CN108314676B - Amino pyridine derivative containing hydroxamic acid fragment and anti-tumor application thereof - Google Patents
Amino pyridine derivative containing hydroxamic acid fragment and anti-tumor application thereof Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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Abstract
The invention provides an aminopyridine derivative containing hydroxamic acid fragments and pharmaceutically acceptable salts thereof as shown in a formula V, and application thereof in the aspect of anti-tumor,
Description
Technical Field
The invention relates to the field of organic chemistry and pharmaceutical chemistry, in particular to aminopyridine derivatives containing hydroxamic acid fragments and anti-tumor application thereof.
Background
The tumor is the result of the interaction of multiple genes and multiple channels, and with the continuous and deep understanding of genetics, biochemistry, oncogene signal transduction and the like, the research and development of the multi-target and multi-channel anti-tumor inhibitor for treating the drug resistance and recurrence of the tumor is a development direction of the research of the anti-tumor drugs in future.
In recent years, with the continuous improvement of molecular biology technology and the further understanding of tumor pathogenesis from cell and molecular level, and the rapid development of technologies such as combinatorial chemistry, structure-based drug design and computer science, the tumor biotherapy has been greatly advanced and enters the era of molecular targeted therapy. Targeted anti-cancer drugs can target specific pathways, prevent tumor growth and reduce toxicity to normal cells. However, the single-target antitumor drug has the problems of poor curative effect, easy generation of drug resistance and the like, and is not enough to meet the requirement of preventing and treating malignant tumors.
At present, research and development of multi-target antitumor drugs are becoming a new focus, research and development of novel multi-target single-molecule antitumor drugs are superior to single-target inhibitors in treatment, drug resistance brought by single-target treatment is avoided, the defect of combined drug administration can be avoided, the novel development direction of tumor treatment and drug development is represented, and huge social and economic benefits are achieved.
c-Met is an important member of the receptor tyrosine kinase family. c-Met is used as a key node in a tumor signal network pathway, can interact with other tumor-related factors (such as integrin family, death-related receptor, other receptor tyrosine kinases and the like) to share and cross-link activation of downstream signal pathways, induce cell proliferation, resist apoptosis, promote cell migration, invasion, angiogenesis and the like.
The A L K kinase and the C-Met kinase inhibitor PF-2341066(Crizotinib) developed by Exelixis company are approved by the FDA to be on the market in 2011, are used for treating patients with advanced non-small cell lung cancer (NSC L C) expressing abnormal anaplastic lymphoma kinase (A L K) genes, are used for treating patients with advanced thyroid cancer (MTC) expressing abnormal anaplastic lymphoma kinase genes, C-Met kinase and VEGFR2 inhibitor Cabozantinib developed by Exelixis company are approved by the FDA to be on the market in 2012, and are used for treating patients with advanced thyroid medullary carcinoma (MTC) expressing the advanced and metastatic thyroid cancer as well as more than ten clinical C-Met inhibitors which are in the clinical research stage and provide strong anti-tumor reliability evidence.
Histone Deacetylase (HDAC) is an important target for tumor therapy that has been developed in recent years. It has been found that HDAC inhibitors may exhibit good anti-metabolic and anti-angiogenic activity in vitro and in vivo experiments. Since the 90's of the 20 th century, a variety of structurally different HDAC inhibitors have been available and are currently in clinical trials. Researches prove that the compounds can inhibit the proliferation of various tumor cells, induce the differentiation and/or apoptosis of the tumor cells and are antitumor drugs with wide application prospects.
SAHA (also called Vorinostat), which belongs to hydroxamic acid, is the first non-selective histone deacetylase inhibitor on the market, and is used for metastatic cutaneous T-cell lymphoma (CTC L) under the condition that the treatment by other drugs cannot be cured or worsened or the disease is repeated.
As is known, tumors are a complex disease with multi-gene and multi-channel interaction, drug resistance is easy to generate by single-target and single-channel inhibition, and the multi-target and multi-channel anti-tumor inhibitor can overcome the drug resistance problem possibly caused by single-target treatment, so that the defect of combined drug administration is avoided, and the development direction of tumor treatment and drug development is represented. The c-Met and the HDAC are hot targets of the current antitumor research, pure c-Met inhibitors and HDAC inhibitors are successfully applied to clinic, and through the analysis and computer-aided drug design of the marketed drug structure and target protein thereof, the invention combines the two targets of the c-Met and the HDAC, obtains a batch of compounds simultaneously having the dual inhibitory activities of the c-Met and the HDAC through a large number of experiments and activity screening, and finds that the compounds have better antitumor activity and lower toxicity, thereby having the value of deep research.
The invention aims to solve the technical problem of providing a pyridine derivative completely different from the prior art, in particular to an aminopyridine compound containing hydroxamic acid fragments, wherein the derivative has good protein kinase inhibition activity and histone deacetylase inhibition activity, namely c-Met/HDAC dual inhibition activity, and shows better anti-tumor effect.
Disclosure of Invention
One of the purposes of the invention is to provide an aminopyridine derivative containing hydroxamic acid fragments and having protein kinase c-Met and/or histone deacetylation kinase HDAC inhibitory activity and a preparation method thereof.
The invention also discloses the application of the aminopyridine derivatives containing hydroxamic acid fragments in the aspect of tumor resistance.
The hydroxamic acid compound is an aminopyridine derivative containing a hydroxamic acid fragment and a pharmaceutically acceptable salt thereof, and the derivative is shown as a formula V:
in the formula V, the reaction mixture is shown in the formula V,
R1、R2and R3Independently selected from hydrogen or halogen;
a is pyrazolyl
Or amino (-NH-);
x is piperidinyl
N in the piperidyl X is connected with a carbon chain; or X is methylene (-CH)2-)；
n represents 0 to 6.
The hydroxamic acid fragment-containing aminopyridine derivatives of the present invention represented by the formula V as described above preferably have a structure represented by the formula V,
R1、R2and R3Independently selected from hydrogen or halogen;
a is pyrazolyl
X is piperidinyl
N in the piperidyl X is connected with a carbon chain;
n represents 0 to 6.
The hydroxamic acid fragment-containing aminopyridine derivatives of the present invention represented by the formula V as described above preferably have a structure represented by the formula V,
R1、R2and R3Independently selected from hydrogen or halogen;
a is pyrazolyl
X is methylene (-CH)2-)；
n represents 0 to 6.
The hydroxamic acid fragment-containing aminopyridine derivatives of the present invention represented by the formula V as described above preferably have a structure represented by the formula V,
R1、R2and R3Independently selected from hydrogen or halogen;
a is amino (-NH-), X is methylene (-CH)2-)；
n represents 0 to 6.
More preferably, the hydroxamic acid fragment containing aminopyridine derivatives of formula V, as described above, preferably, in formula V,
R1、R2and R3Independently selected from hydrogen or halogen;
a is amino (-NH-), X is methylene (-CH)2-) according to the formula (I); n is 4 to 6.
For the convenience of understanding the present invention, the following specific compounds and salts thereof are preferred from among the compounds having the structure of formula V, but the present invention is not limited to the following compounds:
v-17- (4- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N-hydroxyheptanamide,
v-26- (4- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N-hydroxyhexanamide,
v-35- (4- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N-hydroxypentanamide,
v-43- (4- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N-hydroxypropanamide,
v-52- (4- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N-hydroxyacetamide,
v-64- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazol-1-yl) N-hydroxypiperidine-1-carboxamide,
v-77- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3 yl) -1H-pyrazol-1-yl) -N-hydroxyheptanoamide,
v-86- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3 yl) -1H-pyrazol-1-yl) -N-hydroxyhexanamide,
v-95- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3 yl) -1H-pyrazol-1-yl) -N-hydroxypentanamide,
v-104- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3 yl) -1H-pyrazol-1-yl) -N-hydroxybutyramide,
v-117- (4- (6-amino-5- (1-phenylethoxy) pyridin-3 yl) -1H-pyrazol-1-yl) -N-hydroxyheptanamide,
v-127- (4- (6-amino-5- (1- (2-chloro-3-fluorophenyl) ethoxy) pyridin-3 yl) -1H-pyrazol-1-yl) -N-hydroxyheptanamide,
v-137- (4- (6-amino-5- (1- (6-dichloro-3-fluorophenyl) ethoxy) pyridin-3 yl) -1H-pyrazol-1-yl) -N-hydroxyheptanoamide,
v-147- ((6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) amino) -N-hydroxyheptanamide,
v-156- ((6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) amino) -N-hydroxyhexanamide,
v-165- ((6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) amino) -N-hydroxypentanamide,
the structural formula is shown in table 1:
preferred compound numbers and corresponding structural formulas of Table 1
The compound with the structure shown in the formula V can be salified with inorganic acid and organic acid to obtain a substance in the form of a salt of the compound with the structure shown in the formula V, wherein the salt is hydrochloride, hydrobromide, sulfate, bisulfate, acetate, lactate, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulfonic acid or methanesulfonate.
Preferably, the compound of formula V is in the form of a salt selected from the group consisting of hydrochloride, hydrobromide, bisulfate, malate, maleate, succinate, p-toluene sulfonic acid or methanesulfonate.
More preferably, the compound of formula V is in the form of a salt selected from the hydrochloride, acetate, sulfate, tartrate or malate salts.
According to the salt form of the compound with the structure of the formula V, the compound with the structure of the formula V is salified with corresponding inorganic acid or organic acid, wherein the inorganic acid or the organic acid is selected from acid, hydrobromic acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, tannic acid, citric acid, trifluoroacetic acid, malic acid, maleic acid, succinic acid, p-toluenesulfonic acid or methanesulfonic acid.
The preparation method of the amino pyridine derivative containing the hydroxamic acid fragment comprises the following steps as shown in a scheme I:
in the first route, an aminopyridine compound 2 is taken as an initial raw material, is coupled with boron ester 3a through Suzuki to prepare a compound 4a, and then reacts with hydroxylamine under the alkaline condition to prepare a compound V;
in the general reaction scheme shown in the first scheme, A in the compound 3a is pyrazolyl
Wherein, N atom in pyrazolyl A is connected with X, X, N is consistent with the selection range of corresponding group in compound V structural formula; said R in Compound 21、R2、R3The selection range of the corresponding groups in the structural formula of the compound V is kept consistent.
In the preparation method shown in the first route, the related raw materials, compound 2, compound 3a, hydroxylamine hydrochloride and the like can be purchased from commercial sources or prepared according to the method reported in the document WO 2006021881.
In the general synthesis method (scheme one), experimental conditions for preferable implementation are provided below.
Dissolving aminopyridine compound 2(10mmol) and boron pyrazolate 3(12mmol) in 60ml ethylene glycol dimethyl ether, adding 20ml of 2M sodium carbonate aqueous solution, introducing inert gas, adding [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.5mmol), heating to 90 ℃ for reaction for 6h, filtering, concentrating the filtrate to obtain oily substance, directly feeding the oily substance without purification, adding 30M L methanol into the oily substance, stirring in an ice bath, sequentially adding KOH (80mmol), hydroxylamine hydrochloride (40mmol) and 3M L water, reacting in the ice bath for 3h, adjusting the pH of the reaction solution to 4-5 by hydrochloric acid, decompressing, distilling to remove the solvent, recrystallizing the solid by acetonitrile or carrying out ethyl acetate/methanol (2:1-5:1) column chromatography to obtain the V-class target compound.
