CN117486860A - Axl & c-Met dual inhibitor, preparation method and application - Google Patents
Axl & c-Met dual inhibitor, preparation method and application Download PDFInfo
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- CN117486860A CN117486860A CN202210879471.9A CN202210879471A CN117486860A CN 117486860 A CN117486860 A CN 117486860A CN 202210879471 A CN202210879471 A CN 202210879471A CN 117486860 A CN117486860 A CN 117486860A
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Abstract
The invention discloses a kind of Axl&c-Met dual inhibitor, preparation method and application thereof; the inhibitor is a compound shown as a formula (I) or pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof:wherein R is 1 Hydrogen, halogen, substituted or unsubstituted alkyl, alkoxy or haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl; r is R 2 Halogen, substituted or unsubstituted alkyl; n has a value of 1 or 2. Axl of the invention&The c-Met dual inhibitor has excellent pharmacokinetic properties and is expected to be developed into an antitumor drug; in particular, the series of inhibitors have strong capability of penetrating through blood brain barrier, have good exposure to brain tissues, and can be used for developing brain tumor medicaments such as brain glioma, brain metastasis and the like.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a substituted pyridine amide compound, and specifically relates to an Axl & c-Met dual inhibitor, a preparation method and application thereof.
Background
c-MET is a transmembrane receptor tyrosine kinase encoded by the MET gene and has a high affinity structurally for Hepatocyte Growth Factor (HGF). Deregulation of HGF/c-MET signaling leads to activation of downstream pathways, including RAS/MAPK, PI3K/AkT and Rac/Rho pathways, which are involved in cell proliferation, survival and metastasis. High levels of MET gene amplification, protein overexpression or gene mutation are the primary mechanisms leading to aberrant activation of the HGF/c-MET pathway, and there is increasing evidence for a role for c-MET receptor tyrosine kinase in tumor development and metastasis progression. Furthermore, deregulation of MET tyrosine kinase is associated with resistance of cancer patients to targeted therapies and frequently occurs in non-small cell lung cancer (NSCLC) patients resistant to EGFR inhibitors. Drugs targeting MET signaling are expected to improve treatment of MET-deregulated patient populations. Currently, 4 drugs are marketed for c-Met/HGF target development, namely Crizotinib (Critizonib), cabozantinib (Cabozantinib), capmatinib and Teponinib, and the indication is mainly non-small cell lung cancer.
Receptor Tyrosine Kinases (RTKs) are transmembrane proteins that link the extracellular and intracellular environment. As mediators of signal transduction, they play an important role in normal cellular processes, including differentiation, adhesion, migration, apoptosis, metabolism. Axl (also known as Ufo, ark or Tyro 7) is a receptor tyrosine kinase that together with Tyro3 and Mer constitutes the TAM subfamily of receptor tyrosine kinases. Overexpression of Axl kinase was initially found in chronic myelogenous leukemia and chronic myeloproliferative disorders, and subsequently Paccez et al found that Axl kinase overexpression was also found in a variety of cancers such as breast, lung, prostate, colon, esophageal, liver, and the like. Axl abnormal expression activates and antagonizes tumor cell apoptosis, promotes tumor cell invasion and metastasis, promotes tumor angiogenesis, and promotes tumor generation and development through multiple links. Of particular interest, recent studies have shown that dimers produced by Axl overexpression and binding to EGFR are important contributors to acquired resistance of tumor cells to EGFR inhibitors; the combination of Axl inhibitor in preclinical study can effectively overcome EGFR inhibitor resistance. In addition, abnormal activation of Axl overexpression is also closely related to other targeted inhibitors and drug resistance of chemotherapeutic drugs, suggesting that Axl may have a broad range of co-drug application space. Unlike other kinases, axl is highly expressed in macrophages, dendritic cells of the tumor microenvironment, which can synergistically promote tumor progression through interaction with tumor cells and other stromal cells. Thus, in recent years, the development of targeted Axl inhibitors has become a leading edge and hotspot in anti-tumor drug research. Small molecule inhibitors developed therefor have shown effect in tumor therapy.
Meanwhile, research shows that Axl and c-MET are over-expressed in various malignant tumors such as brain glioma and the like. One of the main disorders of brain tumor treatment such as brain glioma is that the drug cannot effectively penetrate the blood brain barrier, and a small molecular drug with the blood brain barrier penetration capability is urgently needed to be found.
The invention provides a novel Axl & c-Met dual inhibitor which has excellent effect in treating various tumors, and the series of inhibitors have strong blood brain barrier penetrating capacity and are expected to be used for treating brain tumors.
Disclosure of Invention
The invention aims to develop a kind of Axl & c-Met dual inhibitor, a preparation method and application. The novel Axl & c-Met dual inhibitor has a brand new structure different from the existing compounds and shows excellent anti-tumor activity.
The aim of the invention is realized by the following technical scheme:
< first aspect >
The present invention provides a series of compounds comprising a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof:
wherein R is 1 Hydrogen, halogen, substituted or unsubstituted alkyl, alkoxy or haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl;
R 2 halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, hydroxyalkyl;
n has a value of 1 or 2.
As one embodiment of the present invention, the alkyl group is C 1 -C 6 The cycloalkyl group is C 3 -C 4 Cycloalkyl of (C), said alkoxy being C 1 -C 6 Alkoxy of (2), said hydroxyalkyl being C 1 -C 6 Is fluorine or chlorine.
The compound has the double inhibition effect of Axl & c-Met, and is a novel double inhibitor of Axl & c-Met.
As one embodiment of the present invention, R 1 Selected from hydrogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy, fluorine or chlorine; r is R 2 Selected from fluorine, chlorine, methyl.
As one embodiment of the present invention, R 1 Selected from hydrogen, methyl, fluoro or chloro, and R 2 Selected from fluorine, chlorine, methyl.
As an embodiment of the present invention, any one selected from the following compounds:
if there is a difference between the chemical nomenclature and the illustrated chemical structure, the illustrated chemical structure is preferred over the chemical nomenclature given.
< second aspect >
The present invention also provides a process for the preparation of an Axl & c-Met dual inhibitor compound, the process comprising the steps of: compounds of formula (I)And the compound->The reaction is carried out to produce the compound shown in the formula (I). The reaction is preferably carried out in the presence of an organic solvent, HATU and triethylamine. The organic solvent includes N, N-dimethylacetamide, N-methylpyrrolidone, methylene chloride, chloroform, tetrahydrofuran, methyl acetate, ethyl acetate, isopropyl acetate, 1, 2-dichloroethane, acetonitrile, etc.
The reaction formula is as follows:
wherein R is 1 、R 2 And n is as defined herein.
Compounds of formula (I)The preparation of the composition comprises the following steps:
a1, compoundReacting with ethyl chloroformylacetate in the presence of dichloromethane and triethylamine to form an intermediate compound +.>
A2, intermediate compoundAnd 4-methoxyl butyl-3-alkene-2-ketone reacts in the presence of ethanol and ethanol solution of sodium ethoxide.
Compounds of formula (I)The preparation of the composition comprises the following steps:
b1, compoundAnd the compound->Reacting at 80-90 ℃ under the protection of nitrogen in the presence of DMAc and potassium tert-butoxide to generate an intermediate compound +.>
B2, intermediate compoundWith 1-methylpyrazole-4-boronic acid pinacol ester in dioxane, potassium carbonate and Pd (PPh) 3 ) 4 And (3) carrying out heat preservation reaction at 90-95 ℃ in the presence condition to obtain the catalyst.
< third aspect >
The invention also provides application of the compound shown in the formula (I) or pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof in preparing medicines for treating related diseases caused by Axl kinase and/or c-Met kinase.
Wherein the diseases associated with Axl kinase and/or c-Met kinase include brain tumor, gastric cancer, cancer of the wings, breast cancer, colorectal cancer, head and neck cancer, renal cancer, liver cancer, lung cancer, ovarian cancer, membranous/gall bladder cancer, prostate cancer, thyroid cancer, osteosarcoma, rhabdomyosarcoma, MFH/fibrosarcoma, glioblastoma/astrocytoma, melanoma or mesothelioma, psoriasis, cirrhosis, diabetes, angiogenesis, restenosis, ophthalmic diseases, rheumatoid arthritis and other inflammatory diseases, immune diseases, cardiovascular diseases such as arteriosclerosis and kidney disease, etc.
Wherein the brain tumor comprises brain glioma, meningioma, brain metastasis tumor and the like.
< fourth aspect >
The invention also provides application of the compound shown in the formula (I) or pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof in preparing the Axl & c-Met inhibitor.
The invention also provides the application of a series of Axl & c-Met inhibitors in preparing medicaments for treating tumors. The tumor comprises: brain tumors, stomach cancer, cancer of the wings, breast cancer, colorectal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, membranous/gall bladder cancer, prostate cancer, thyroid cancer, osteosarcoma, rhabdomyosarcoma, MFH/fibrosarcoma, glioblastoma/astrocytoma, melanoma or mesothelioma, and the like.
As one embodiment of the invention, the tumor drug is a brain tumor drug, including brain glioma drug meningioma drug and brain metastasis drug.
Compared with the prior art, the invention has the following beneficial effects:
1) The dual Axl & c-Met inhibitor provided by the invention has stronger inhibitory activity compounds on AXL, c-Met, can simultaneously inhibit two signal paths of GAS6/AXL and HGF/c-Met, is expected to generate more remarkable anti-tumor effect,
2) The Axl and c-Met kinase inhibition effect of the compound of the invention is superior to that of positive control BMS777607. In a humanized gastric cancer MKN45 model, the Axl & c-Met dual inhibitor provided by the invention has obvious anti-tumor activity, and is obviously superior to a positive control medicine BMS777607, so that animal tolerance is good.
3) The Axl & c-Met dual inhibitor has excellent pharmacokinetic properties and is expected to be developed into antitumor drugs; in particular, the series of inhibitors have strong capability of penetrating through blood brain barrier, have good exposure to brain tissues, and can be used for developing brain tumor medicaments such as brain glioma, brain metastasis tumor, meningioma and the like.
4) The dual inhibition of Axl & c-Met of the invention is expected to overcome drug resistance of neoplastic agents.
5) The invention also provides a simple preparation method of a series of compounds with double inhibition effects on Axl & c-Met.
Drawings
Other features, objects and advantages of the present invention will become more apparent upon reading of the detailed description of non-limiting embodiments, given with reference to the accompanying drawings in which:
FIG. 1 is a graph of plasma concentration versus time (dose 10 mg/kg) of Compound 1 following intragastric administration to mice;
FIG. 2 is a graph of brain concentration versus time (dose 10 mg/kg) of Compound 1 following intragastric administration to mice;
FIG. 3 is a graph comparing the effect of compounds on nude mice body weight;
FIG. 4 is a graph showing the effect of the compound on tumor volume of human gastric cancer cell MKN45 subcutaneous transplantation tumor model;
FIG. 5 is a graph showing the effect of the compound on tumor volume versus human gastric cancer cell MKN45 subcutaneous transplantation tumor model;
fig. 6 is a graph comparing the effect of the compound on human gastric cancer cell MKN45 subcutaneous transplantation tumor.
Detailed Description
The present invention will be described in detail with reference to examples. The following examples will assist those skilled in the art in further understanding the present invention, but are not intended to limit the invention in any way. It should be noted that several modifications and improvements can be made by those skilled in the art without departing from the inventive concept. These are all within the scope of the present invention. All publications mentioned are incorporated by reference in their entirety.
Example 1 Synthesis of Compound 1
1.1 Synthesis of intermediate B1
To a 1000mL reaction flask was added 20g of 4-fluoroaniline, 200mL of methylene chloride, 23.6g of triethylamine, and the mixture was cooled to 0℃with stirring. 35.2g of chloroformylacetic acid ethyl ester is dissolved in 100mL of methylene dichloride, and the temperature is controlled between 0 and 5 ℃ and added into a reaction bottle in a dropwise manner. After the completion of the dropping, the temperature was raised to 20℃for 2 hours, 200mL of water was added, and the mixture was stirred and separated. The dichloromethane phase was washed with 200mL of saturated brine and concentrated to dryness. The residue was slurried with 90mL of petroleum ether and 30mL of ethyl acetate, filtered, and dried to give 30.0g of intermediate B1A in a yield of 74.1%.
MS:m/z＝226.35[M+H] +
1 H NMR(400MHz,Chloroform-d)δ9.29(s,1H),7.54(m,2H),7.04(m,2H),4.28(q,J＝7.1Hz,2H),3.49(s,2H),1.35(t,J＝7.1Hz,3H).
15g of intermediate B1A, 150mL of ethanol, 10g of 4-methoxybut-3-en-2-one and 50mL of sodium ethoxide ethanol solution are added into a 500mL reaction bottle, and the mixture is heated to reflux at 70-80 ℃ for reaction for 6 hours under heat preservation. Cooling to room temperature, adding 150mL of 1mol/L hydrochloric acid and dichloromethane, stirring, and separating. The dichloromethane phase was concentrated to dryness. The concentrated residue was slurried with 50mL ethyl acetate at 5 ℃, filtered, and dried to give intermediate B1.8 g in 53.9% yield.
MS:m/z＝248.33[M+H] +
1 H NMR(400MHz,Chloroform-d)δ13.87(s,1H),8.53(d,J＝7.5Hz,1H),7.36–7.30(m,2H),7.28–7.23(m,2H),6.57(d,J＝7.5Hz,1H),2.18(s,3H).
1.2 Synthesis of intermediate A1
To a 500mL reaction flask was added 3.07g of 4-amino-2-fluorophenol, 50mL of DMAc, 2.71g of potassium tert-butoxide, and the mixture was stirred under nitrogen for 0.5 hour. 5.5g of 2, 3-dichloro-4-iodopyridine was added thereto, and the temperature was raised to 85℃to react for 4 hours. Cooling to room temperature, and concentrating the reaction solution under reduced pressure. To the concentrated residue was added 150mL of ethyl acetate, stirred, and filtered. The ethyl acetate phase was concentrated to dryness under reduced pressure to give intermediate A1B.
MS:m/z＝273.21[M+H] +
1 H NMR(400MHz,Chloroform-d)δ8.09(d,J＝5.6Hz,1H),6.99(t,J＝8.6Hz,1H),6.59–6.52(m,2H),6.49(ddd,J＝8.7,2.7,1.3Hz,1H),3.86(s,2H).
