CN104829613B (en) | Diaryl-substituted pyrazolo ring derivative, preparation method thereof and application thereof in medical field | |
| CN101302199B (en) | Guidemycin and use thereof in tumor treatment | |
| CN111171017B (en) | Pyrimidine-based derivatives, their preparation and use | |
| KR102394934B1 (en) | Salt form and crystal form thereof as Akt inhibitor | |
| CN111171033B (en) | Pyrimidine derivative and synthesis method and application thereof | |
| CN104892580A (en) | Novel benzimidazole-pyrilamine derivative and application thereof | |
| CN115433207A (en) | Macrocyclic heterocyclic compound as EGFR inhibitor and application thereof | |
| US9499552B2 (en) | Pyrazolo[1,5-A]pyrimidine derivative and use of anti-tumor thereof | |
| US20140038991A1 (en) | Protein Kinase Inhibitors | |
| EP3369740A1 (en) | New cytidine derivative dimers and applications thereof | |
| WO2020042729A1 (en) | 6-disulfide-substituted-2'-deoxyguanosine compound and preparation method therefor and use thereof | |
| CN110183471B (en) | Piperazine derivative, preparation method and application | |
| CN113354631B (en) | 1,3,4-oxadiazole derivative and preparation method and application thereof | |
| CN114380800B (en) | Pyridine-pyrimidine amine-benzimidazole derivative, and preparation method and application thereof | |
| CN111170996B (en) | Pyrimidine derivative with ALK inhibitory activity and synthetic method and application thereof |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |