CN117946165A - Novel structural compound AXL inhibitor and application thereof - Google Patents

Novel structural compound AXL inhibitor and application thereof Download PDF

Info

Publication number
CN117946165A
CN117946165A CN202410099479.2A CN202410099479A CN117946165A CN 117946165 A CN117946165 A CN 117946165A CN 202410099479 A CN202410099479 A CN 202410099479A CN 117946165 A CN117946165 A CN 117946165A
Authority
CN
China
Prior art keywords
mmol
axl
ring
reduced pressure
under reduced
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.)
Pending
Application number
CN202410099479.2A
Other languages
Chinese (zh)
Inventor
何勇
秦绪荣
豆远尧
韩睿
刘弋辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Southwest University
Chinese Peoples Liberation Army Army Specialized Medical Center
Original Assignee
Southwest University
Chinese Peoples Liberation Army Army Specialized Medical Center
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Southwest University, Chinese Peoples Liberation Army Army Specialized Medical Center filed Critical Southwest University
Priority to CN202410099479.2A priority Critical patent/CN117946165A/en
Publication of CN117946165A publication Critical patent/CN117946165A/en
Pending legal-status Critical Current

Links

Abstract

The invention belongs to the technical field of biological medicines, and discloses a novel structural compound AXL inhibitor and application thereof. According to the invention, through constructing a plurality of cell models simulating over-expression of AXL, and screening a plurality of newly synthesized compounds, small molecular compounds capable of effectively inhibiting AXL protein are screened, and experiments prove that the novel AXL inhibitor can obviously inhibit AXL expression in tumors (especially EGFR mutant advanced non-small cell lung cancer), is a novel AXL inhibitor which can be used in clinic, and has important clinical value for overcoming AXL high expression induced oxtinib resistance.