Into a 250mL reaction flask was charged 100mL of intermediate A1B, 100mL of dioxane, 5.25g of 1-methylpyrazole-4-boronic acid pinacol ester, 8.37g of potassium carbonate, 20mL of water, nitrogen substitution, and Pd (PPh) was added 3 ) 4 1.5g, nitrogen replacement, heating to 90-95 ℃ and preserving heat for 16 hours. Cooling to room temperature, adding 200mL of water and ethyl acetate, and stirring to separate the liquid. The aqueous phase was extracted twice with 100mL ethyl acetate. The ethyl acetate phases were combined, concentrated to dryness under reduced pressure and separated by column chromatography on silica gel (dichloromethane: ethanol=100:1, v/v) to give intermediate a 1.36 g in 67.6% yield.
MS:m/z＝319.37[M+H] +
1 H NMR(400MHz,Chloroform-d)δ8.29(s,1H),8.27(d,J＝5.5Hz,1H),8.21(s,1H),7.01(t,J＝8.7Hz,1H),6.55(dd,J＝11.9,2.7Hz,1H),6.49(ddd,J＝8.7,2.8,1.3Hz,1H),6.46(dd,J＝5.5,1.3Hz,1H),4.01(s,3H),3.83(s,2H).
1.3 Synthesis of Compound 1
To a 500mL reaction flask was added 19 g of intermediate A, 6.98g,DMF 200mL,HATU 12.88g g of intermediate B, and 5.70g of triethylamine, and the mixture was stirred overnight for reaction. 400mL of water was added dropwise, the mixture was filtered, and the cake was dried to give 10.53g of crude compound 1 in a yield of 68.0%. 500mg of sample were purified by TLC (developing solvent dichloromethane: ethanol 15:1) to give 289mg of product with a purity of 98.18%.
MS:m/z＝548.45[M+H] +
1 H NMR(400MHz,Chloroform-d)δ11.94(s,1H),8.66(d,J＝7.5Hz,1H),8.28(d,J＝5.5Hz,2H),8.21(s,1H),7.97(dd,J＝12.4,2.5Hz,1H),7.38–7.31(m,3H),7.28–7.24(m,2H),7.15(t,J＝8.7Hz,1H),6.54(dd,J＝7.6,0.9Hz,1H),6.47(dd,J＝5.5,1.3Hz,1H),4.01(s,3H),2.15(s,3H).
Example 2 Synthesis of Compound 2
2.1 Synthesis of intermediate A2
To a 250mL reaction flask was added 2.37g of 4-amino-2-fluorophenol, 50mL of DMAc, 2.09g of potassium tert-butoxide, and the mixture was stirred under nitrogen for 0.5 hour. 4g of 2-chloro-3-fluoro-4-iodopyridine was added thereto, and the temperature was raised to 85℃to react for 4 hours. Cooling to room temperature, adding 200mL of water and ethyl acetate, stirring, standing and separating. The aqueous phase was extracted twice with 100mL ethyl acetate. The ethyl acetate phases were combined and concentrated to dryness under reduced pressure to afford intermediate A2B.
Into a 250mL reaction flask, 100mL of intermediate A2B obtained in the previous step, 4.03g of 1-methylpyrazole-4-boronic acid pinacol ester, 6.43g of potassium carbonate, 20mL of water, and nitrogen substitution were added, and Pd (PPh 3 ) 4 2.5g, nitrogen replacement, heating to 90-95 ℃ and reacting for 20 hours with heat preservation. Cooling to room temperature, and concentrating the reaction solution under reduced pressure. The concentrated residue was slurried with ethyl acetate and filtered through celite. The filtrate was concentrated and separated by column chromatography on silica gel (dichloromethane: ethanol=100:1, v/v) to give intermediate a 2.5g, yield 53.4%.
2.2 Synthesis of Compound 2
To a 100mL reaction flask was added 0.6g of intermediate A2, 0.49g,DMF 15mL,HATU 0.91g g of intermediate B1, and 0.40g of triethylamine, and the mixture was stirred overnight for reaction. 30mL of water was added dropwise, the mixture was filtered, and the cake was dried to give 0.70g of crude compound 2 in a yield of 66.5%. 360mg of sample were purified by TLC to give 118mg of product with a purity of 95.28%.
MS:m/z＝532.47[M+H] +
1 H NMR(400MHz,Chloroform-d)δ11.94(s,1H),8.66(d,J＝7.6Hz,1H),8.19–8.16(m,2H),8.04(d,J＝2.0Hz,1H),7.96(dd,J＝12.5,2.5Hz,1H),7.37–7.31(m,3H),7.27–7.24(m,2H),7.15(t,J＝8.7Hz,1H),6.56–6.51(m,2H),4.01(s,3H),2.15(s,3H).
Example 3 Synthesis of Compound 3
3.1 Synthesis of intermediate B2
To a 100mL reaction flask was added 2g of 4-toluidine, 20mL of methylene chloride and 2.64g of triethylamine, and the mixture was stirred and cooled to 0 ℃. 3.65g of chloroformylacetic acid ethyl ester is dissolved in 10mL of methylene dichloride, and the temperature is controlled between 0 and 5 ℃ and added into a reaction bottle in a dropwise manner. After the completion of the dropping, the temperature was raised to 20℃for 2 hours, 20mL of water was added, and the mixture was stirred and separated. The dichloromethane phase was washed with 20mL of saturated brine and concentrated to dryness. The residue was slurried with 12mL of petroleum ether and 3mL of ethyl acetate, filtered, and dried to give intermediate B2A3.8g in 92.0% yield.
To a 100mL reaction flask was added 3.8g of intermediate B2A, 38mL of ethanol, 2.58g of 4-methoxybut-3-en-2-one, 12.9mL of sodium ethoxide and ethanol solution, and the mixture was heated to reflux and the reaction was performed for 6 hours. Cooling to room temperature, adding 60mL of 1mol/L hydrochloric acid and dichloromethane, stirring, and separating. The dichloromethane phase was concentrated to dryness. The concentrated residue was slurried with 20mL ethyl acetate at 5 ℃, filtered, and dried to give intermediate B1.73 g in 41.6% yield.
3.2 Synthesis of Compound 3
To a 100mL reaction flask was added 0.6g of intermediate A2, 0.48g,DMF 15mL,HATU 0.91g of intermediate B2, 0.40g of triethylamine, and the mixture was stirred overnight for reaction. 30mL of water was added dropwise, the mixture was filtered, and the cake was dried to give 0.50g of crude compound 3 in a yield of 48.2%. 360mg of sample were purified by TLC to give 168mg of product with a purity of 98.95%.
MS:m/z＝528.50[M+H] +
1 H NMR(400MHz,Chloroform-d)δ12.05(s,1H),8.64(d,J＝7.5Hz,1H),8.18(d,J＝5.5Hz,2H),8.04(s,1H),7.96(dd,J＝12.5,2.4Hz,1H),7.44(d,J＝8.0Hz,2H),7.35(d,J＝8.9Hz,1H),7.18–7.10(m,3H),6.56–6.49(m,2H),4.01(s,3H),2.49(s,3H),2.15(s,3H).
Example 4 Synthesis of Compound 4
To a 100mL reaction flask was added 11 g of intermediate A, 0.76g,DMF 25mL,HATU 1.43g g of intermediate B, and 0.63g of triethylamine, and the mixture was stirred overnight for reaction. 50mL of water was added dropwise, the mixture was filtered, and the cake was dried to give 0.98g of crude compound 4 in a yield of 57.1%. 360mg of sample were purified by TLC to give 214mg of product with a purity of 97.86%.