The preparation method shown in the first scheme can further comprise the steps of reacting the compound with the structure shown in the formula V with an inorganic acid (or an inorganic base) and an organic acid (or an organic base), and cooling to separate out the salt of the compound with the structure shown in the formula V.
Another method for preparing an aminopyridine derivative containing a hydroxamic acid fragment includes the steps of scheme two:
in the second route, aminopyridine compound 2 is used as a starting material, Buchwald-Hartwig coupling is carried out on the aminopyridine compound 2 and carbamate compound 3b to prepare compound 4b, and then the compound 4b reacts with hydroxylamine under the alkaline condition to prepare compound V;
in the general reaction scheme shown in the second scheme, A in the compound 3b is an amino group (-NH)2) X, n is consistent with the selection range of the corresponding group in the compound V structural formula; r of Compound 21、R2、R3The selection range of the corresponding groups in the structural formula of the compound V is kept consistent.
In the preparation method shown in the first route, the related raw materials, compound 2, compound 3b, hydroxylamine hydrochloride and the like can be purchased from commercial sources or prepared according to the method reported in the document WO 2006021881.
Further, the following provides experimental conditions for preferable implementation of the general synthesis method shown in the second scheme.
Dissolving aminopyridine compound 2(10mmol) and ethyl carbamate compound 3a (15mmol) in 40ml DMF, adding cuprous iodide (15mmol) and potassium carbonate (30mmol), heating to 110 ℃ for reaction for 5h, filtering, concentrating the filtrate to obtain oily substance, directly feeding without purification, adding 30m L methanol into the oily substance, stirring in ice bath, sequentially adding KOH (80mmol), hydroxylamine hydrochloride (40mmol) and 3m L water, reacting in ice bath for 3h, adjusting pH of the reaction liquid to 4-5 with hydrochloric acid, decompressing, rotary steaming to remove the solvent, and recrystallizing the solid with acetonitrile or performing ethyl acetate/methanol (2:1-5:1) column chromatography to obtain the V-class target compound.
The preparation method can also further comprise the steps of reacting the compound with the structure shown in the formula V with an inorganic acid (or an inorganic base) and an organic acid (or an organic base), and cooling to separate out the salt of the compound with the structure shown in the formula V.
Pharmacological tests show that the compound has stronger inhibition effect on c-Met kinase and HDAC kinase (example 17), wherein the compounds V-1-V-16 have obvious inhibition activity on c-Met, and the c-Met inhibition activity of partial compounds such as V-5 and V-6 is better than that of a positive control drug PF-2341066; in addition, partial compounds such as V-7, V-9, V-10, V-11, V-12, and V-13 have HDAC inhibitory activity superior to that of SAHA.
Pharmacological tests show that the compound has strong induced differentiation and anti-proliferation activity on multiple tumor cells (example 18). The partial compounds tested have better anti-tumor cell proliferation activity, and the inhibitory activity of V-1 and V-5 on HCT116 is equivalent to that of positive controls SAHA and PF-2341066; the inhibitory activity of V-7 and V-9 on HCT116 is better than that of PF-2341066; the inhibition activity of V-7 and V-9 on Hut78 is equivalent to that of positive control SAHA; the inhibiting activity of V-5 and V-9 on A549 is equivalent to that of a positive control PF-2341066; the inhibiting activity of V-7 on A549 is better than that of PF-2341066; the inhibitory activity of V-3, V-4, V-5, V-7 and V-9 on H1993 is equivalent to that of a positive control PF-2341066; the inhibiting activity of V-1 on H1993 is better than that of PF 2341066. Therefore, the amino pyridine derivatives containing hydroxamic acid fragments provided by the invention have good inhibitory activity on various tumor cells.
The inhibiting activity of V-7 on A549 is better than that of PF-2341066; the inhibitory activity of V-3, V-4, V-5, V-7 and V-9 on H1993 is equivalent to that of a positive control PF-2341066; the inhibiting activity of V-1 to H1993 is better than that of PF2341066
Pharmacological tests show that the preferable compound V-7 has weak inhibitory activity on normal cells and lower toxic and side effects (example 19), indicating that the preferable compound has lower toxic and side effects when being used as an antitumor drug and is easy to be used as the antitumor drug.
Pharmacological tests show that the compound of the invention has low acute toxicity in mice (example 20). the L D of the compounds V-5, V-7, V-9 and V-13 mice administrated by single administration501.2g/kg, 1.6g/kg, 1.3g/kg and 1.9g/kg, respectively.
Pharmacological experiments show that the compound has the following beneficial effects:
1) the compound has good dual inhibition activity of c-Met and HDAC, and has good inhibition activity on various tumor cells of a human body.
2) The compound of the invention has weak inhibition effect on normal cells while effectively inhibiting tumor cells, shows better selective inhibition activity and has good anti-tumor clinical application prospect.
3) The initial acute toxicity experiment shows that the compound has high safety and low toxicity in mice.
The compound of the invention can be applied to mammals (including human beings) needing tumor treatment in the form of composition by oral administration, injection and the like.
The composition includes a therapeutically effective amount of a compound having the structure of formula V or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The carrier refers to a carrier which is conventional in the pharmaceutical field, such as: diluents, excipients such as water, etc.; binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.; fillers such as starch and the like; disintegrating agents such as calcium carbonate, sodium bicarbonate; in addition, other adjuvants such as flavoring agents and sweeteners may also be added to the composition.