Description

Novel structural compound AXL inhibitor and application thereof
Technical Field
The invention relates to the technical field of biological medicines, in particular to a novel structural compound AXL inhibitor and application thereof.
Background
The octenib (Osimertinib, osi) is widely used as a third generation EGFR tyrosine kinase inhibitor (EGFR-TKI) for the primary and secondary treatment of patients with EGFR mutant advanced non-small cell lung cancer (NSCLC) and has remarkable curative effect. However, patients receiving octreotide eventually develop resistance, severely limiting their clinical use. The drug resistance mechanism of the Ornitinib is complex, and at present, the definite drug resistance mechanism such as C797S site mutation or EGFR bypass C-MET amplification and the like can only explain part of acquired drug resistance, and still a large part of patients have unknown drug resistance mechanism.
Receptor tyrosine kinases (receptor tyrosine kinase, RTKs) are the largest class of enzyme linked receptors, which are both receptors and enzymes, and are capable of binding ligands and phosphorylating tyrosine residues of target proteins. All RTKs are composed of three parts: an extracellular domain containing a ligand binding site, a single transmembrane hydrophobic alpha-helical region, an intracellular domain containing tyrosine protein kinase (PTK) activity. Receptor Tyrosine Kinases (RTKs) are high affinity cell surface receptors for many polypeptides growth factors, cytokines and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, there are 58 encoding receptor tyrosine kinase proteins, one of which is the AXL protein.
In recent years, several studies have demonstrated that activation of the AXL signaling pathway mediates resistance to octenib. Therefore, the method overcomes the acquired drug resistance of the AXL protein induced AXylb, and has important clinical significance. In recent years, a variety of AXL inhibitors have been developed for clinical trials to treat NSCLC, such as: bemcentinib (R428), CB469, ONO-7475, DS-1205c, and the like, which provides a desire to overcome the resistance of Ornitinib. Bemcentinib is a selective oral bioavailable small molecule AXL inhibitor, bemcentinib + docetaxel combination has been used in phase I clinical trials for the treatment of advanced NSCLC. Additional clinical trials with DS-1205c inhibitor targeting AXL have been performed in EGFR mutated, austitinib-acquired resistant NSCLC patients. However, the effect of these AXL inhibitors is not satisfactory. Although most AXL inhibitors are in preclinical stages, they are far from clinical use. To date, there is no particularly effective therapeutic approach to inhibiting AXL in a clinical setting. Therefore, further exploration of novel AXL inhibitors that can be used clinically is necessary, with important clinical value for overcoming AXL high expression induced resistance to oxtinib.
Disclosure of Invention
The object of the present invention is to solve the above problems and to provide a novel structural compound AXL inhibitor.
In order to achieve the purpose, the invention adopts the following technical scheme:
The first aspect of the present invention provides a compound which is a compound having a structure as shown in the general formula (I):
Wherein Z 1 in the general formula (I) is selected from O, S, N, CH 2,Z2 and O, S, N, CH 2;
r 1 is selected from the following structures:
r 2 is selected from the following structures:
R 3 is selected from: halogen: fluorine, chlorine, bromine, iodine, methoxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, or H, 5-methyl, 5-chlorine, 5-bromine, 5-methoxy, 5-thiomethyl, 5-isopropyl, 5-tert-butyl, 5-methoxyacyl, 5-fluoro, 5-trifluoromethyl, 5-chlorine, 5-phenyl.
Preferably, R 2 is selected from (2-aminophenyl) dimethylphosphine oxide, halogen, trifluoromethyl or trifluoromethoxy, thiomethyl, isopropyl, tert-butyl, methoxyacyl, phenyl, pyrazole ring, oxadiazole ring, imidazole ring, isoxazole ring, oxazole ring, thiazole ring, thiadiazole ring, thiophene ring, pyridine ring, pyrimidine ring, furan ring, triazole ring, pyrrole ring or tetrazole ring;
Wherein R 1 and R 2 are combined as 4, 5-dimethoxy, 4, 5-dithiomethyl, 4, 5-diisopropyl, 4, 5-di-tert-butyl, 4, 5-dimethoxyacyl, 4, 5-difluoro, 4, 5-bistrifluoromethyl, 4, 5-dichloro, 4, 5-diphenyl, 4-fluoro-5-methoxy, 4, 5-dichlorothiophene;
R 3 is alkylamine, chain and cyclic alcohol.
Preferably, the compound is BG-325, BG-381, or BG-272, having the structural formula:
In a second aspect, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a compound according to any one of the preceding claims or a tautomer, mesomer, racemate, stereoisomer or a pharmaceutically acceptable salt thereof.
In a third aspect, the invention provides the use of a compound as defined in any one of the preceding claims or a pharmaceutical composition as defined above for the preparation of an AXL inhibitor.
In a fourth aspect, the invention provides the use of a compound as defined in any one of the preceding claims or a pharmaceutical composition as defined above for the manufacture of a medicament for the treatment of a tumor in which AXL is highly expressed.
Preferably, the AXL-highly expressed tumors include lung cancer, liver cancer and melanoma.
Preferably, the lung cancer is non-small cell lung cancer.
Preferably, the lung cancer is EGFR mutant advanced non-small cell lung cancer.
Preferably, the lung cancer is EGFR-TKI drug resistant non-small cell lung cancer, and the compound is BG-267, BG-325 or BG-381.
The beneficial effects of the invention are as follows: in order to screen the inhibitor for inhibiting the tumor cell AXL protein target, the inventor prepares various cell line models of lung cancer, liver cancer, breast cancer, melanoma, intestinal cancer and the like in advance, and constructs various cell models simulating over-expression of AXL. By utilizing the multiple cell models, through multiple rounds of screening, we screen out two small molecular compounds capable of effectively inhibiting AXL protein, namely BG-325 and BG-381 from multiple compounds innovatively synthesized by themselves, and through experimental verification, the novel AXL inhibitor can obviously inhibit AXL expression in tumors (especially EGFR mutant advanced non-small cell lung cancer), is a novel AXL inhibitor which can be used in clinic, and has important clinical value for overcoming the AXL high expression induced drug resistance of the oxtinib.
Drawings
FIG. 1 shows the results of evaluation of the activity of novel structural compounds of AXL inhibitors on octreotide resistant cells PC-9 OR.
FIG. 2 is the results of experiments on the effect of novel structural compounds BG-325, BG-381 of the AXL inhibitor on the activity of EGFR mutated NSCLC cells.
FIG. 3 is the results of an experiment for inhibiting AXL by novel structural compounds of the AXL inhibitor on EGFR TKI resistant cells.
FIG. 4 shows the experimental results of a tumor model for screening for high AXL expression.
FIG. 5 shows the results of the activity of compounds BG-272, BG-325, BG-381 on liver cancer and melanoma cells.
Fig. 6 shows the results of AXL inhibition experiments of novel structural compounds of AXL inhibitors on liver cancer (a) and melanoma cells (B).
Detailed Description
The invention is further illustrated, but is not limited, by the following examples.
The experimental methods in the following examples are conventional methods unless otherwise specified; chemical and biological agents used, e.g.
The reagents are all conventional in the art, unless otherwise specified.
Example 1 Synthesis of Compounds
1. Synthesis of (2- ((5-chloro-2- (4- (3- (3-fluoropyrrolidin-1-yl) propoxy) -2-methoxy) amino) pyrimidin-4 yl) amino) phenyl) dimethylphosphine oxide (BG-235)
The compound 5-fluoro-2-nitroanisole (4476 mg,2.6 mmol) was dissolved in dimethyl sulfoxide (8 mL), sodium hydroxide (1 g,25 mL) and water (8 mL) were added sequentially, and the resulting mixture was stirred at 80℃for 5h. The system was a yellow clear solution, water (50 mL) was added to the reaction system to dilute, the aqueous layer was made acidic with dilute hydrochloric acid, extracted twice with ethyl acetate (50 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give compound a26 as a yellow solid (420 mg, yield 95%).
To a solution of the crude A26 (168 mg,1 mmol) in acetonitrile (8 mL) were added 1, 3-dibromopropane (1 mg,5 mmol) and potassium carbonate (276 mg,2 mmol), and the reaction mixture was heated to 70℃for 12 hours, after which the reaction was completed by TLC. The reaction mixture was naturally cooled to room temperature, acetonitrile was concentrated under reduced pressure, 1, 3-dibromopropane was distilled off from the system by vacuum heating, water (30 mL) was added to the reaction system for dilution, and methylene chloride (20 mL. Times.3) was used for extraction three times. The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give crude A27 as a yellow solid (290 mg, yield 100%).
To a 25mL three-necked flask was successively added 3- (R) -fluoropyrrolidine hydrochloride (126 mg,1 mmol), sodium hydride (60 mg,2.5 mmol), and after evacuating the flask, the atmosphere was changed to argon, tetrahydrofuran (4 mL) was added, and the resulting mixture was stirred under argon atmosphere at 60℃for 30 minutes. The reaction solution was cooled to room temperature, A27 (277 mg,1.2 mmol) was added, and the resulting mixture was stirred overnight under argon atmosphere at 60 ℃. The reaction mixture was cooled to room temperature and TLC was complete. Tetrahydrofuran was concentrated under reduced pressure, extracted three times with dichloromethane (20 mL. Times.3), and dried over anhydrous sodium sulfate. The organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=60:1) to give compound a28 (160 mg, yield 47%) as a yellow oily liquid.
Compound A28 (80 g,0.27 mmol) was dissolved in a mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL), palladium on carbon (14 mg, 5%) was added to the mixed system, air in the round-bottomed flask was purged to make a negative pressure in the round-bottomed flask, hydrogen gas was introduced into the round-bottomed flask, and the mixed system was reacted at room temperature for 16 hours. After completion of the TLC detection, palladium on carbon was removed by suction filtration through celite, and the mixed solvent was concentrated under reduced pressure to give Compound A29 (72 mg, yield 100%) as a yellow oily liquid.
To a solution of (2-aminophenyl) dimethylphosphine oxide (1 g,5.9 mmol) in DMF was added 2,4, 5-trichloropyrimidine (1 g,8.9 mmol) and dipotassium hydrogen phosphate (3 g,18 mmol), and the reaction mixture was heated to 60℃for 12 hours, after which the reaction was completed by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=3:2) to give compound A3 as a white solid (1.3 g, yield 70%).
Compound A29 (77 mg,0.27 mmol), A3 (71 mg,0.22 mmol) and ethylene glycol monomethyl ether (1 mL) were taken and put into a 25mL three-necked flask, and the flask was purged three times under the protection of argon, and trifluoroacetic acid (51. Mu.L, 0.45 mmol) was added dropwise under the ice bath condition, and after the addition was completed, the temperature was raised to 60℃and the reaction was carried out for 10 hours. Cooled to room temperature, poured into ice water, stirred for 30min, extracted with ethyl acetate ((10 ml x 3)), the aqueous layer was PH-adjusted with saturated sodium bicarbonate=10, extracted again with ethyl acetate (10 ml x 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered off with suction and spun dry under reduced pressure to give the crude product. The crude product was dissolved with a small amount of dichloromethane, n-hexane was added, solids were precipitated, the solvent was distilled off under reduced pressure, and the filtrate after spin-drying was recrystallized with ethyl acetate and ethanol to give the white or off-white product BG-235 (122 mg, yield 37%).