MS:m/z＝544.47[M+H] +
1 H NMR(400MHz,Chloroform-d)δ12.06(s,1H),8.64(d,J＝7.5Hz,1H),8.28(d,J＝5.5Hz,2H),8.21(s,1H),7.97(dd,J＝12.5,2.4Hz,1H),7.44(d,J＝8.0Hz,2H),7.35(d,J＝9.4Hz,1H),7.17–7.11(m,3H),6.49(dd,J＝19.6,6.2Hz,2H),4.01(s,3H),2.49(s,3H),2.15(s,3H).
Example 5 Synthesis of Compound 5
5.1 Synthesis of intermediate B3
To a 100mL reaction flask was added 3g of aniline, 30mL of methylene chloride, 4.56g of triethylamine, and the mixture was cooled to 0℃with stirring. 6.30g of chloroformylacetic acid ethyl ester is dissolved in 15mL of methylene dichloride, and the temperature is controlled between 0 and 5 ℃ and added into a reaction bottle in a dropwise manner. After the completion of the dropping, the temperature was raised to 20℃for 2 hours, 30mL of water was added, and the mixture was stirred and separated. The dichloromethane phase was washed with 30mL of saturated brine and concentrated to dryness to give intermediate B3A.
To a 100mL reaction flask, 30mL of the intermediate B3A obtained in the previous step, 4.84g of 4-methoxybut-3-en-2-one and 24.1mL of sodium ethoxide ethanol solution were added, and the mixture was heated to reflux and the reaction was performed for 7 hours. Cooling to room temperature, adding 60mL of 1mol/L hydrochloric acid and dichloromethane, stirring, and separating. The dichloromethane phase was concentrated to dryness. The concentrated residue was slurried with 20mL ethyl acetate at 5 ℃, filtered, and dried to give intermediate B3.76 g in 50.9% yield.
5.2 Synthesis of Compound 5
To a 100mL reaction flask was added 0.6g of intermediate A2, 0.46g,DMF 15mL,HATU 0.91g of intermediate B3, 0.40g of triethylamine, and the mixture was stirred overnight for reaction. 30mL of water was added dropwise, the mixture was filtered, and the cake was dried to give 0.52g of crude compound 5 in a yield of 51.1%. 360mg of sample were purified by TLC to give 210mg of product with a purity of 99.01%.
MS:m/z＝514.47[M+H] +
1 H NMR(400MHz,Chloroform-d)δ12.00(s,1H),8.66(d,J＝7.5Hz,1H),8.18(d,J＝5.5Hz,2H),8.04(d,J＝1.6Hz,1H),7.96(dd,J＝12.5,2.4Hz,1H),7.69–7.53(m,3H),7.35(dd,J＝8.8,1.4Hz,1H),7.27(s,1H),7.14(t,J＝8.7Hz,1H),6.58–6.49(m,2H),4.01(s,3H),2.15(s,3H).
EXAMPLE 6 Synthesis of Compound 6
Into a 100mL reaction flask were charged 11 g of intermediate A, 0.72g,DMF 25mL,HATU 1.43g g of intermediate B, and 0.63g of triethylamine, and the mixture was stirred overnight for reaction. 50mL of water was added dropwise, the mixture was filtered, and the cake was dried to give 0.95g of crude compound 6 in a yield of 56.9%. 360mg of sample were purified by TLC to give 169mg of product with 99.01% purity.
MS:m/z＝530.45[M+H] +
1 H NMR(400MHz,Chloroform-d)δ12.02(s,1H),8.66(d,J＝7.5Hz,1H),8.28(d,J＝5.4Hz,2H),8.21(s,1H),7.97(dd,J＝12.5,2.3Hz,1H),7.69–7.55(m,3H),7.36(d,J＝8.3Hz,1H),7.27(s,2H),7.14(t,J＝8.7Hz,1H),6.50(dd,J＝25.7,6.5Hz,2H),4.01(s,3H),2.14(s,3H).
EXAMPLE 7 Synthesis of Compound 7
7.1 Synthesis of intermediate B4
To a 100mL reaction flask was added 3g of 4-chloroaniline, 30mL of dichloromethane, 3.33g of triethylamine, and the mixture was cooled to 0℃with stirring. 4.6g of chloroformylacetic acid ethyl ester is dissolved in 15mL of methylene dichloride, and the temperature is controlled between 0 and 5 ℃ and added into a reaction bottle in a dropwise manner. After the completion of the dropping, the temperature was raised to 20℃for 2 hours, 30mL of water was added, and the mixture was stirred and separated. The dichloromethane phase was washed with 30mL of saturated brine, concentrated to dryness, and the concentrated residue was slurried with 13.5mL of petroleum ether and 4.5mL of ethyl acetate, and filtered to give intermediate B4A4.52g in 79.5% yield.
To a 100mL reaction flask was added 4g of intermediate B4A, 40mL of ethanol, 2.48g of 4-methoxybut-3-en-2-one, 12.5mL of sodium ethoxide ethanol solution, and the mixture was heated to reflux and reacted at a constant temperature for 7 hours. Cooling to room temperature, adding 60mL of 1mol/L hydrochloric acid and dichloromethane, stirring, and separating. The dichloromethane phase was concentrated to dryness. The concentrated residue was slurried with 20mL ethyl acetate at 5 ℃, filtered, and dried to give intermediate B4.49 g in 57.1% yield.
7.2 Synthesis of Compound 7
To a 100mL reaction flask was added 0.6g of intermediate A2, 0.52g,DMF 15mL,HATU 0.91g of intermediate B4, 0.40g of triethylamine, and the mixture was stirred overnight for reaction. 30mL of water was added dropwise, the mixture was filtered, and the cake was dried to give 0.60g of crude compound 7 in 55.3% yield. 360mg of sample were purified by TLC to give 144mg of product with a purity of 98.59%.
MS:m/z＝548.46[M+H] +
1 H NMR(400MHz,Chloroform-d)δ11.91(s,1H),8.66(d,J＝7.5Hz,1H),8.18(d,J＝5.6Hz,2H),8.04(s,1H),7.96(dd,J＝12.5,2.4Hz,1H),7.63(d,J＝8.6Hz,2H),7.34(d,J＝8.8Hz,1H),7.23(d,J＝8.6Hz,2H),7.15(t,J＝8.7Hz,1H),6.56–6.51(m,2H),4.01(s,3H),2.16(s,3H).
Example 8 Synthesis of Compound 8
To a 100mL reaction flask was added 11 g of intermediate A, 0.83g,DMF 25mL,HATU 1.43g g of intermediate B, and 0.63g of triethylamine, and the mixture was stirred overnight for reaction. 50mL of water was added dropwise, the mixture was filtered, and the cake was dried to give 1.18g of crude compound 8 in 66.7% yield. 360mg of sample were purified by TLC to give 160mg of product with a purity of 97.92%.
MS:m/z＝564.39[M+H] +
1 H NMR(400MHz,Chloroform-d)δ11.92(s,1H),8.66(d,J＝7.6Hz,1H),8.28(d,J＝5.4Hz,2H),8.21(s,1H),7.97(dd,J＝12.5,2.4Hz,1H),7.63(d,J＝8.8Hz,2H),7.35(ddd,J＝8.7,2.4,1.3Hz,1H),7.25–7.20(m,2H),7.15(t,J＝8.7Hz,1H),6.57–6.43(m,2H),4.01(s,3H),2.16(d,J＝0.7Hz,3H).