The composition can be prepared into conventional solid preparations, such as tablets, capsules and the like, and is used for oral administration; it can also be made into injection.
The composition of the invention can be prepared into various dosage forms by adopting a conventional method in the field of pharmacy, wherein the content of the compound with the structure of the formula V as an active ingredient is 0.1-99.5 percent (weight ratio) of the weight of the composition.
The compound with the structure of the formula V can be clinically administered to mammals (including human beings) by oral administration or injection, wherein the oral administration is the best mode. The dosage is 0.0001 mg/kg-200 mg/kg body weight per day. The optimum dose depends on the individual, and usually the dose is initially smaller and then gradually increased.
The invention has the advantages that a batch of amino pyridine derivatives containing hydroxamic acid fragments with novel structures are obtained through a large number of experiments and activity screening, and simultaneously act on two targets of c-Met and HDAC, and the compounds and medicinal preparations thereof can treat diseases caused by abnormal gene expression, such as: has good curative effect on tumor, immune system diseases and genetic diseases.
Therefore, the compound with the structure of the formula V and the salt thereof can be used for preparing anti-tumor drugs, wherein the tumors are solid tumors and blood tumors, such as liver cancer, lung cancer, breast cancer, esophagus cancer, stomach cancer, nasopharyngeal cancer, ovarian cancer, bladder cancer, rectal cancer, skin cancer and lymphoma.
More preferably, the tumor is selected from liver cancer, lung cancer, rectal cancer, lymphoma.
The aminopyridine derivative containing hydroxamic acid fragments provided by the invention preferably has obvious proliferation inhibition activity on c-Met over-expressed tumor cells, namely human non-small cell lung cancer cells (A549 and H1993 cell strains), T lymphocyte leukemia cells (Hut78 cell strains) and human colon cancer cells (HCT116 cell strains), and provides possibility for designing a novel c-Met/HDAC inhibitor for overcoming single-target drug resistance.
In conclusion, the compound has smaller toxic and side effects when being applied as an anti-tumor medicament, is easier to be used as the anti-tumor medicament, is equivalent to the prior art, and has novelty, creativity and scientific progress.
Detailed Description
The present invention is described in further detail with reference to the following examples, but the embodiments of the present invention are not limited thereto, and the technical scope of the present invention is defined by the claims.
Example 1
Synthesis of 7- (4- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridine) 3-yl) pyrazol-1-yl) piperidin-1-yl-N-hydroxyheptanoamide (V-1) and hydrochloride thereof
5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -2-aminopyridine (0.5g,1.3mmol), 1- (4-piperidine-1- (7-heptanoic acid ethyl ester) -4-pyrazolonapinacol boron ester (0.68g,1.5mmol), KOH (0.58g,10.4mmol), hydroxylamine hydrochloride (0.36g,5.3mmol) were used as raw materials, and V-1 was synthesized according to Scheme 1, general Synthesis method for V-type compounds, to obtain 0.35g of the objective compound, with a yield of 45%.
ESI-MS[M+H]+:m/z 593.22
1H NMR(400MHz,DMSO-d6)ppm:7.78(s,1H),7.63(m,1H),7.52(s,1H),7.42(m,1H),7.20(m,1H),6.89(m,1H),6.14(q,J＝6.7Hz,1H),4.23(s,1H),3.15(m,3H),2.58(s,2H),2.45(s,2H),2.18(m,5H),1.84(m,2H),1.60(s,3H),1.34(s,3H),1.26(m,3H)
The compound V-1(0.20g, 0.3mmol) was dissolved in isopropanol, concentrated hydrochloric acid was added dropwise to precipitate a white solid, and the target compound hydrochloride was obtained in 0.17g with a yield of 90% by filtration.
Example 2
Synthesis of 6- (4- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridine) 3-yl) pyrazol-1-yl) piperidin-1-yl-N-hydroxyhexanamide (V-2)
5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -2-aminopyridine (0.5g,1.3mmol), 1- (4-piperidine-1- (6-hexanoic acid ethyl ester) -4-pyrazolonapinacol boron ester (0.65g,1.5mmol), KOH (0.58g,10.4mmol), and hydroxylamine hydrochloride (0.36g,5.3mmol) were used as raw materials, and V-2 was synthesized according to Scheme 1, the general Synthesis method for V-type compounds, to obtain 0.39g of the objective compound, with a yield of 52%.
ESI-MS[M+H]+:m/z 579.21
1H NMR(400MHz,DMSO-d6)ppm:10.49(s,1H),8.81(s,1H),8.00(s,1H),7.75(s,1H),7.58(m,1H),7.53(s,1H),7.45(m,1H),6.90(s,1H),6.09(q,J＝6.7Hz,1H),5.67(s,2H),4.36(m,1H),4.02(m,2H),3.16(m,2H),2.97(s,2H),1.99(s,2H),1.80(m,4H),1.60(m,4H),1.23(s,3H).
Example 3
Synthesis of 5- (4- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridine) 3-yl) pyrazol-1-yl) piperidin-1-yl-N-hydroxypentanamide (V-3)
5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -2-aminopyridine (0.5g,1.3mmol), 1- (4-piperidine-1- (5-pentanoic acid ethyl ester) -4-pyrazolonapinacol boron ester (0.64g,1.5mmol), KOH (0.58g,10.4mmol), and hydroxylamine hydrochloride (0.36g,5.3mmol) were used as raw materials, and V-3 was synthesized according to Scheme 1, general Synthesis method for V-type compounds, to obtain 0.37g of the objective compound, with a yield of 51%.