2. Synthesis of (2- ((5-chloro-2- ((4- (3, 3-difluoropyrrolidin-1 yl) propoxy) -2-methoxyphenyl) amino) pyrimidin-4 yl) amino) phenyl) dimethylphosphine oxide (BG-239)
The compound 5-fluoro-2-nitroanisole (4476 mg,2.6 mmol) was dissolved in dimethyl sulfoxide (8 mL), sodium hydroxide (1 g,25 mL) and water (8 mL) were added sequentially, and the resulting mixture was stirred at 80℃for 5h. The system was a yellow clear solution, water (50 mL) was added to the reaction system to dilute, the aqueous layer was made acidic with dilute hydrochloric acid, extracted twice with ethyl acetate (50 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give compound a26 as a yellow solid (420 mg, yield 95%).
To a solution of the crude A26 (168 mg,1 mmol) in acetonitrile (8 mL) were added 1, 3-dibromopropane (1 mg,5 mmol) and potassium carbonate (276 mg,2 mmol), and the reaction mixture was heated to 70℃for 12 hours, after which the reaction was completed by TLC. The reaction mixture was naturally cooled to room temperature, acetonitrile was concentrated under reduced pressure, 1, 3-dibromopropane was distilled off from the system by vacuum heating, water (30 mL) was added to the reaction system for dilution, and methylene chloride (20 mL. Times.3) was used for extraction three times. The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give crude A27 as a yellow solid (290 mg, yield 100%).
To a 25mL three-necked flask was successively added 3, 3-difluoropyrrolidine hydrochloride (247 mg,1 mmol), potassium carbonate (415 mg,3 mmol), and after the air in the flask was purged, tetrahydrofuran (3 mL) was added after changing to argon, and the resultant mixture was stirred under argon atmosphere at 60℃for 30 minutes. The reaction solution was cooled to room temperature, A27 (277 mg,1.2 mmol) was added, and the resulting mixture was stirred overnight under argon atmosphere at 60 ℃. The reaction mixture was cooled to room temperature and TLC was complete. Tetrahydrofuran was concentrated under reduced pressure, extracted three times with dichloromethane (20 mL. Times.3), and dried over anhydrous sodium sulfate. The organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/acetone=5:1) to give compound a30 (172 mg, yield 55%) as a yellow oily liquid.
Compound A30 (160 mg,0.51 mmol) was dissolved in a mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL), palladium on carbon (27 mg, 5%) was added to the mixed system, air in the round-bottomed flask was purged to make a negative pressure in the round-bottomed flask, hydrogen gas was introduced into the round-bottomed flask, and the mixed system was reacted at room temperature for 16 hours. After completion of the TLC detection, palladium on carbon was removed by suction filtration through celite, and the mixed solvent was concentrated under reduced pressure to give Compound A31 (146 mg, yield 100%) as a yellow oily liquid.
To a solution of (2-aminophenyl) dimethylphosphine oxide (1 g,5.9 mmol) in DMF was added 2,4, 5-trichloropyrimidine (1 g,8.9 mmol) and dipotassium hydrogen phosphate (3 g,18 mmol), and the reaction mixture was heated to 60℃for 12 hours, after which the reaction was completed by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=3:2) to give compound A3 as a white solid (1.3 g, yield 70%).
Compound A3 (146 mg,0.51 mmol), A3 (133 mg,0.42 mmol) and ethylene glycol monomethyl ether (2 mL) were taken and put into a25 mL three-necked flask, and the flask was purged three times under the protection of argon, and trifluoroacetic acid (65. Mu.L, 0.84 mmol) was added dropwise under the ice bath condition, and after the addition was completed, the temperature was raised to 60℃and the reaction was carried out for 10 hours. Cooled to room temperature, poured into ice water, stirred for 30 min, extracted with ethyl acetate ((10 ml x 3)), the aqueous layer was PH-adjusted with saturated sodium bicarbonate=10, extracted again with ethyl acetate (10 ml x 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered off with suction and spun dry under reduced pressure to give the crude product. The crude product was dissolved with a small amount of dichloromethane, n-hexane was added, solids were precipitated, the solvent was distilled off under reduced pressure, and the filtrate after spin-drying was recrystallized from ethyl acetate and ethanol to give the white or off-white product BG-239 (239 mg, yield 50%).
3. Synthesis of (2- ((5-chloro-2- ((4- (3- (4, 4-difluoropiperidin-1-yl) propoxy) -2-methoxy) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (BG-247)
The compound 5-fluoro-2-nitroanisole (4476 mg,2.6 mmol) was dissolved in dimethyl sulfoxide (8 mL), sodium hydroxide (1 g,25 mL) and water (8 mL) were added sequentially, and the resulting mixture was stirred at 80℃for 5h. The system was a yellow clear solution, water (50 mL) was added to the reaction system to dilute, the aqueous layer was made acidic with dilute hydrochloric acid, extracted twice with ethyl acetate (50 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give compound a26 as a yellow solid (420 mg, yield 95%).
To a solution of the crude A26 (168 mg,1 mmol) in acetonitrile (8 mL) were added 1, 3-dibromopropane (1 mg,5 mmol) and potassium carbonate (276 mg,2 mmol), and the reaction mixture was heated to 70℃for 12 hours, after which the reaction was completed by TLC. The reaction mixture was naturally cooled to room temperature, acetonitrile was concentrated under reduced pressure, 1, 3-dibromopropane was distilled off from the system by vacuum heating, water (30 mL) was added to the reaction system for dilution, and methylene chloride (20 mL. Times.3) was used for extraction three times. The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give crude A27 as a yellow solid (290 mg, yield 100%).
To a 25mL three-necked flask, 4-difluoropiperidine (121 mg,1 mmol) and potassium carbonate (691 mg,5 mmol) were successively added, the air in the flask was evacuated, argon was changed to argon, tetrahydrofuran (3 mL) was added, and the resultant mixture was stirred under argon atmosphere at 60℃for 30 minutes. The reaction solution was cooled to room temperature, A27 (277 mg,1.2 mmol) was added, and the resulting mixture was stirred overnight under argon atmosphere at 60 ℃. The reaction mixture was cooled to room temperature and TLC was complete. Tetrahydrofuran was concentrated under reduced pressure, extracted three times with dichloromethane (20 mL. Times.3), and dried over anhydrous sodium sulfate. The organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/acetone=5:1) to give compound a32 (285 mg, yield 86%) as a yellow oily liquid.
Compound A32 (142 mg,0.4 mmol) was dissolved in a mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL), palladium on carbon (21 mg, 5%) was added to the mixed system, air in the round-bottomed flask was purged, a negative pressure was formed in the round-bottomed flask, hydrogen gas was introduced into the round-bottomed flask, and the mixed system was reacted at room temperature for 16 hours. After completion of the TLC detection, palladium on carbon was removed by suction filtration through celite, and the mixed solvent was concentrated under reduced pressure to give Compound A33 (129 mg, yield 100%) as a yellow oily liquid.
To a solution of (2-aminophenyl) dimethylphosphine oxide (1 g,5.9 mmol) in DMF was added 2,4, 5-trichloropyrimidine (1 g,8.9 mmol) and dipotassium hydrogen phosphate (3 g,18 mmol), and the reaction mixture was heated to 60℃for 12 hours, after which the reaction was completed by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=3:2) to give compound A3 as a white solid (1.3 g, yield 70%).
Compound A33 (129 mg,0.44 mmol), A3 (156 mg,0.44 mmol) and ethylene glycol monomethyl ether (2 mL) were taken and placed in a 25mL three-necked flask, and the flask was purged three times under the protection of argon, and trifluoroacetic acid (67. Mu.L, 0.87 mmol) was added dropwise under the ice bath condition, and after the addition was completed, the temperature was raised to 60℃and the reaction was carried out for 10 hours. Cooled to room temperature, poured into ice water, stirred for 30 min, extracted with ethyl acetate ((10 ml x 3)), the aqueous layer was PH-adjusted with saturated sodium bicarbonate=10, extracted again with ethyl acetate (10 ml x 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered off with suction and spun dry under reduced pressure to give the crude product. The crude product was dissolved with a small amount of dichloromethane, n-hexane was added, solids were precipitated, suction filtration was performed, the solvent was distilled off under reduced pressure, and the filtrate after spin-drying was recrystallized with ethyl acetate and ethanol to give the white or off-white product BG-247 (166 mg, yield 65%).
4. Synthesis of (2- ((5-chloro-2- (4- (3- (3-fluoropiperidin-1-yl) propoxy) -2-methoxy) amino) pyrimidin-4 yl) amino) phenyl) dimethylphosphine oxide (BG-248)
The compound 5-fluoro-2-nitroanisole (4476 mg,2.6 mmol) was dissolved in dimethyl sulfoxide (8 mL), sodium hydroxide (1 g,25 mL) and water (8 mL) were added sequentially, and the resulting mixture was stirred at 80℃for 5h. The system was a yellow clear solution, water (50 mL) was added to the reaction system to dilute, the aqueous layer was made acidic with dilute hydrochloric acid, extracted twice with ethyl acetate (50 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give compound a26 as a yellow solid (420 mg, yield 95%).
To a solution of the crude A26 (168 mg,1 mmol) in acetonitrile (8 mL) were added 1, 3-dibromopropane (1 mg,5 mmol) and potassium carbonate (276 mg,2 mmol), and the reaction mixture was heated to 70℃for 12 hours, after which the reaction was completed by TLC. The reaction mixture was naturally cooled to room temperature, acetonitrile was concentrated under reduced pressure, 1, 3-dibromopropane was distilled off from the system by vacuum heating, water (30 mL) was added to the reaction system for dilution, and methylene chloride (20 mL. Times.3) was used for extraction three times. The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give crude A27 as a yellow solid (290 mg, yield 100%).
To a 25mL three-necked flask, 3-fluoropiperidine hydrochloride (140 mg,1 mmol) and potassium carbonate (691 mg,5 mmol) were successively added, and after the air in the flask was purged, tetrahydrofuran (3 mL) was added after changing to argon, and the resultant mixture was stirred under argon atmosphere at 60℃for 30 minutes. The reaction solution was cooled to room temperature, A27 (277 mg,1.2 mmol) was added, and the resulting mixture was stirred overnight under argon atmosphere at 60 ℃. The reaction mixture was cooled to room temperature and TLC was complete. Tetrahydrofuran was concentrated under reduced pressure, extracted three times with dichloromethane (20 mL. Times.3), and dried over anhydrous sodium sulfate. The organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/acetone=8:1) to give compound a34 (285 mg, yield 91%) as a yellow oily liquid.
Compound A34 (142 mg,0.46 mmol) was dissolved in a mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL), palladium on carbon (24 mg, 5%) was added to the mixed system, air in the round-bottomed flask was purged to make a negative pressure in the round-bottomed flask, hydrogen gas was introduced into the round-bottomed flask, and the mixed system was reacted at room temperature for 16 hours. After completion of the TLC detection, palladium on carbon was removed by suction filtration through celite, and the mixed solvent was concentrated under reduced pressure to give Compound A35 (130 mg, yield 100%) as a yellow oily liquid.