Example 9 Synthesis of Compound 9
9.1 Synthesis of intermediate A3
To a 50mL reaction flask was added 0.84g of 4-amino-3-fluorophenol, 9mL of DMAc, 0.74g of potassium t-butoxide, and the mixture was stirred under nitrogen for 0.5 hours. 1.5g of 2, 3-dichloro-4-iodopyridine was added thereto, and the temperature was raised to 85℃for reaction at 9. Cooling to room temperature, and concentrating the reaction solution under reduced pressure. To the concentrated residue was added 60mL of ethyl acetate, stirred, and filtered. The ethyl acetate phase was concentrated to dryness under reduced pressure to give intermediate A3B.
Into a 100mL reaction flask was charged 30mL of intermediate A3B, 30mL of dioxane, 1.43g of 1-methylpyrazole-4-boronic acid pinacol ester, 2.27g of potassium carbonate, 6mL of water, nitrogen substitution, and Pd (PPh) was added 3 ) 4 0.5g, nitrogen replacement, heating to 90-95 ℃ and reacting for 30 hours with heat preservation. Cooling to room temperature, adding 20mL of water and ethyl acetate, and stirring to separate the liquid. The aqueous phase was extracted twice with ethyl acetate 20 mL. The ethyl acetate phases were combined, concentrated to dryness under reduced pressure and separated by column chromatography on silica gel (dichloromethane: ethanol=100:1, v/v) to give intermediate a 3.03 g in 59.2% yield.
9.1 Synthesis of Compound 9
To a 100mL reaction flask was added 1.03g of intermediate A3, 0.80g,DMF 15mL,HATU 1.47g of intermediate B1, 0.65g of triethylamine, and the mixture was stirred overnight for reaction. 30mL of water was added dropwise, the mixture was filtered, and the cake was dried to give 1.05g of crude compound 9 in a yield of 59.3%. 360mg of sample were purified by TLC to give 125mg of product with a purity of 98.14%.
MS:m/z＝548.43[M+H] +
1 H NMR(400MHz,Chloroform-d)δ11.98(s,1H),8.64(d,J＝7.5Hz,1H),8.59(t,J＝9.0Hz,1H),8.31(d,J＝5.4Hz,1H),8.29(s,1H),8.21(s,1H),7.31(dd,J＝9.8,7.2Hz,2H),7.28–7.23(m,2H),6.97–6.90(m,2H),6.58(d,J＝5.4Hz,1H),6.51(d,J＝7.9Hz,1H),4.01(s,3H),2.13(s,3H).
Example 10 Synthesis of Compound 10
10.1 Synthesis of intermediate A4
A50 mL reaction flask was charged with 0.64g of 4-amino-2, 3-difluorophenol and DMAc6mL, 0.50g of potassium tert-butoxide, and stirred under nitrogen for 0.5 hours. 1.0g of 2, 3-dichloro-4-iodopyridine was added thereto, and the temperature was raised to 85℃for reaction at 4 hours. Cooled to room temperature, added with 30mL of ethyl acetate and water, stirred and separated. The ethyl acetate phase was concentrated to dryness under reduced pressure to give intermediate A4B. Into a 100mL reaction flask, 30mL of intermediate A4B obtained in the previous step, 1.15g of 1-methylpyrazole-4-boronic acid pinacol ester, 1.83g of potassium carbonate, 6mL of water, and nitrogen substitution were added, and Pd (PPh 3 ) 4 0.5g, nitrogen replacement, heating to 90-95 ℃ and reacting for 20 hours with heat preservation. Cooling to room temperature, adding 20mL of water and ethyl acetate, and stirring to separate the liquid. The aqueous phase was extracted twice with ethyl acetate 20 mL. The ethyl acetate phases were combined, concentrated to dryness under reduced pressure and separated by column chromatography on silica gel (dichloromethane: ethanol=100:1, v/v) to give intermediate a 4.30 g in 87.5% yield.
10.2 Synthesis of Compound 10
To a 100mL reaction flask was added 1.30g of intermediate A4, 0.95g,DMF 15mL,HATU 1.76g of intermediate B1, 0.78g of triethylamine, and the mixture was stirred overnight for reaction. 30mL of water was added dropwise, the mixture was filtered, and the cake was dried to give 1.82g of crude compound 10 in 83.3% yield. 400mg of sample was purified by TLC to give 160mg of product with 96.17% purity.
MS:m/z＝566.46[M+H] +
1 H NMR(400MHz,Chloroform-d)δ12.10(s,1H),8.64(d,J＝7.5Hz,1H),8.40–8.33(m,1H),8.31(d,J＝5.5Hz,1H),8.30(d,J＝0.7Hz,1H),8.22(s,1H),7.35–7.30(m,2H),7.28–7.24(m,2H),7.03–6.97(m,1H),6.55–6.48(m,2H),4.01(s,3H),2.15(s,3H).
EXAMPLE 11 Synthesis of Compound 11
11.1 Synthesis of intermediate A5
To a 50mL reaction flask, 0.93g of 4-amino-2, 5-difluorophenol, 9mL of DMAc, 0.72g of potassium t-butoxide and stirring under nitrogen for 0.5 hours were added. 1.46g of 2, 3-dichloro-4-iodopyridine was added thereto, and the temperature was raised to 85℃for reaction at 4 hours. Cooled to room temperature, added with 30mL of ethyl acetate and water, stirred and separated. The ethyl acetate phase was concentrated to dryness under reduced pressure to give intermediate A5B.
Into a 100mL reaction flask was charged 30mL of intermediate A5B, 30mL of dioxane, 1.67g of 1-methylpyrazole-4-boronic acid pinacol ester, 2.66g of potassium carbonate, 6mL of water, nitrogen substitution, and Pd (PPh) was added 3 ) 4 0.5g, nitrogen replacement, heating to 90-95 ℃ and reacting for 20 hours with heat preservation. Cooling to room temperature, adding 20mL of water and ethyl acetate, and stirring to separate the liquid. The aqueous phase was extracted twice with ethyl acetate 20 mL. The ethyl acetate phases were combined, concentrated to dryness under reduced pressure and separated by column chromatography on silica gel (dichloromethane: ethanol=100:1, v/v) to give intermediate a 5.97 g in 44.9% yield.
11.2 Synthesis of Compound 11
To a 100mL reaction flask was added 0.97g of intermediate A, 0.71g,DMF 15mL,HATU 1.31g g of intermediate B1, and 0.58g of triethylamine, and the mixture was stirred overnight for reaction. 30mL of water was added dropwise, the mixture was filtered, and the cake was dried to give 1.13g of crude compound 11 in 69.6% yield. 400mg of sample was purified by TLC to give 143mg of product with 99.00% purity.
MS:m/z＝566.46[M+H] +
1 H NMR(400MHz,Chloroform-d)δ12.13(s,1H),8.67–8.62(m,2H),8.32(d,J＝5.4Hz,1H),8.29(s,1H),8.21(s,1H),7.36–7.32(m,2H),7.28–7.22(m,2H),7.01(dd,J＝10.3,7.0Hz,1H),6.52(t,J＝6.9Hz,2H),4.01(s,3H),2.14(s,3H).
EXAMPLE 12 Synthesis of Compound 12
12.1 Synthesis of intermediate A6
To a 50mL reaction flask, 1.25g of 4-amino-2, 6-difluorophenol, 12mL of DMAc, 0.97g of potassium t-butoxide and stirring under nitrogen for 0.5 hour were added. 1.96g of 2, 3-dichloro-4-iodopyridine was added thereto, and the temperature was raised to 85℃for reaction at 5 hours. Cooled to room temperature, 50mL of ethyl acetate and water were added, and the mixture was stirred and separated. The ethyl acetate phase was concentrated to dryness under reduced pressure to give intermediate A6B.