ESI-MS[M+H]+:m/z 565.20
1H NMR(400MHz,DMSO-d6)ppm:10.50(s,1H),8.81(s,1H),8.00(s,1H),7.75(s,1H),7.58(m,1H),7.53(s,1H),7.45(m,1H),6.90(s,1H),6.09(q,J＝6.7Hz,1H),5.67(s,2H),4.36(m,1H),4.02(m,4H),3.16(m,1H),2.97(s,2H),1.99(s,3H),1.80(m,4H),1.60(m,5H).
Example 4
Synthesis of 4- (4- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridine) 3-yl) pyrazol-1-yl) piperidin-1-yl-N-hydroxypropionamide (V-4)
5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -2-aminopyridine (0.5g,1.3mmol), 1- (4-piperidine-1- (3-propionic acid ethyl ester) -4-pyrazolonapinacol boron ester (0.59g,1.5mmol), KOH (0.58g,10.4mmol), and hydroxylamine hydrochloride (0.36g,5.3mmol) were used as raw materials, and V-4 was synthesized according to Scheme 1, general Synthesis method for V-type compounds, to obtain 0.31g of the objective compound, with a yield of 45%.
ESI-MS[M+H]+:m/z 537.16
1H NMR(400MHz,DMSO-d6)ppm:7.96(s,1H),7.75(m,1H),7.58(m,1H),7.52(s,1H),7.45(t,J＝8.7Hz,1H),6.90(m,1H),6.08(m,1H),5.66(s,2H),4.10(m,1H),2.92(m,2H),2.56(m,2H),2.16(m,2H),2.08(m,2H),1.96(s,3H),1.90(m,2H),1.70(m,2H).
Example 5
Synthesis of 2- (4- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridine) 3-yl) pyrazol-1-yl) piperidin-1-yl-N-hydroxyacetamide (V-5)
5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -2-aminopyridine (0.5g,1.3mmol), 1- (4-piperidine-1- (2-ethyl acetate) -4-pyrazolonapinacol boronate (0.56g,1.5mmol), KOH (0.58g,10.4mmol), and hydroxylamine hydrochloride (0.36g,5.3mmol) were used as raw materials, and V-5 was synthesized according to Scheme 1, general Synthesis method for class V compounds, to obtain 0.36g of the objective compound, with a yield of 53%.
ESI-MS[M+H]+:m/z 523.15
1H NMR(400MHz,DMSO-d6)ppm:10.49(s,1H),8.80(s,1H),7.94(s,1H),7.75(m,1H),7.58(m,1H),7.53(s,1H),7.45(m,1H),6.89(m,1H),6.09(t,J＝6.7Hz,1H),5.64(s,2H),4.08(m,1H),2.90(m,2H),2.26(m 2H),1.97(m,4H),1.80(m,2H),1.23(s,3H).
Example 6
Synthesis of 4- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridine) 3-yl) pyrazol-1-yl) piperidin-1-yl-N-hydroxyformamide (V-6)
5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -2-aminopyridine (0.5g,1.3mmol), 1- (4-piperidine-1- (1-carboxylic acid ethyl ester) -4-pyrazolonapinacol boron ester (0.54g,1.5mmol), KOH (0.58g,10.4mmol), and hydroxylamine hydrochloride (0.36g,5.3mmol) were used as raw materials, and V-6 was synthesized according to Scheme 1, general Synthesis method for V-type compounds, to obtain 0.31g of the objective compound, with a yield of 47%.
ESI-MS[M+H]+:m/z 509.15
1H NMR(400MHz,DMSO-d6)ppm:14.41(s,1H),9.14(s,1H),8.12(s,1H),7.88(s,2H),7.80(m,1H),7.60(m,2H),7.49(m,1H),7.15(s,1H),6.28(q,J＝6.6Hz,1H),4.36(m,1H),3.98(m,2H),2.87(m,2H),1.98(m,2H),1.87(d,J＝6.6Hz,3H),1.72(m,2H)
Example 7
Synthesis of 7- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridine) -3-yl) -N-hydroxyheptanamide (V-7) and its hydrochloride salt
5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -2-aminopyridine (0.5g,1.3mmol), 1- (7-heptanoic acid ethyl ester) -4-pyrazolpinacol boronate (0.53g,1.5mmol), KOH (0.58g,10.4mmol), and hydroxylamine hydrochloride (0.36g,5.3mmol) were used as raw materials, and V-7 was synthesized according to Scheme 1, Synthesis of V-type compounds, to obtain 0.37g of the objective compound, with a yield of 56%.
ESI-MS[M+H]+:m/z 510.15
1H NMR(400MHz,DMSO-d6)ppm:10.43(s,1H),8.70(s,1H),7.92(s,1H),7.76(s,1H),7.66–7.35(m,3H),6.95(s,1H),6.31(s,2H),6.14(m,1H),4.06(t,J＝7.1Hz,2H),1.93(m,2H),1.86–1.63(m,4H),1.46(s,2H),1.23(s,5H).
The compound V-7(0.51g, 1mmol) was dissolved in isopropanol, concentrated hydrochloric acid was added dropwise to precipitate a white solid, and the desired compound hydrochloride was obtained in an amount of 0.49g with a yield of 90% by filtration.
Example 8
Synthesis of 6- (4 (6-amino-5 (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin) -3-yl) -N-hydroxyhexanamide (V-8) and its sulfate salt
5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -2-aminopyridine (0.5g,1.3mmol), ethyl 1- (6-hexanoate) -4-pyrazolonapinacol boronate (0.50g,1.5mmol), KOH (0.58g,10.4mmol), and hydroxylamine hydrochloride (0.36g,5.3mmol) were used as raw materials, and V-8 was synthesized according to general method for synthesizing V-type compounds Scheme 1, to obtain 0.33g of the objective compound with a yield of 51%.