To a solution of (2-aminophenyl) dimethylphosphine oxide (1 g,5.9 mmol) in DMF was added 2,4, 5-trichloropyrimidine (1 g,8.9 mmol) and dipotassium hydrogen phosphate (3 g,18 mmol), and the reaction mixture was heated to 60℃for 12 hours, after which the reaction was completed by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=3:2) to give compound A3 as a white solid (1.3 g, yield 70%).
Compound a35 (130 mg,0.45 mmol), A3 (142 mg,0.45 mmol) and ethylene glycol monomethyl ether (2 mL) were taken and put into a25 mL three-necked flask, and after the addition, trifluoroacetic acid (69 μl,0.9 mmol) was added dropwise under the condition of three-fold ventilation under the protection of argon gas, and after the addition, the temperature was raised to 60 ℃ for 10 hours. Cooled to room temperature, poured into ice water, stirred for 30 min, extracted with ethyl acetate ((10 ml x 3)), the aqueous layer was PH-adjusted with saturated sodium bicarbonate=10, extracted again with ethyl acetate (10 ml x 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered off with suction and spun dry under reduced pressure to give the crude product. The crude product was dissolved with a small amount of dichloromethane, n-hexane was added, solids were precipitated, the solvent was distilled off under reduced pressure, and the filtrate after spin-drying was recrystallized from ethyl acetate and ethanol to give the white or off-white product BG-248 (164 mg, 65% yield).
5. Synthesis of (2- (5-chloro-2- (2-methoxy-4- (4-methylpiperazin-1 yl) phenyl) amino) pyrimidin-4 yl) amino) phenyl) dimethylphosphine oxide (BG-267)
To a solution of N-methylpiperazine (648. Mu.L, 5.8 mmol) in DMF was added 5-fluoro-2-nitroanisole (1 g,5.8 mmol) and potassium carbonate (1.2 g,8.8 mmol), and the reaction mixture was heated to 80℃for 12 hours, followed by completion of the reaction by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol=97:3) to give compound A1 as a yellow solid (973 mg, yield 66％).1H NMR(400MHz,CDCl3):δ＝7.89-7.87(d,J＝6.8Hz,1H),6.61-6.58(m,1H),6.53-6.52(m,1H),3.90(s,3H),3.45-3.42(t,J＝5.2Hz,4H),2.44-2.41(t,J＝5.2Hz,4H),2.22(s,3H).
Compound A1 (500 mg,2 mmol) was dissolved in a mixed solvent of methanol and tetrahydrofuran, palladium on carbon (43 mg, 20%) was added to the mixed system, air in the round-bottomed flask was purged to make a negative pressure in the round-bottomed flask, and hydrogen was introduced into the round-bottomed flask, and the mixed system was reacted at room temperature for 16 hours. After completion of the TLC detection, palladium on carbon was removed by suction filtration through celite, and the mixed solvent was concentrated under reduced pressure to give compound A2 (443 mg, yield 100%) as a yellow solid.
To a solution of (2-aminophenyl) dimethylphosphine oxide (1 g,5.9 mmol) in DMF was added 2,4, 5-trichloropyrimidine (1 g,8.9 mmol) and dipotassium hydrogen phosphate (3 g,18 mmol), and the reaction mixture was heated to 60℃for 12 hours, after which the reaction was completed by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=3:2) to give compound A3 as a white solid (1.3 g, yield 70％).1H NMR(400MHz,CDCl3):δ＝11.53(s,1H),8.68-8.64(m,1H),8.21(s,1H),7.61-7.56(m,1H),7.31-7.25(m,1H),7.19-7.15(m,1H),1.85(s,3H),1.82(s,3H).
Compound A2 (250 mg,0.8 mmol), A3 (210 mg,0.95 mmol) and ethylene glycol monomethyl ether (2.5 mL) were taken and put into a 25mL three-necked flask, and trifluoroacetic acid (121. Mu.L, 1.6 mmol) was added dropwise under the condition of argon gas protection and three times of ventilation and ice bath, and after the addition was completed, the temperature was raised to 60℃and the reaction was carried out for 10 hours. Cooled to room temperature, poured into ice water (0.8 mmole a2, 10 mL), stirred for 30 min, extracted with ethyl acetate ((10 mL x 3)), the aqueous layer was ph=10 adjusted with saturated sodium bicarbonate, extracted again with ethyl acetate ((10 mL x 3)), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered off with suction and spun dry under reduced pressure to give the crude product. Dissolving the crude product with small amount of dichloromethane, adding n-hexane, precipitating solid, vacuum filtering, evaporating solvent under reduced pressure, recrystallizing the filtrate with ethyl acetate and ethanol to obtain white or off-white product BG-267 (308 mg, yield) 78％).1H NMR(400MHz,CDCl3):δ＝11.16(s,3H),8.47(s,1H),8.073-8.07(m,2H),7.56-7.50(m,1H),7.42-7.40(d,J＝8.8Hz,1H),7.36-7.32(m,1H),7.12-7.08(m,1H),6.64-6.63(m,1H),6.48-6.45(m,1H),3.76(s,3H),3.19-3.17(m,4H),2.60-2.56(m,4H),2.30(m,3H),1.78-1.75(dd,J＝13.2Hz,6H).
6. Synthesis of (2- ((5-chloro-2- ((4- (4-isopropylpiperazin-1-yl) -2 methoxyphenyl) amino) pyrimidin-4 yl) amino) phenyl) dimethylphosphine oxide (BG-272)
To a solution of N-isopropylpiperazine (836. Mu.L, 5.8 mmol) in DMF was added 5-fluoro-2-nitroanisole (1 g,5.8 mmol) and potassium carbonate (1.2 g,8.8 mmol), and the reaction was heated to 80℃and reacted for 12 hours by TLC to detect the completion of the reaction. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol=97:3) to give compound A4 as a yellow solid (1.5 g, yield 91％).1H NMR(400MHz,CDCl3):δ＝7.85-7.82(d,J＝9.2Hz,1H),6.55-6.52(m,1H),6.47-6.46(m,1H),3.86(s,3H),3.37-3.36(t,J＝5.0Hz,4H),2.68-2.61(m,1H),2.51-2.49(t,J＝5.2Hz,4H),0.96-0.95(d,J＝6.4Hz,6H).
Compound A4 (1 g,3.6 mmol) was dissolved in a mixed solvent of methanol and tetrahydrofuran, palladium on carbon (77 mg, 20%) was added to the mixed system, air in the round-bottomed flask was purged to make a negative pressure in the round-bottomed flask, and hydrogen was introduced into the round-bottomed flask, and the mixed system was reacted at room temperature for 16 hours. After completion of TLC detection, palladium on carbon was removed by suction filtration through celite, and the mixed solvent was concentrated under reduced pressure to give compound A5 (891 mg, yield 99%) as a yellow solid.
To a solution of (2-aminophenyl) dimethylphosphine oxide (1 g,5.9 mmol) in DMF was added 2,4, 5-trichloropyrimidine (1 g,8.9 mmol) and dipotassium hydrogen phosphate (3 g,18 mmol), and the reaction mixture was heated to 60℃for 12 hours, after which the reaction was completed by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=3:2) to give compound A3 as a white solid (1.3 g, yield 70％).1H NMR(400MHz,CDCl3):δ＝11.53(s,1H),8.68-8.64(m,1H),8.21(s,1H),7.61-7.56(m,1H),7.31-7.25(m,1H),7.19-7.15(m,1H),1.85(s,3H),1.82(s,3H).
Compound A5 (250 mg,0.8 mmol), A3 (210 mg,0.95 mmol) and ethylene glycol monomethyl ether (2.5 mL) were taken and added into a 25mL three-necked flask, and the flask was purged three times under the protection of argon, and trifluoroacetic acid (121. Mu.L, 1.6 mmol) was added dropwise under the ice bath condition, and after the addition was completed, the temperature was raised to 60℃and the reaction was carried out for 10 hours. Cooled to room temperature, poured into ice water (0.8 mmole a5, 10 mL), stirred for 30 min, extracted with ethyl acetate ((10 mL x 3)), the aqueous layer was ph=10 adjusted with saturated sodium bicarbonate, extracted again with ethyl acetate ((10 mL x 3)), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered off with suction and spun dry under reduced pressure to give the crude product. Dissolving the crude product with small amount of dichloromethane, adding n-hexane, precipitating solid, vacuum filtering, evaporating solvent under reduced pressure, recrystallizing the filtrate with ethyl acetate and ethanol to obtain white or off-white product BG-272 (308 mg, yield) 74％).1H NMR(400MHz,CDCl3):δ＝10.70(s,1H),8.60-8.57(m,1H),8.10-8.06(m,2H),7.49-7.45(m,1H),7.31-7.25(m,2H),7.13-7.09(m,1H),6.55-6.54(m,1H),6.50-6.46(m,1H),3.86(s,3H),3.23(s,3H),2.90-2.82(m,2H),1.84-1.81(d,J＝13.2Hz,6H),1.17-1.54(d,J＝6.4Hz,6H).
7. Synthesis of (2- (5-chloro-2- (4- (4- (4- (4-isopropylpiperazin-1-yl) piperazin-1-yl) -2-methoxy) aminopyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (BG-296)
To a 25mL single port flask, 1-Boc-4-piperidone (200 mg,1 mmol), 1-isopropylpiperazine (286. Mu.L, 2 mmol) and methanol (5 mL) were added sequentially, sodium cyanoborohydride (99 mg,1.5 mmol) was added in small portions, acetic acid (100. Mu.L) was added after the addition, and the resulting mixture was stirred at 60℃overnight, and the reaction was completed by TLC detection. The reaction mixture was cooled to room temperature, quenched by addition of saturated sodium bicarbonate solution (5 mL), and concentrated under reduced pressure. The reaction system was diluted with water, extracted three times with ethyl acetate (10 ml×3), washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20:1) to give compound A6 as a white solid (174 mg, yield 56%).
Compound A6 (174 mg,0.56 mmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (0.2M) was added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to give a crude product of compound A7 (182 mg, yield 100%, white solid) in the form of trifluoroacetate salt.
To a solution of crude A7 (407 mg,1.25 mmol) in DMF was added 5-fluoro-2-nitroanisole (214 mg,1.25 mmol) and potassium carbonate (433 mg,3 mmol), and the reaction was heated to 80℃for 12 hours, and the reaction was completed by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane/methanol=97:3) to give compound A8 as a yellow solid (128 mg, yield 30%).
Compound A8 (128 g,0.35 mmol) was dissolved in a mixed solvent of methanol and tetrahydrofuran, palladium on carbon (7.5 mg, 5%) was added to the mixed system, air in the round-bottomed flask was purged to make a negative pressure in the round-bottomed flask, hydrogen gas was introduced into the round-bottomed flask, and the mixed system was reacted at room temperature for 16 hours. After completion of the TLC detection, palladium on carbon was removed by suction filtration through celite, and the mixed solvent was concentrated under reduced pressure to give compound A9 (116 mg, yield 100%) as a yellow solid.
To a solution of (2-aminophenyl) dimethylphosphine oxide (1 g,5.9 mmol) in DMF was added 2,4, 5-trichloropyrimidine (1 g,8.9 mmol) and dipotassium hydrogen phosphate (3 g,18 mmol), and the reaction mixture was heated to 60℃for 12 hours, after which the reaction was completed by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=3:2) to give compound A3 as a white solid (1.3 g, yield 70%).
Compound A9 (138 mg,0.42 mmol), A3 (111 mg,0.35 mmol) and ethylene glycol monomethyl ether (1 mL) were taken and put into a 25mL three-necked flask, and then, the flask was purged three times under the protection of argon, and trifluoroacetic acid (54. Mu.L, 0.7 mmol) was added dropwise under the ice bath condition, and after the addition was completed, the temperature was raised to 60℃and the reaction was carried out for 10 hours. Cooled to room temperature, poured into ice water (0.42 mmole a9, 10 mL), stirred for 30 min, extracted with ethyl acetate ((10 mL x 3)), the aqueous layer was ph=10 adjusted with saturated sodium bicarbonate, extracted again with ethyl acetate ((10 mL x 3)), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered off with suction and spun dry under reduced pressure to give the crude product. Dissolving the crude product with small amount of dichloromethane, adding n-hexane, precipitating solid, vacuum filtering, evaporating solvent under reduced pressure, recrystallizing the filtrate with ethyl acetate and ethanol to obtain white or off-white product BG-296 (117 mg, yield) 55％).1H NMR(400MHz,DMSO):δ＝11.13(s,1H),8.49-8.46(m,1H),8.06(s,1H),8.02(s,1H),7.55-7.49(m,1H),7.40-7.32(m,2H),7.12-7.07(m,1H),6.62-6.61(m,1H),6.47-6.45(m,1H),4.12-4.08(m,2H),3.75(s,3H),3.74-3.68(m,2H),3.17-3.16(m,7H),2.69-2.62(m,3H),1.87-1.83(m,2H),1.78-1.74(d,J＝13.2Hz,6H),1.57-1.47(m,2H),0.99-0.97(d,J＝6.4Hz,6H).
8. Synthesis of (2- ((5-chloro-2- (4- (3-fluoro- [1,4 '-bipiperazine ] -1' -yl) -2-methoxy) amino) pyrimidin-4 yl) amino) phenyl) dimethylphosphine oxide (BG-325)