Into a 100mL reaction flask was charged 30mL of intermediate A6B, 30mL of dioxane, 2.24g of 1-methylpyrazole-4-boronic acid pinacol ester, 3.57g of potassium carbonate, 6mL of water, nitrogen substitution, and Pd (PPh) was added 3 ) 4 0.5g, nitrogen replacement, heating to 90-95 ℃ and reacting for 20 hours with heat preservation. Cooling to room temperature, adding 20mL of water and ethyl acetate, and stirring to separate the liquid. The aqueous phase was extracted twice with ethyl acetate 20 mL. The ethyl acetate phases were combined, concentrated to dryness under reduced pressure and separated by column chromatography on silica gel (dichloromethane: ethanol=100:1, v/v) to give intermediate a 6.05 g in 70.7% yield.
12.2 Synthesis of Compound 12
To a 100mL reaction flask was added 2.05g of intermediate A6, 1.51g,DMF 15mL,HATU 2.78g g of intermediate B1, 1.23g of triethylamine, and the mixture was stirred overnight for reaction. 30mL of water was added dropwise, the mixture was filtered, and the cake was dried to give 2.40g of crude compound 12 in 69.6% yield. 450mg of sample was purified by TLC to give 184mg of product with 99.52% purity.
MS:m/z＝566.43[M+H] +
1 H NMR(400MHz,Chloroform-d)δ12.04(s,1H),8.65(d,J＝7.5Hz,1H),8.33–8.28(m,2H),8.22(s,1H),7.57–7.50(m,2H),7.39–7.31(m,2H),7.28–7.23(m,2H),6.55(d,J＝7.9Hz,1H),6.48(d,J＝5.4Hz,1H),4.01(s,3H),2.16(s,3H).
EXAMPLE 13 Synthesis of Compound 13
13.1 Synthesis of intermediate A7
To a 50mL reaction flask, 0.50g of 4-amino-3, 5-difluorophenol, 5mL of DMAc, 0.39g of potassium t-butoxide and stirring under nitrogen for 0.5 hour were charged. 0.79g of 2, 3-dichloro-4-iodopyridine was added thereto, and the temperature was raised to 85℃for reaction at 5 hours. Cooled to room temperature, 50mL of ethyl acetate and water were added, and the mixture was stirred and separated. The ethyl acetate phase was concentrated to dryness under reduced pressure to give intermediate A7B.
Into a 100mL reaction flask, intermediate A7B obtained in the previous step, 30mL of dioxane, 0.90g of 1-methylpyrazole-4-boronic acid pinacol ester, 1.43g of potassium carbonate, 6mL of water, nitrogen substitution and Pd (PPh) were added 3 ) 4 0.5g, nitrogen replacement, heating to 90-95 ℃ and reacting for 20 hours with heat preservation. Cooling to room temperature, adding 20mL of water and ethyl acetate, and stirring to separate the liquid. The aqueous phase was extracted twice with ethyl acetate 20 mL. The ethyl acetate phases were combined, concentrated to dryness under reduced pressure and separated by column chromatography on silica gel (dichloromethane: ethanol=100:1, v/v) to give intermediate a 7.05 g in 90.2% yield.
13.2 Synthesis of Compound 13
To a 100mL reaction flask was added 1.05g of intermediate A7, 0.77g,DMF 15mL,HATU 1.42g of intermediate B1, 0.63g of triethylamine, and the mixture was stirred overnight for reaction. 30mL of water was added dropwise, the mixture was filtered, and the cake was dried to give 1.06g of crude compound 13 in a yield of 60.2%. 500mg of sample was purified by TLC to give 151mg of product with 96.61% purity.
MS:m/z＝566.45[M+H] +
1 H NMR(400MHz,Chloroform-d)δ11.17(s,1H),8.65(d,J＝7.5Hz,1H),8.39(d,J＝5.4Hz,1H),8.29(d,J＝0.7Hz,1H),8.22(s,1H),7.35–7.30(m,3H),7.25(t,J＝5.0Hz,1H),6.77–6.71(m,3H),6.51(d,J＝8.3Hz,1H),4.01(s,3H),2.15(s,3H).
EXAMPLE 14 Synthesis of Compound 15
14.1 Synthesis of intermediate A9
To a 50mL reaction flask was added 0.90g of 4-amino-2-fluorophenol, 9mL of DMAc, 0.80g of potassium t-butoxide, and the mixture was stirred under nitrogen for 0.5 hours. 1.5g of 2-chloro-4-iodo-3-methylpyridine was added thereto, and the temperature was raised to 85℃to react 3 hours. Cooled to room temperature, added with 30mL of ethyl acetate and water, stirred and separated. The ethyl acetate phase was concentrated to dryness under reduced pressure to give intermediate A9B. Into a 100mL reaction flask was charged 30mL of intermediate A9B, 30mL of dioxane, 1.54g of 1-methylpyrazole-4-boronic acid pinacol ester, 2.45g of potassium carbonate, 6mL of water, nitrogen substitution, and Pd (PPh) was added 3 ) 4 0.5g, nitrogen replacement, heating to 90-95 ℃ and reacting for 20 hours with heat preservation. Cooling to room temperature, adding 20mL of water and ethyl acetate, and stirring to separate the liquid. The aqueous phase was extracted twice with ethyl acetate 20 mL. The ethyl acetate phases were combined, concentrated to dryness under reduced pressure and separated by column chromatography on silica gel (dichloromethane: ethanol=100:1, v/v) to give intermediate a 9.96 g in 54.4% yield.
14.2 Synthesis of Compound 15
To a 100mL reaction flask was added 0.96g of intermediate A9, 0.79g,DMF 15mL,HATU 1.46g g of intermediate B1, and 0.65g of triethylamine, and the mixture was stirred overnight for reaction. 30mL of water was added dropwise, the mixture was filtered, and the cake was dried to give 1.25g of crude compound 15 in 73.9% yield. 360mg of sample were purified by TLC to give 191mg of product with a purity of 99.16%.
MS:m/z＝528.50[M+H] +
1 H NMR(400MHz,Chloroform-d)δ11.91(s,1H),8.66(d,J＝7.5Hz,1H),8.27(d,J＝5.7Hz,1H),7.97–7.90(m,2H),7.86(s,1H),7.37–7.31(m,3H),7.26(dt,J＝6.8,2.3Hz,2H),7.09(t,J＝8.7Hz,1H),6.54(dd,J＝7.5,0.9Hz,1H),6.43(d,J＝5.5Hz,1H),4.00(s,3H),2.51(s,3H).
EXAMPLE 15 kinase Activity assay
This experiment detects the inhibition of MET and AXL kinase by the compounds of the present invention by using fluorescence microfluidic Mobility detection technology (Mobility-Shift Assay). Kinase catalyzes ATP to remove a phosphate group to generate ADP, and transfers the phosphate group to a substrate peptide, wherein the substrate peptide is provided with a fluorescent label, the product is added with a phosphate group, the charge is changed, and during electrophoresis, the substrate and the phosphorylated product are separated due to different mobilities and are respectively detected, and the quantity of the substrate and the phosphorylated product is proportional to a fluorescent signal. And measuring the amount of the substrate and the product by using a Caliper instrument, and calculating the conversion rate of the product, thereby calculating the inhibition rate.