ESI-MS[M+H]+:m/z 496.13
1H NMR(400MHz,DMSO-d6)ppm:8.03(s,1H),8.01(s,1H),7.80(d,J＝1.6Hz,1H),7.68–7.57(m,2H),7.49(t,J＝8.7Hz,1H),7.14(d,J＝1.6Hz,1H),6.30(q,J＝6.6Hz,1H),5.81(s,2H),4.09(t,J＝6.9Hz,2H),2.29(t,J＝7.4Hz,2H),1.87(d,J＝6.5Hz,3H),1.81–1.71(m,2H),1.54(p,J＝7.5Hz,2H),1.26–1.16(m,2H).
Dissolving the compound V-8(0.30g, 0.6mmol) in isopropanol, dropwise adding dilute sulfuric acid to precipitate white solid, and filtering to obtain the target compound sulfate 0.32g with yield of 90%.
Example 9
Synthesis of 5- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridine) -3-yl) -N-hydroxypentanamide (V-9) and tartrate salt thereof
5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -2-aminopyridine (0.5g,1.3mmol), 1- (5-pentanoic acid ethyl ester) -4-pyrazolonaphthorolate (0.48g,1.5mmol), KOH (0.58g,10.4mmol), and hydroxylamine hydrochloride (0.36g,5.3mmol) were used as raw materials, and V-9 was synthesized according to general method for V-series compound synthesis Scheme 1 to obtain 0.33g of the target compound with a yield of 53%.
ESI-MS[M+H]+:m/z 482.15
1H NMR(400MHz,DMSO-d6)ppm:10.49(s,1H),8.03(s,1H),8.01(s,1H),7.80(m,1H),7.68–7.57(m,2H),7.49(m,1H),7.14(d,J＝1.6Hz,1H),6.30(q,J＝6.6Hz,1H),5.81(s,2H),4.09(t,J＝6.9Hz,2H),2.29(t,J＝7.4Hz,2H),1.87(d,J＝6.5Hz,3H),1.81–1.71(m,2H),1.26–1.16(m,2H).
The compound V-9(0.30g, 0.6mmol) was dissolved in isopropanol, tartaric acid was added to precipitate a white solid, and the target compound tartrate salt was obtained in an amount of 0.32g with a yield of 85% by filtration.
Example 10
Synthesis of 4- (6-amino-5 (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridine) -3-yl) -N-hydroxybutyramide (V-10) and its malate salt
5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -2-aminopyridine (0.5g,1.3mmol), 1- (4-ethyl butyrate) -4-pyrazolonaquindox boronate (0.46g,1.5mmol), KOH (0.58g,10.4mmol), and hydroxylamine hydrochloride (0.36g,5.3mmol) were used as raw materials, and V-10 was synthesized according to Scheme 1, Synthesis general method for V-type compounds, to obtain 0.33g of the objective compound, with a yield of 54%.
ESI-MS[M+H]+:m/z 468.10
1H NMR(400MHz,DMSO-d6)ppm:10.49(s,1H),8.03(s,1H),8.01(s,1H),7.80(m,1H),7.68–7.57(m,2H),7.49(m,1H),7.14(d,J＝1.6Hz,1H),6.30(q,J＝6.6Hz,1H),5.81(s,2H),4.09(t,J＝6.9Hz,2H),1.87(d,J＝6.5Hz,3H),1.74(m,2H),1.32(m,2H).
Dissolving the compound V-10(0.30g, 0.6mmol) in isopropanol, adding malic acid, precipitating white solid, and filtering to obtain target compound malate salt 0.31g with yield of 86%.
Example 11
Synthesis of 7- (4- (6-amino-5 (1- (3-fluorophenyl) ethoxy) pyridine) -3-yl) -N-hydroxyheptanamide (V-11)
5-bromo-3- (1-phenylethoxy) -2-aminopyridine (0.5g,1.7mmol), 1- (7-heptanoic acid ethyl ester) -4-pyrazolonapinacol boron ester (0.70g,2.0mmol), KOH (0.76g,13.6mmol), hydroxylamine hydrochloride (0.47g,6.8mmol) were used as raw materials, and V-11 was synthesized according to general method for synthesizing V-type compounds Scheme 1, to obtain 0.35g of the objective compound with a yield of 49%.
ESI-MS[M+H]+:m/z 424.30
1H NMR(400MHz,DMSO-d6)ppm:10.43(s,1H),8.70(s,1H),7.92(s,1H),7.76(s,1H),7.45(m,2H),7.15(m,3H),6.95(m,2H),6.14(m,1H),5.81(s,2H),4.06(t,J＝7.1Hz,2H),1.93(m,2H),1.86(d,J＝6.7Hz,3H),1.74(m,2H),1.46(s,2H),1.23(s,4H)
Example 12
Synthesis of 7- (4- (6-amino-5 (1- (2-chloro-3-fluorophenyl) ethoxy) pyridine) -3-yl) -N-hydroxyheptanamide (V-12)
5-bromo-3- (1- (2-chloro-3-fluorophenyl) ethoxy) -2-aminopyridine (0.5g,1.4mmol), 1- (7-heptanoic acid ethyl ester) -4-pyrazolonapinacol boronate (0.59g,1.7mmol), KOH (0.63g,11.2mmol), and hydroxylamine hydrochloride (0.37g,5.6mmol) were used as raw materials, and V-12 was synthesized according to general method for synthesizing V-type compounds Scheme 1, to obtain 0.34g of the objective compound, with a yield of 51%.