To a25 mL three-necked flask was successively added 1-Boc-4-piperidone (200 mg,1 mmol), 3-fluoropiperidine hydrochloride (279 mg,2 mmol), N, N-diisopropylethylamine (348. Mu.L, 2 mmol), the atmosphere in the flask was evacuated, argon was changed to, and methanol (5 mL) was added, and the resultant mixture was stirred under argon atmosphere at 60℃for 2 hours. The reaction solution was cooled to room temperature naturally, acetic acid (100. Mu.L) was added thereto, and the resultant mixture was stirred overnight under argon atmosphere at 60 ℃. The reaction mixture was cooled to room temperature naturally, sodium cyanoborohydride (99 mg,1.5 mmol) was added a few times, and the resulting mixture was stirred at 60℃overnight, after which the reaction was completed by TLC. The reaction mixture was cooled to room temperature, quenched by addition of saturated sodium bicarbonate solution (5 mL), and concentrated under reduced pressure. The reaction system was diluted with water, extracted three times with ethyl acetate (10 ml×3), washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20:1) to give compound a10 as a white solid (206 mg, yield 72%).
Compound A10 (206 mg,0.72 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.2M) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to give a crude product (216 mg, yield 100% as a white solid) of compound a11 in the form of trifluoroacetate salt.
To a solution of crude A11 (216 mg,0.72 mmol) in DMF was added 5-fluoro-2-nitroanisole (123 mg,0.72 mmol) and potassium carbonate (247 mg,1.8 mmol), and the reaction mixture was heated to 80℃for 12 hours, and the reaction was completed by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol=97:3) to give compound a12 as a yellow solid (197 mg, yield 81%).
Compound A12 (197g, 0.58 mmol) was dissolved in a mixed solvent of methanol and tetrahydrofuran, palladium on carbon (3.1 mg, 5%) was added to the mixed system, air in the round-bottomed flask was purged to make a negative pressure in the round-bottomed flask, hydrogen gas was introduced into the round-bottomed flask, and the mixed system was reacted at room temperature for 16 hours. After completion of the TLC detection, palladium on carbon was removed by suction filtration through celite, and the mixed solvent was concentrated under reduced pressure to give compound A13 (178 mg, yield 100%) as a yellow solid.
To a solution of (2-aminophenyl) dimethylphosphine oxide (1 g,5.9 mmol) in DMF was added 2,4, 5-trichloropyrimidine (1 g,8.9 mmol) and dipotassium hydrogen phosphate (3 g,18 mmol), and the reaction mixture was heated to 60℃for 12 hours, after which the reaction was completed by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and concentrated under reduced pressure to give ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=3:2) to give compound A3 as a white solid (1.3 g, yield 70%).
Compound A13 (186 mg,0.57 mmol), A3 (152 mg,0.48 mmol) and ethylene glycol monomethyl ether (1 mL) were taken and placed in a 25mL three-necked flask, and the flask was purged three times under the protection of argon, and trifluoroacetic acid (73.46. Mu.L, 0.96 mmol) was added dropwise under the ice bath condition, and after the addition was completed, the temperature was raised to 60℃and the reaction was carried out for 10 hours. Cooled to room temperature, poured into ice water, stirred for 30min, extracted with ethyl acetate ((10 ml x 3)), the aqueous layer was PH-adjusted with saturated sodium bicarbonate=10, extracted again with ethyl acetate (10 ml x 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered off with suction and spun dry under reduced pressure to give the crude product. Dissolving the crude product with small amount of dichloromethane, adding n-hexane, precipitating solid, vacuum filtering, evaporating solvent under reduced pressure, recrystallizing the filtrate with ethyl acetate and ethanol to obtain white or off-white product BG-325 (169 mg, yield) 60％).1H NMR(400MHz,CD3OD):δ＝8.35-8.31(m,1H),8.02(s,1H),7.67-7.63(m,1H),7.62-7.56(m,1H),7.52-7.47(m,1H),7.26-7.22(m,1H),6.66-6.64(m,1H),6.46-6.42(m,1H),4.74-4.60(m,1H),3.83(s,3H),3.77-3.68(m,2H),3.51-3.47(m,1H),3.01-2.82(m,2H),2.71-2.52(m,5H),2.00-1.96(m,3H),1.84(s,3H),1.81(s,3H),1.77-1.59(m,4H).
9. Synthesis of (2- ((5-chloro-2- ((4- (4, 4-difluoro- [1,4 '-bipiperazine ] -1' -yl) -2-methoxy) amino) pyrimidin-4 yl) amino) phenyl) dimethylphosphine oxide (BG-328)
To a 25mL three-necked flask was successively added 1-Boc-4-piperidone (200 mg,1 mmol), 4-difluoropiperidine (199mg, 2 mmol), N, N-diisopropylethylamine (348. Mu.L, 2 mmol), the atmosphere in the flask was evacuated, argon was changed to, and methanol (5 mL) was added, and the resultant mixture was stirred under argon atmosphere at 60℃for 2 hours. The reaction solution was cooled to room temperature naturally, acetic acid (100. Mu.L) was added thereto, and the resultant mixture was stirred overnight under argon atmosphere at 60 ℃. The reaction mixture was cooled to room temperature naturally, sodium cyanoborohydride (99 mg,1.5 mmol) was added a few times, and the resulting mixture was stirred at 60℃overnight, after which the reaction was completed by TLC. The reaction mixture was cooled to room temperature, quenched by addition of saturated sodium bicarbonate solution (5 mL), and concentrated under reduced pressure. The reaction system was diluted with water, extracted three times with ethyl acetate (10 ml×3), washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20:1) to give compound a14 as a white solid (189 mg, yield 62%).
Compound A14 (189 mg,0.62 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.2M) was added and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to give a crude product (197 mg, yield 100% as a white solid) of compound a15 in the form of trifluoroacetate.
To a solution of crude A15 (197mg, 0.62 mmol) in DMF was added 5-fluoro-2-nitroanisole (106 mg,0.62 mmol) and potassium carbonate (214 mg,1.6 mmol), and the reaction was heated to 80℃for 12 hours, and the reaction was completed by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane/methanol=97:3) to give compound a16 as a yellow solid (75 mg, yield 34%).
Compound A16 (75 g,0.2 mmol) was dissolved in a mixed solvent of methanol and tetrahydrofuran, palladium on carbon (1.1 mg, 5%) was added to the mixed system, air in the round-bottomed flask was purged to make a negative pressure in the round-bottomed flask, hydrogen gas was introduced into the round-bottomed flask, and the mixed system was reacted at room temperature for 16 hours. After completion of TLC detection, palladium on carbon was removed by suction filtration through celite, and the mixed solvent was concentrated under reduced pressure to give compound A17 (75 mg, yield 92%) as a yellow solid.
To a solution of (2-aminophenyl) dimethylphosphine oxide (1 g,5.9 mmol) in DMF was added 2,4, 5-trichloropyrimidine (1 g,8.9 mmol) and dipotassium hydrogen phosphate (3 g,18 mmol), and the reaction mixture was heated to 60℃for 12 hours, after which the reaction was completed by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=3:2) to give compound A3 as a white solid (1.3 g, yield 70%).
Compound A17 (75 mg,0.23 mmol), A3 (63 mg,0.2 mmol) and ethylene glycol monomethyl ether (1 mL) were taken and put into a 25mL three-necked flask, and after the addition was completed, the mixture was warmed to 60℃and reacted for 10 hours under the protection of argon and three times of ventilation, trifluoroacetic acid (31. Mu.L, 0.4 mmol) was added dropwise under the ice bath condition. Cooled to room temperature, poured into ice water, stirred for 30 min, extracted with ethyl acetate ((10 ml x 3)), the aqueous layer was PH-adjusted with saturated sodium bicarbonate=10, extracted again with ethyl acetate ((10 ml x 3)), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered off with suction and spun dry under reduced pressure to give the crude product. Dissolving the crude product with small amount of dichloromethane, adding n-hexane, precipitating solid, vacuum filtering, evaporating solvent under reduced pressure, recrystallizing the filtrate with ethyl acetate and ethanol to obtain white or off-white product BG-328 (71 mg, yield) 58％).1H NMR(400MHz,CDCl3):δ＝10.81(s,1H),8.64-8.61(m,1H),8.11(s,1H),8.08(s,1H),7.52-7.47(m,1H),7.31-7.27(m,1H),7.14-7.10(m,1H),6.55-6.54(m,1H),6.50-6.48(m,1H),3.87(s,3H),3.67-3.64(m,2H),2.72-2.66(m,6H),2.53-2.54(m,1H),2.02-2.03(m,4H),1.93-1.90(m,2H),1.85-1.81(d,J＝13.2Hz,6H),1.76-1.73(m,2H).
10. Synthesis of (R) - (2- ((5-chloro-2- ((4- (4- (3-fluoropyrrolidin-1 yl) piperidin-1 yl) -2-methoxyphenyl) amino) pyrimidin-4 yl) amino) phenyl) dimethylphosphine oxide (BG-380)
To a 25mL three-necked flask was successively added 1-Boc-4-piperidone (502 mg,4 mmol), 3- (R) -fluoropyrrolidine hydrochloride (400 mg,2 mmol), N, N-diisopropylethylamine (697. Mu.L, 4 mmol), the atmosphere in the flask was evacuated, and after changing to argon, methanol (10 mL) was added, and the resultant mixture was stirred under argon atmosphere at 60℃for 2 hours. The reaction solution was cooled to room temperature naturally, acetic acid (200. Mu.L) was added thereto, and the resultant mixture was stirred overnight under argon atmosphere at 60 ℃. The reaction mixture was cooled to room temperature naturally, and sodium cyanoborohydride (189 mg,3 mmol) was added in small portions, and the resulting mixture was stirred at 60℃overnight, after which the reaction was completed by TLC. The reaction mixture was cooled to room temperature, quenched by addition of saturated sodium bicarbonate solution (10 mL), and concentrated under reduced pressure. The reaction system was diluted with water, extracted three times with ethyl acetate (20 ml×3), washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20:1) to give compound a18 as a white solid (400 mg, yield 73％).1H NMR(400MHz,CDCl3):δ＝5.25-5.07(m,1H),4.02(s,2H),2.96-2.73(m,5H),2.54-2.48(m,1H),2.31-1.97(m,3H),1.90-1.79(m,3H),1.48-1.38(m,10H).
Compound A18 (400 mg,1.5 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (0.2M) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to give a crude product of compound a19 (421 mg, yield 100% as a white solid) in the form of trifluoroacetate salt.
To a solution of crude A19 (426 mg,1.5 mmol) in DMF was added 5-fluoro-2-nitroanisole (252 mg,1.5 mmol) and potassium carbonate (509 mg,3.7 mmol), and the reaction mixture was heated to 80℃for 12 hours, followed by completion of the reaction by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and extracted with ethyl acetate (40 mL. Times.3). The organic phases were combined, washed with saturated aqueous sodium chloride (100 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (dichloromethane/methanol=97:3) to give compound a20 as a yellow solid (360 mg, yield 76%).
Compound A20 (360 g,1.1 mmol) was dissolved in a mixed solvent of methanol and tetrahydrofuran, palladium on carbon (59 mg, 5%) was added to the mixed system, air in the round-bottomed flask was purged to make a negative pressure in the round-bottomed flask, and hydrogen was introduced into the round-bottomed flask, and the mixed system was reacted at room temperature for 16 hours. After completion of TLC detection, palladium on carbon was removed by suction filtration through celite, and the mixed solvent was concentrated under reduced pressure to give compound A21 (287 mg, yield 88%) as a yellow solid.
To a solution of (2-aminophenyl) dimethylphosphine oxide (1 g,5.9 mmol) in DMF was added 2,4, 5-trichloropyrimidine (1 g,8.9 mmol) and dipotassium hydrogen phosphate (3 g,18 mmol), and the reaction mixture was heated to 60℃for 12 hours, after which the reaction was completed by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=3:2) to give compound A3 as a white solid (1.3 g, yield 70%).