The MET kinase reaction system was 25uL, which included 5nM MET, a concentration gradient of small molecule inhibitor, 10mM MgCl2, 1M DTT, 26uM ATP (measured Km value), 3uM Peptide2 (5-FAM-EAIYAAPFAKKK-CONH 2), 0.0015% Brij-35 and 50mM HEPES,2mM DTT,10mM MgCl2 at pH 7.5; the AXL kinase reaction system was 25uL and included 6nM AXL, a concentration gradient of small molecule inhibitor, 10mM MgCl2, 1M DTT, 81uM ATP (measured Km value), 3uM Peptide22 (5-FAM-EEPLYWSFPAKKK-CONH 2), 0.0015% Brij-35 and 50mM HEPES,2mM DTT,10mM MgCl2 at pH 7.5.
The enzyme and inhibitor were added to 384 well plates for 10 minutes at room temperature, then substrate and ATP were added, the reaction was started, 25uLStop Buffer was added after 30 minutes to terminate the reaction, and the data were plotted on a Caliper instrument with the Log concentration of the inhibitor as the X axis and the inhibition rate as the Y axis, and IC50 was obtained according to the formula Y=bottom+ (Top-Bottom)/(1+ (IC 50/X)/(HillSlope).
The data are measured as follows in table 1:
TABLE 1
| Compounds of formula (I) | c-MET IC 50 (nM) | AXL IC 50 (nM) |
| Compound 1 | 2.99 | 3.01 |
| Compound 2 | 4.20 | 2.58 |
| Compound 3 | 98 | 95 |
| Compound 4 | 179 | 235 |
| Compound 5 | 5.07 | 2.74 |
| Compound 6 | 5.19 | 5.39 |
| Compound 7 | 52 | 53 |
| Compound 8 | 85 | 121 |
| Compound 9 | 8.53 | 11.91 |
| Compound 10 | 47 | 50 |
| Compound 11 | 5.0 | 6.89 |
| Compound 12 | 10 | 17 |
| Compound 13 | 119 | 187 |
| Compound 15 | 2.86 | 3.88 |
| BMS777607 | 4.94 | 6.73 |
| Staurosporine | 148 | 5.66 |
Example 16 in vitro tumor inhibiting Activity assay
The inhibition of proliferation of the compounds of the present invention in vitro on human tumor cells of different tissue origin was examined.
Experimental method
1) Cell culture and seeding
The experimental tumor cell line was cultured in RPMI-1640 and DMEM containing 10-20% Gibco serum, and cultured in a 5% CO2 incubator at 37 ℃. According to laboratory background data, 4000 tumor cells per well were seeded in 96-well plates and the cells were in log phase throughout the experiment.
2) Administration of drugs
After cells were seeded in 96-well plates, attached overnight, and then 5 concentration gradients (0.625-10. Mu.M/6.25-100. Mu.M) were set for each compound, two duplicate wells per concentration.
3) Test sample preparation
The test substances were taken out separately, dissolved in DMSO was added to each tube, and stored in sub-packages at-20 ℃. The fresh culture solution is diluted to the working concentration before use. Specific concentration settings are found in the experimental results section. Cell proliferation inhibition was measured 72 hours after administration.
4) SRB method
After the test object acts on the cells for 72 hours, removing the culture solution, adding pre-cooled 10% trichloroacetic acid (TCA) solution into each hole to fix the cells, placing the cells in a refrigerator at 4 ℃ for fixing for 2 hours, washing each hole of a culture plate with deionized water for 5 times to remove the trichloroacetic acid solution, adding SRB solution (4 mg/ml) prepared by 1% acetic acid into each hole after drying, placing the cells at room temperature for 20 minutes, washing the cells with 1% acetic acid for 5 times after removing the liquid in each hole, washing unbound SRB dye, adding 10mM Tris-base (Tris-hydroxymethyl aminomethane) solution with proper volume into each hole for dissolving after drying, and measuring the absorbance OD value at 515nm wavelength of an enzyme-labeled instrument after complete dissolving.
5) Result processing
According to the OD value measured by the enzyme label instrument, the inhibition rate is calculated according to the following formula:
inhibition (%) = 1-OD dosing/OD control x 100%, if inhibition was 0 or less, it was noted as 0.
The IC50 is calculated.
6) Experimental results
The tested compounds had different degrees of inhibition on 2 different tissue-derived human tumor cells U87-MG and MKN45, with compound 1, compound 2, compound 5, compound 6, compound 9, compound 11 and compound 12 and compound 15 each having a significant inhibition on U87-MG cells, especially compound 11 being more sensitive to U87-MG cells and having an IC50 value of 2.71. Mu.M (see Table 2 for details). Compound 11 had significant inhibitory effect on MKN45 cells with IC50 values up to 8.71 μm, significantly better than 19.37 μm of control BMS777607.
Proliferation inhibition of tumor cells by the compounds of Table 2
EXAMPLE 17 evaluation of the ability to penetrate the blood brain Barrier
Compound 1 was dissolved in DMSO: PEG400: water=1:6:3 (V/V/V) to prepare a 1mg/mL formulation solution, which was administered to CD1 mice by intragastric administration at a dose of 10 mg/kg. Samples were taken in sequence in the plasma and brain at 0.25h,0.5h,1h,2h,4h,8h,24h, respectively, and the amounts of chemical components of plasma and brain tissue were then detected by LC-MS/MS to obtain a series of pharmacokinetic parameters, the results of which are shown in table 3 and figures 1 and 2 below.
TABLE 3 Table 3
| PK parameters | Unit (B) | In blood plasma | In brain tissue |
| T 1/2 | h | 8.91 | 10.1 |
| T max | h | 4.00 | 4.00 |
| C max | ng/mL | 6597 | 1434.67 |
| AUC last | h*ng/mL | 96413 | 22146 |
| AUC Inf | h*ng/mL | 114972 | 27618 |
| AUC inf /D | h*mg/mL | 11497 | 2762 |
The results show that the compound 1 has excellent oral pharmacokinetic property, can pass through the blood brain barrier, has the transmittance of 0.24 and high exposure of the brain tissue, and can be developed into the medicine for treating brain tumors such as brain glioma, meningioma, brain metastasis and the like.
EXAMPLE 18 Experimental therapeutic Effect of Compound 1 on human gastric cancer cell MKN45 nude mice subcutaneously transplanted tumor
The method comprises the following steps: 5X 106 human gastric cancer cells MKN45 were injected into the left underarm of nude mice. Cutting into round blocks of MKN45 mice, placing into a glass dish containing normal saline, removing surface blood vessel, cutting to remove necrotic region, cutting into 1-2mm pieces 3 The left armpit of the nude mouse is accessed by a trocar until the tumor grows to an average volume of 100mm 3 After left and right animals were randomly grouped according to tumor volume and dosed. The 32 mice were divided into 4 groups: g1 blank vehicle group (Control), G2BMS77760730mg/kg group, G3 compound 115mg/kg group and G4 compound 1 30mg/kg group. Each group was given 8 subjects each at a dose capacity of 10mL/kg by gavage, 1 time a day for 21 days.
Tumor volumes were weighed and measured 2 times per week, body weights were measured on day 21, tumor mass weights were sacrificed after tumor size measurement, relative Tumor Volumes (RTV), relative tumor proliferation rate (T/C), tumor growth inhibition rate (TGI) and percent tumor Inhibition (IR) were calculated, and statistical analysis was performed using SPSS.
Results:
at the end of the experiment, no significant change in body weight was seen in the mice in each dosing group compared to the G1 blank vehicle group. See table 4 and fig. 3 for details.