ESI-MS[M+H]+:m/z 476.22
1H NMR(400MHz,DMSO-d6)ppm:10.43(s,1H),8.70(s,1H),7.92(s,1H),7.76(s,1H),7.45(m,2H),7.15(m,2H),6.95(m,1H),6.14(m,1H),5.81(s,2H),4.06(t,J＝7.1Hz,2H),1.93(m,2H),1.86(d,J＝6.7Hz,3H),1.74(m,2H),1.46(s,2H),1.23(s,4H)
Example 13
Synthesis of 7- (4- (6-amino-5 (1- (6-chloro-3-fluorophenyl) ethoxy) pyridine) -3-yl) -N-hydroxyheptanamide (V-13) and its acetate salt
5-bromo-3- (1- (6-chloro-3-fluorophenyl) ethoxy) -2-aminopyridine (0.5g,1.4mmol), 1- (7-heptanoic acid ethyl ester) -4-pyrazolonapinacol boronate (0.59g,1.7mmol), KOH (0.63g,11.2mmol), and hydroxylamine hydrochloride (0.37g,5.6mmol) were used as raw materials, and V-13 was synthesized according to general method for Synthesis of V-type compounds Scheme 1, to obtain 0.34g of the objective compound, with a yield of 51%.
ESI-MS[M+H]+:m/z 476.22
1H NMR(400MHz,DMSO-d6)ppm:10.43(s,1H),8.70(s,1H),7.92(s,1H),7.76(s,1H),7.45(m,2H),7.15(m,1H),6.95(m,2H),6.14(m,1H),5.81(s,2H),4.06(t,J＝7.1Hz,2H),1.93(m,2H),1.86(d,J＝6.7Hz,3H),1.74(m,2H),1.46(s,2H),1.23(s,4H)
The compound V-13(0.30g, 0.6mmol) was dissolved in isopropanol, glacial acetic acid was added dropwise to precipitate a white solid, and the target compound acetate was obtained in an amount of 0.26g with a yield of 80% by filtration.
Example 14
N-hydroxy-7- (8-chloroquinazoline-4-amino) heptanamide (V-14) and synthesis thereof
5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -2-aminopyridine (0.5g,1.3mmol), ethyl 7-aminoheptanoate (0.26g,1.5mmol), KOH (0.58g,10.4mmol), and hydroxylamine hydrochloride (0.36g,5.3mmol) were used as starting materials, and V-14 was synthesized according to Scheme 2, the general Synthesis method for class V compounds, to obtain 0.18g of the objective compound in 31% yield.
ESI-MS[M+H]+:m/z 459.20
1H NMR(400MHz,DMSO-d6)ppm:10.43(s,1H),8.70(s,1H),7.45(m,1H),7.15(m,1H),6.95(m,1H),6.14(m,1H),5.81(s,2H),4.06(t,J＝7.1Hz,2H),1.93(m,2H),1.86(d,J＝6.7Hz,3H),1.74(m,2H),1.46(s,2H),1.23(s,4H)
The compound V-14(0.30g, 0.7mmol) was dissolved in isopropanol, concentrated hydrochloric acid was added dropwise to precipitate a white solid, and the desired compound hydrochloride was obtained in an amount of 0.27g with a yield of 85% by filtration.
Example 15
Synthesis of V-15N-hydroxy-7- (5-fluoroquinazoline-4-amino) heptanamide
5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -2-aminopyridine (0.5g,1.3mmol), ethyl 7-aminoheptanoate (0.24g,1.5mmol), KOH (0.58g,10.4mmol), and hydroxylamine hydrochloride (0.36g,5.3mmol) were used as starting materials, and Synthesis of V-15 was carried out according to general Synthesis method of class V Compound Scheme 2 to obtain 0.16g of the objective compound in 28% yield.
ESI-MS[M+H]+:m/z 445.13
1H NMR(400MHz,DMSO-d6)ppm:10.43(s,1H),8.70(s,1H),7.45(m,1H),7.15(m,1H),6.95(m,1H),6.14(m,1H),5.81(s,2H),4.09(t,J＝6.9Hz,2H),2.29(t,J＝7.4Hz,2H),1.87(d,J＝6.5Hz,3H),1.81–1.71(m,2H),1.54(p,J＝7.5Hz,2H),1.26–1.16(m,2H).
Example 16
Synthesis of V-16N-hydroxy-7- (2-chloroquinazoline-4-amino) heptanamide
5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -2-aminopyridine (0.5g,1.3mmol), ethyl 7-aminoheptanoate (0.22g,1.5mmol), KOH (0.58g,10.4mmol), and hydroxylamine hydrochloride (0.36g,5.3mmol) were used as starting materials to synthesize V-16 according to Scheme 2, a target compound of 0.16g was obtained in 28% yield.
ESI-MS[M+H]+:m/z 431.12
1H NMR(400MHz,DMSO-d6)ppm:10.43(s,1H),8.70(s,1H),7.45(m,1H),7.15(m,1H),6.95(m,1H),6.14(m,1H),5.81(s,2H),4.09(t,J＝6.9Hz,2H),2.29(t,J＝7.4Hz,2H),1.87(d,J＝6.5Hz,3H),1.81–1.71(m,2H),1.26–1.16(m,2H).
Example 17
Inhibition activity test of compounds on tumor kinase:
test of c-Met inhibitory enzyme IC by using 08-151 kit produced from Carna50Values, assay procedures were performed with reference to kit instructions.
The K340-100 kit from Biovision is selected to test the HDAC enzyme inhibitor IC of the compound50The test and experimental operation are carried out according to the kit instruction.
The results are shown in Table 2.
TABLE 2 in vitro inhibitory Activity of the Compounds of the invention on c-Met and HDAC
In Table 2, NT indicates no detectable activity.