Compound A21 (287 mg,1 mmol), A3 (399 mg,0.82 mmol) and ethylene glycol monomethyl ether (2 mL) were taken and put into a 25mL three-necked flask, and under the protection of argon gas, trifluoroacetic acid (126. Mu.L, 1.64 mmol) was added dropwise under the ice bath condition three times of ventilation, and after the addition was completed, the temperature was raised to 60℃for 10 hours. Cooled to room temperature, poured into ice water, stirred for 30 min, extracted with ethyl acetate ((10 ml x 3)), the aqueous layer was PH-adjusted with saturated sodium bicarbonate=10, extracted again with ethyl acetate ((10 ml x 3)), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered off with suction and spun dry under reduced pressure to give the crude product. The crude product was dissolved with a small amount of dichloromethane, n-hexane was added, solids were precipitated, suction filtration was performed, the solvent was distilled off under reduced pressure, and the filtrate after spin-drying was recrystallized from ethyl acetate and ethanol to give the white or off-white product BG-380 (226 mg, yield 48%).
11. Synthesis of (2- ((5-chloro-2- ((4- (4- (3, 3-difluoropyrrolidin-1-yl) piperidin-1-yl) -2-methoxy) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (BG-381)
To a 25mL three-necked flask was successively added 1-Boc-4-piperidone (209 mg,1.1 mmol), 3-difluoropyrrolidine hydrochloride (500 mg,2 mmol), N, N-diisopropylethylamine (366. Mu.L, 2.1 mmol), the air in the flask was evacuated, and after changing to argon, methanol (5 mL) was added, and the resultant mixture was stirred under argon atmosphere at 60℃for 2 hours. The reaction solution was cooled to room temperature, acetic acid (105. Mu.L) was then added thereto, and the resultant mixture was stirred under argon atmosphere at 60℃overnight. The reaction mixture was cooled to room temperature naturally, sodium cyanoborohydride (101 mg,1.6 mmol) was added a few times, and the resulting mixture was stirred at 60℃overnight, after which the reaction was completed by TLC. The reaction mixture was cooled to room temperature, quenched by addition of saturated sodium bicarbonate solution (10 mL), and concentrated under reduced pressure. The reaction system was diluted with water, extracted three times with ethyl acetate (20 ml×3), washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20:1) to give compound a22 as a white solid (253 mg, yield 83%).
1H NMR(400MHz,CDCl3):δ＝3.99-3.97(m,2H),2.98-2.91(t,J＝13.6Hz,2H),2.84-2.75(m,4H),2.31-2.20(m,3H),1.79-1.75(m,2H),1.44(s,9H),1.41-1.34(m,2H).
Compound A22 (255 mg,0.9 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (0.2M) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to give a crude product (265 mg, 100% yield, white solid) of compound a23 in the form of trifluoroacetate salt.
To a solution of crude A23 (265 mg,0.9 mmol) in DMF was added 5-fluoro-2-nitroanisole (149 mg,0.9 mmol) and potassium carbonate (301 mg,2.2 mmol), and the reaction mixture was heated to 80℃for 12 hours, and the reaction was completed by TLC. The reaction mixture was cooled to room temperature, DMF was concentrated under reduced pressure, and extracted with ethyl acetate (20 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol=97:3) to give compound a24 as a yellow solid (240 mg, yield 81%).
Compound A24 (240 g,0.7 mmol) was dissolved in a mixed solvent of methanol and tetrahydrofuran, palladium on carbon (37 mg, 5%) was added to the mixed system, air in the round-bottomed flask was purged to make a negative pressure in the round-bottomed flask, and hydrogen was introduced into the round-bottomed flask, and the mixed system was reacted at room temperature for 16 hours. After completion of TLC detection, palladium on carbon was removed by suction filtration through celite, and the mixed solvent was concentrated under reduced pressure to give compound A25 (201 mg, yield 92%) as a yellow solid.
To a solution of (2-aminophenyl) dimethylphosphine oxide (1 g,5.9 mmol) in DMF was added 2,4, 5-trichloropyrimidine (1 g,8.9 mmol) and dipotassium hydrogen phosphate (3 g,18 mmol), and the reaction mixture was heated to 60℃for 12 hours, after which the reaction was completed by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to DMF, and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=3:2) to give compound A3 as a white solid (1.3 g, yield 70%).
Compound a25 (201 mg,0.65 mmol), A3 (171 mg,0.54 mmol) and ethylene glycol monomethyl ether (2 mL) were taken and put into a25 mL three-necked flask, and then, the flask was purged three times under the protection of argon, and trifluoroacetic acid (83 μl,1.1 mmol) was added dropwise under the ice bath condition, and after the addition was completed, the temperature was raised to 60 ℃ for 10 hours. Cooled to room temperature, poured into ice water, stirred for 30 min, extracted with ethyl acetate ((10 ml x 3)), the aqueous layer was PH-adjusted with saturated sodium bicarbonate=10, extracted again with ethyl acetate (10 ml x 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered off with suction and spun dry under reduced pressure to give the crude product. The crude product was dissolved with a small amount of dichloromethane, n-hexane was added, solids were precipitated, suction filtration was performed, the solvent was distilled off under reduced pressure, and the filtrate after spin-drying was recrystallized with ethyl acetate and ethanol to give the white or off-white product BG-381 (255 mg, yield 80%).
EXAMPLE 2 evaluation analysis of the Effect of novel structural Compounds on killing and inhibiting the AXL protein by lung cancer cells
The cellular materials used in this example were: EGFR mutated cells were used as model: PC-9, H1975 and HCC827 and octenib resistant cells PC-9OR, H1975OR and HCC827OR. The compounds used were the BG-x series prepared in example 1.
Evaluation of Activity of novel structural Compounds of 1AXL inhibitor on Ornitinib resistant cells PC-9OR
The octenib resistant cells PC-9OR were seeded at a density of 3X 10 3 cells/well in 96-well plates and cultured for 12 hours. Different concentrations of BG-x compound (concentrations 100, 20, 4, 0.8, 0.16, 0.032, 0.006, 0.001, 0. Mu.M) were added and incubated at 37℃for 48h. Cell samples were washed 3 times with PBS and 100. Mu.l of CCK-8 solution was added to each well. Incubation was continued for 2 hours and the culture was terminated. The light absorption value of each well was measured on a microplate reader at a wavelength of 450nm, the results were recorded, and the IC50 of the compound was calculated, and the results are shown in Table 1 and FIG. 1.
TABLE 1
Numbering of compounds BG-235 BG-239 BG-247 BG-248 BG-267 BG-272
IC50(μM) 5.28 7.08 6.37 3.37 3.26 2.19
Numbering of compounds BG-296 BG-325 BG-328 BG-380 BG-381
IC50(μM) 1.71 1.49 4.7 5.28 0.91
The killing effect of the BG-x compound on drug-resistant cells shows that the effects of the two drugs, namely BG-325 and BG-381, are better. Therefore, the BG-325 and BG-381 drugs are preferable for subsequent studies.
Killing effect of 2BG-325 and BG-381 compounds on lung cancer cells
Lung cancer resistant cells were seeded at a density of 3 x 10 3 cells/well in 96-well plates and cultured for 12h. Different concentrations of BG-325, BG-381 compound (concentration settings: 100, 20, 4, 0.8, 0.16, 0.032, 0.006, 0.001, 0. Mu.M) were added and incubated at 37℃for 48h. Cell samples were washed 3 times with PBS for 5min and 100. Mu.l of CCK-8 solution was added to each well. Incubation was continued for 2 hours and the culture was terminated. The wavelength of 450nm was selected, the light absorption value of each well was measured on a microplate reader, and the results were recorded to calculate IC 25 and IC 50 for the BG-325, BG-381 compounds. And analyzing the killing effect of the BG-325 and BG-381 compounds on the cells of the Ornitinib. The results are shown in tables 2-5 and FIG. 2: BG-325 and BG-381 have better killing effect on most drug-resistant strains, especially BG-381.
IC of tables 2 BG-325 25
Cells PC-9 PC-9OR1 PC-9OR2 H1975 H1975OR1 H1975OR2
IC25(μM) 0.10 1.36 0.83 0.15 0.97 0.77
Cells HCC827 HCC827OR1 HCC827OR2 HCC827OR3 HCC827OR4 HCC827OR5
IC25(μM) 0.52 0.56 0.68 1.19 0.55 0.61
IC of tables 3 BG-325 50
IC of tables 4 BG-381 25
Cells PC-9 PC-9OR1 PC-9OR2 H1975 H1975OR1 H1975OR2
IC25(μM) 0.22 0.68 0.22 0.17 0.75 0.43
Cells HCC827 HCC827OR1 HCC827OR2 HCC827OR3 HCC827OR4 HCC827OR5
IC25(μM) 0.79 0.54 0.45 0.68 0.83 0.30
IC of tables 5 BG-381 50
Numbering of compounds PC-9 PC-9OR1 PC-9OR2 H1975 H1975OR1 H1975OR2
IC50(μM) 0.79 1.81 0.62 0.69 4.03 1.92
Numbering of compounds HCC827 HCC827OR1 HCC827OR2 HCC827OR3 HCC827OR4 HCC827OR5
IC50(μM) 6.74 2.15 1.80 2.91 3.50 1.92
3 Inhibiting effect of compound on lung cancer drug-resistant cell AXL protein
Lung cancer resistant cells were seeded at a density of 3 x 10 5 cells/well in 6-well plates and cultured for 12h. Further adding BG-325 and BG-381 compounds, and incubating at 37deg.C for 48 hr at the concentration of IC 25 obtained above. And collecting cells and lysate, and detecting the change condition of the AXL protein of the AXl drug-resistant cells treated by the BG-325 and BG-381 compounds by using Western Blot.
The results are shown in FIG. 3: ornitinib resistant PC-9OR#1-6; h1975or#1, 4, 6, 7; PC-9GROR#1, 3,4, 6, 8; the AXL protein of HCC827OR #1, 3,4 is significantly elevated compared to its parent cells PC-9, H1975, PC-9GR and HCC 827. After treatment with the compounds BG-325 and BG-381, a significant down-regulation of the AXL protein band of drug resistant cells was observed. It was shown that BG-325 and BG-381 significantly inhibited the expression of AXL in four drug resistant cells, PC-9, H1975, PC-9GR and HCC 827.
EXAMPLE 3 evaluation of the Effect of Compounds on inhibition of other tumor cells by AXL protein
1 Screening of AXL high expression other tumor models
The tumor types analyzed were: lung cancer (PC-9 GR), liver cancer (HepG 2 cell), colorectal cancer (HCT-8 cell), breast cancer (MCF-7 cell), gastric cancer (N87 cell) and melanoma (WM-115).
Western Blot was used to analyze the AXL expression of the tumor model cells. The results are shown in FIG. 4: in addition to lung cancer, AXL is expressed higher in liver cancer and melanoma, and the inhibitory effect of BG-X compounds on AXL was subsequently analyzed in liver cancer and melanoma.
Inhibition of AXL from liver cancer and melanoma cells by novel structural compounds of 2 AXL inhibitor
Referring to the procedure in example 2, IC 25 concentrations were calculated from the activity of compounds BG-272, BG-325, BG-381 on liver cancer and melanoma cells (FIG. 5), as shown in Table 6:
IC 25 (mu M) of the compounds of Table 6 against liver cancer and melanoma cells
Compounds/cells HepG2 cells WM-115
BG-272 0.77 1.17
BG-325 0.53 1.41
BG-381 0.22 0.95
The changes in AXL protein of other tumor cells after compound treatment were detected using Western Blot.
The inhibitory effect on HepG2 cells AXL is shown in fig. 6A: the results show that the compounds BG-272, BG-325 and BG-381AXL have better inhibition effect and the BG-272 has the best effect.
The inhibitory effect on WM-115 cells AXL is shown in FIG. 6B: the results show that all three of the compounds BG-272, BG-325, BG-381 can significantly inhibit the expression of AXL by melanoma cells.
The amino acid sequence of the AXL protein is shown below (SEQ ID No. 1):
MAWRCPRMGRVPLAWCLALCGWACMAPRGTQAEESPFVGNPGNITGARGLTGTLRCQLQVQGEPPEVHWLRDGQILELADSTQTQVPLGEDEQDDWIVVSQLRITSLQLSDTGQYQCLVFLGHQTFVSQPGYVGLEGLPYFLEEPEDRTVAANTPFNLSCQAQGPPEPVDLLWLQDAVPLATAPGHGPQRSLHVPGLNKTSSFSCEAHNAKGVTTSRTATITVLPQQPRNLHLVSRQPTELEVAWTPGLSGIYPLTHCTLQAVLSDDGMGIQAGEPDPPEEPLTSQASVPPHQLRLGSLHPHTPYHIRVACTSSQGPSSWTHWLPVETPEGVPLGPPENISATRNGSQAFVHWQEPRAPLQGTLLGYRLAYQGQDTPEVLMDIGLRQEVTLELQGDGSVSNLTVCVAAYTAAGDGPWSLPVPLEAWRPGQAQPVHQLVKEPSTPAFSWPWWYVLLGAVVAAACVLILALFLVHRRKKETRYGEVFEPTVERGELVVRYRVRKSYSRRTTEATLNSLGISEELKEKLRDVMVDRHKVALGKTLGEGEFGAVMEGQLNQDDSILKVAVKTMKIAICTRSELEDFLSEAVCMKEFDHPNVMRLIGVCFQGSERESFPAPVVILPFMKHGDLHSFLLYSRLGDQPVYLPTQMLVKFMADIASGMEYLSTKRFIHRDLAARNCMLNENMSVCVADFGLSKKIYNGDYYRQGRIAKMPVKWIAIESLADRVYTSKSDVWSFGVTMWEIATRGQTPYPGVENSEIYDYLRQGNRLKQPADCLDGLYALMSRCWELNPQDRPSFTELREDLENTLKALPPAQEPDEILYVNMDEGGGYPEPPGAAGGADPPTQPDPKDSCSCLTAAEVHPAGRYVLCPSTTPSPAQPADRGSPAAPGQEDGA.