TABLE 4 influence of Compound 1 on nude mouse body weight
There was no significant difference between the groups compared to the G1 blank vehicle group.
Tumor volume 2220+ -248 mm with G1 blank vehicle 3 In contrast, the tumor volumes of the G2BMS777607 30mg/kg group, the G3 compound 115mg/kg group and the G4 compound 1 30mg/kg group were 1600.+ -.135, 900.+ -.112 (P)<0.01 859+ -96 mm3 (P)<0.01). Compared with the RTV value of 24.25+/-3.24 of the G1 blank vehicle group, the RTV values of the G2BMS777607 30mg/kg group, the G3 compound 115mg/kg group and the G4 compound 1 30mg/kg group are 16.92+/-1.17, 9.72+/-1.28 (P)<0.05 8.94+ -0.72 (P)<0.05 A) is provided; T/C values were 69.78%, 40.07% and 36.87%, respectively, and TGI values were 30.22%, 59.93% and 63.13%, respectively. (see FIGS. 4 and 5 for details).
Compared with the tumor mass weight of the G1 blank vehicle group of 1.5907 +/-0.2323G, the tumor mass weights of the G2BMS777607 30mg/kg group, the G3 compound 115mg/kg group and the G4 compound 1 30mg/kg group are 1.1525 +/-0.1271, 0.6556 +/-0.0907 (P < 0.05) and 0.5886 +/-0.0840G (P < 0.05), respectively, and the IR is 27.55%, 58.79% and 63.00% respectively. Effect of compound 1 on human gastric cancer cell MKN45 subcutaneous transplantation tumor (see fig. 6 for details).
Conclusion: under the experimental condition, the compound 1-30 mg/kg (q.d. for 21 days) can be administrated to the naked mouse by lavage, the growth of subcutaneous transplantation tumor of the human gastric cancer cell MKN45 naked mouse can be obviously inhibited in a dose-dependent manner, and the effect is better than that of a positive control medicine BMS777607.
Example 19 inhibition of 7 CYP450 subtypes (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3 A4) by compound 1 of the present invention was evaluated using human liver microsomes.
The inhibitor is CYP1A2 a-Naphthofenone; CYP2C9, sulfaphenazole; CYP2C19:Omeprazole; CYP3A4 Ketoconazole; CYP2D6 quinidine; CYP2C8, nicardipine; CYP2B6, clopidogrel;
the matrix is CYP1A2, phenacetin at 30 mu M; CYP2C9, diclofenac at 10. Mu.M; CYP2C 19S-Mephenytoin at 35. Mu.M; CYP3A4 Midazolam at 5. Mu.M; CYP2D6, bufuralol at 10 mu M; CYP2C8: paclitaxel at 10. Mu.M; CYP2B6 Bupropion at 70. Mu.M.
A detection system Human liver microsomes from Corning, incubation conditions CYP1A2,2C9,2D6,2C8,2B6 for 10 minutes at 37 ℃; CYP2C19 for 45 minutes at 37 ℃; CYP3A4 for 5 min, 37 ℃ sample size 2 (n=2), biological analysis method is LC-MS/MS.
The calculation mode is as follows: based on the data calculation using the following formula, curve fitting was performed using Sigmoidal (nonlinear) dose response model (GraphPad Prism 5.0 or Xlfit model 205) to calculate IC50: y=bottom+ (Top-Bottom)/(1+10 ((log ic 50-X) ×hillslope)). Where X is the logarithm of the concentration. Y is the response from bottom to top of the sigmoid from high to low concentration of response inhibitor. The results are shown in Table 5.
TABLE 5 inhibition of 7 CYP450 subtypes by Compound 1 of the invention
The foregoing describes specific embodiments of the present invention. It is to be understood that the invention is not limited to the particular embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the claims without affecting the spirit of the invention.
Claims (10)
1. A compound of formula (I) or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof:
wherein R is 1 Hydrogen, halogen, substituted or unsubstituted alkyl, alkoxy or haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl;
R 2 halogen, substituted or unsubstituted alkyl;
n has a value of 1 or 2.
2. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, wherein the alkyl is a C1-C6 alkyl, and the cycloalkyl is C 3 -C 4 Cycloalkyl of (C), said alkoxy being C 1 -C 6 Alkoxy of (2), said hydroxyalkyl being C 1 -C 6 Is fluorine or chlorine.
3. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, wherein R 1 Selected from hydrogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy, fluorine or chlorine; r is R 2 Selected from fluorine, chlorine, methyl.
4. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, wherein the compound is any one of the following compounds:
5. a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more therapeutically effective amounts of a compound of claim 1, or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.
6. A process for the preparation of a compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, comprising the steps of:
compounds of formula (I)And the compound->The reaction is carried out to produce the compound shown in the formula (I).
7. Use of a compound according to claim 1 or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof in the preparation of an antitumor drug.
8. Use of a compound according to claim 1 or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof in the manufacture of a medicament for the treatment of a disease associated with Axl kinase and/or c-Met kinase.
9. Use according to claim 8 wherein the Axl kinase and/or c-Met kinase associated diseases include brain tumours, stomach cancer, cancer of the shoulders, breast cancer, colorectal cancer, head and neck cancer, renal cancer, liver cancer, lung cancer, ovarian cancer, membranous/gall bladder cancer, prostate cancer, thyroid cancer, osteosarcoma, rhabdomyosarcoma, MFH/fibrosarcoma, glioblastoma/astrocytoma, melanoma or mesothelioma, psoriasis, cirrhosis, diabetes, angiogenesis, restenosis, ophthalmic diseases, rheumatoid arthritis and other inflammatory diseases, immune diseases, cardiovascular diseases such as arteriosclerosis and kidney disease.
10. The use of claim 9, wherein the brain tumor comprises a brain glioma, a meningioma, a brain metastasis.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210879471.9A CN117486860A (en) | 2022-07-25 | 2022-07-25 | Axl & c-Met dual inhibitor, preparation method and application |
| PCT/CN2023/106523 WO2024022095A1 (en) | 2022-07-25 | 2023-07-10 | Axl＆c-met dual inhibitor, and preparation method and use |
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| CN202210879471.9A CN117486860A (en) | 2022-07-25 | 2022-07-25 | Axl & c-Met dual inhibitor, preparation method and application |
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| UA85087C2 (en) * | 2004-04-23 | 2008-12-25 | Бристол-Майэрс Сквибб Компани | Monocyclic heterocycles as kinase inhibitors |
| AU2011248441A1 (en) * | 2010-04-29 | 2012-12-20 | Deciphera Pharmaceuticals, Llc | Pyridone amides and analogs exhibiting anti-cancer and anti-proliferative activites |
| WO2014145004A1 (en) * | 2013-03-15 | 2014-09-18 | Deciphera Pharmaceuticals, Llc | Pyridone amides and analogs exhibiting anti-cancer and anti-proliferative activities |
| US10208034B2 (en) * | 2014-12-25 | 2019-02-19 | Ono Pharmaceutical Co., Ltd. | Quinoline derivative |
| WO2020042618A1 (en) * | 2018-08-27 | 2020-03-05 | 北京越之康泰生物医药科技有限公司 | Multi-substituted pyridone derivatives and medical use thereof |
| CN110330479A (en) * | 2019-07-19 | 2019-10-15 | 南京华威医药科技集团有限公司 | A kind of antitumoral compounds and application thereof as AXL inhibitor |
| GB202004960D0 (en) * | 2020-04-03 | 2020-05-20 | Kinsenus Ltd | Inhibitor compounds |
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