Claims (10)

1. A compound having a structure according to formula (I):
Wherein Z 1 in the general formula (I) is selected from O, S, N, CH 2,Z2 and O, S, N, CH 2;
r 1 is selected from the following structures:
r 2 is selected from the following structures:
R 3 is selected from: halogen: fluorine, chlorine, bromine, iodine, methoxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, or H, 5-methyl, 5-chlorine, 5-bromine, 5-methoxy, 5-thiomethyl, 5-isopropyl, 5-tert-butyl, 5-methoxyacyl, 5-fluoro, 5-trifluoromethyl, 5-chlorine, 5-phenyl.
2. A compound according to claim 1, characterized in that:
R 2 is selected from (2-aminophenyl) dimethylphosphine oxide, halogen, trifluoromethyl or trifluoromethoxy, thiomethyl, isopropyl, tert-butyl, methoxyacyl, phenyl, pyrazole ring, oxadiazole ring, imidazole ring, isoxazole ring, oxazole ring, thiazole ring, thiadiazole ring, thiophene ring, pyridine ring, pyrimidine ring, furan ring, triazole ring, pyrrole ring or tetrazole ring;
Wherein R 1 and R 2 are combined as 4, 5-dimethoxy, 4, 5-dithiomethyl, 4, 5-diisopropyl, 4, 5-di-tert-butyl, 4, 5-dimethoxyacyl, 4, 5-difluoro, 4, 5-bistrifluoromethyl, 4, 5-dichloro, 4, 5-diphenyl, 4-fluoro-5-methoxy, 4, 5-dichlorothiophene;
R 3 is alkylamine, chain and cyclic alcohol.
3. A compound according to claim 1, characterized in that: the compound is BG-325, BG-381 or BG-272, and has the structural formula as follows:
4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a compound according to any one of claims 1 to 3 or a tautomer, mesomer, racemate, stereoisomer or a pharmaceutically acceptable salt thereof.
5. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 4 for the preparation of an AXL inhibitor.
6. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 4 for the preparation of a medicament for the treatment of tumors in which AXL is highly expressed.
7. The use according to claim 6, characterized in that: tumors in which AXL is highly expressed include lung cancer, liver cancer and melanoma.
8. The use according to claim 6, characterized in that: the lung cancer is non-small cell lung cancer.
9. The use according to claim 8, characterized in that: the lung cancer is EGFR mutant advanced non-small cell lung cancer.
10. The use according to claim 8, characterized in that: the lung cancer is EGFR-TKI drug resistant non-small cell lung cancer, and the compound is BG-267, BG-325 or BG-381.
CN202410099479.2A 2024-01-24 2024-01-24 Novel structural compound AXL inhibitor and application thereof Pending CN117946165A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202410099479.2A CN117946165A (en) 2024-01-24 2024-01-24 Novel structural compound AXL inhibitor and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202410099479.2A CN117946165A (en) 2024-01-24 2024-01-24 Novel structural compound AXL inhibitor and application thereof

Publications (1)

Publication Number Publication Date
CN117946165A true CN117946165A (en) 2024-04-30

Family

ID=90791786

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202410099479.2A Pending CN117946165A (en) 2024-01-24 2024-01-24 Novel structural compound AXL inhibitor and application thereof

Country Status (1)

Country Link
CN (1) CN117946165A (en)

Similar Documents

Publication Publication Date Title
CN106928206B (en) Aldehyde compound and its preparation method and use
JP6457623B2 (en) 2,4-disubstituted 7H-pyrrolo [2,3-d] pyrimidine derivatives, process for their preparation and use in medicine
CA3016826C (en) Salt of pyridinyl amino pyrimidine derivative, preparation method therefor, and application thereof
JP6704422B2 (en) Quinazoline derivative salt and method for producing the same
CN107922348A (en) Bicyclic heterocycle amide derivatives
EP3641776B1 (en) Atropisomerism for enhanced kinase inhibitor selectivity
CN107383004B (en) 2-amino imidazopyridine derivative and preparation and application thereof
WO2017088723A1 (en) Substituted triazolopiperazine parp inhibitor, preparation method therefor, and use thereof
CN113024544A (en) Cyano-containing heterocyclic compound and application thereof
EP3418277B1 (en) Substituted amino six-membered nitric heterocyclic ring compound and preparation and use thereof
TW479058B (en) 2,7-substituted octahydro-pyrrolo[1,2-a]pyrazine derivatives
EP3617198B1 (en) Guanidine derivative
CN114276333B (en) Dihydroquinoxaline bromodomain bivalent inhibitors
CN113717245B (en) EGFR degradation agent containing 2,8, 9-trisubstituted-9H-purine structural fragment, salt and application thereof
CN117946165A (en) Novel structural compound AXL inhibitor and application thereof
CN115160321A (en) Vardenafil analogue and synthetic method and application thereof
CN115703761A (en) Compound as WWP1 inhibitor and application thereof
CN112125908B (en) CDK kinase inhibitors, methods of preparing, pharmaceutical compositions and uses thereof
CN108947904B (en) Compound containing seven-membered lactam ring and application thereof
CN110684022B (en) SET8 lysine methyltransferase inhibitor and intermediate, preparation method and application thereof
CN114533733A (en) Isoquinoline-1, 3-diamine analogue pharmaceutical preparation and preparation method thereof
CN113105459A (en) Triazolopyrimidine derivative and preparation method and application thereof
KR20210123314A (en) Fluorine-containing substituted benzothiophene compounds, pharmaceutical compositions and applications thereof
CN109912620B (en) Tetrahydrobenzo [4,5] thieno [2,3-d ] pyrimidine compound and application thereof
CN113980003B (en) 2- ((2-methoxyphenyl) sulfonyl) isoindoline compound and preparation method thereof

Legal Events

Date Code Title Description
PB01 Publication
SE01 Entry into force of request for substantive examination