As can be seen from the above table 2, the compounds of the present invention show c-Met inhibitory activity equivalent to that of the positive control drug PF-2341066, and some compounds such as V-5 and V-6 have c-Met inhibitory activity superior to that of the positive control drug; in addition, the compound of the invention also has stronger inhibition activity on HDAC, and the inhibition activity of partial compounds such as V-7, V-9, V-10, V-11, V-12 and V-13 on HDAC is better than that of a positive control drug SAHA.
Example 18
This example is an in vitro anti-tumor cell proliferation assay of the compounds prepared in example 1, example 3, example 4, example 5, example 7, and example 9. Wherein, the selected tumor sensitive cells are HCT116 (human colon cancer cells), A549 (human lung adenocarcinoma cells), Hut78(T lymphocyte leukemia cells), H1993 (human lung cancer non-small cells); SAHA and PF-02341066 were selected as control drugs. The specific results are shown in Table 3 (unit: μ M):
TABLE 3 in vitro inhibitory Activity of some Compounds of the invention on tumor cells
As can be seen from Table 3 above, some of the compounds of the present invention tested had better anti-tumor cell proliferation activity, wherein the inhibitory activity of V-1 and V-5 on HCT116 was comparable to that of positive controls SAHA and PF-2341066; the inhibitory activity of V-7 and V-9 on HCT116 is better than that of PF-2341066; the inhibition activity of V-7 and V-9 on Hut78 is equivalent to that of positive control SAHA; the inhibiting activity of V-5 and V-9 on A549 is equivalent to that of a positive control PF-2341066; the inhibiting activity of V-7 on A549 is better than that of PF-2341066; the inhibitory activity of V-3, V-4, V-5, V-7 and V-9 on H1993 is equivalent to that of a positive control PF-2341066; the inhibiting activity of V-1 on H1993 is better than that of PF 2341066. Therefore, the hydroxamic acid compound containing the aminopyridine has good inhibitory activity on various tumor cells.
Example 19
Determination of the in vitro inhibitory Activity of Normal cells of Compounds:
this example is an in vitro inhibitory activity test of the compound prepared in example 7 on normal cells MRC-5 (human embryonic lung cells), H L-7702 (human liver cells), HEK-293 (embryonic kidney cells). the specific results are as follows:
TABLE 4 in vitro inhibitory Activity of Compounds of the invention and control drugs on Normal cells (IC)50,μM)
As can be seen from Table 4, the compound V-7 of the invention has weaker inhibitory activity on normal cells and lower toxic and side effects compared with a control drug Cabozantinib, indicates that the compound has lower toxic and side effects when being used as an antitumor drug and is easy to be used as the antitumor drug.
Example 20
Acute toxicity test by adopting the method reported by modern pharmacological experiment method compiled by Zhang Shanda (Beijing medical university, China cooperative medical university United Press, published in 1998), primarily screening, and performing statistics by Bliss method (practical pharmaceutical preparation technology, national health Press, published in 1999) to obtain L D of compounds V-5, V-7, V-9 and V-13 administered by mice in single administration501.2g/kg, 1.6g/kg, 1.3g/kg and 1.9g/kg, respectively.
Example 21
The preparation method comprises the following steps: mixing any one of active ingredients V-1 to V-17 with sucrose and corn starch, moistening with water, stirring, drying, pulverizing, sieving, adding calcium stearate, mixing, and tabletting. Each tablet weighs 290mg, and the content of active ingredients is 100 mg.
Example 22
Injection preparation: 15mg of any one compound selected from V-1 to V-17
Water for injection 80mg
The preparation method comprises the following steps: dissolving any one of the active ingredients V-1 to V-17 in water for injection, mixing uniformly, filtering, and subpackaging the obtained solution in ampoule bottles under aseptic condition, wherein each bottle contains 95mg of the active ingredient, and the content of the active ingredient is 15mg per bottle.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (11)
1. An aminopyridine derivative containing hydroxamic acid fragments and pharmaceutically acceptable salts thereof, the derivative is represented by formula V:
in the formula V, the reaction mixture is shown in the formula V,
R1、R2and R3Independently selected from hydrogen or halogen;
a.A is pyrazolyl
X is methylene-CH2N of said pyrazolyl radical is linked to the X radical,
n represents 0 to 6;
b.A is amino-NH-, and X is methylene-CH2-，
n represents 0 to 6.
2. A derivative according to claim 1 of formula V, wherein:
R1、R2and R3Independently selected from hydrogen or halogen;
a is amino-NH-, and X is methylene-CH2-; n is 4 to 6.
3. The derivative of formula V and salts thereof according to claim 1, wherein formula V is selected from the following structures:
v-77- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3 yl) -1H-pyrazol-1-yl) -N-hydroxyheptanoamide,
v-95- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3 yl) -1H-pyrazol-1-yl) -N-hydroxypentanamide,
v-104- (4- (6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3 yl) -1H-pyrazol-1-yl) -N-hydroxybutyramide,
v-117- (4- (6-amino-5- (1-phenylethoxy) pyridin-3 yl) -1H-pyrazol-1-yl) -N-hydroxyheptanamide,
v-127- (4- (6-amino-5- (1- (2-chloro-3-fluorophenyl) ethoxy) pyridin-3 yl) -1H-pyrazol-1-yl) -N-hydroxyheptanamide,
v-137- (4- (6-amino-5- (1- (6-dichloro-3-fluorophenyl) ethoxy) pyridin-3 yl) -1H-pyrazol-1-yl) -N-hydroxyheptanoamide,
v-147- ((6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) amino) -N-hydroxyheptanamide,
v-156- ((6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) amino) -N-hydroxyhexanamide,
v-165- ((6-amino-5- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) amino) -N-hydroxypentanamide.
4. A derivative of formula V according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt thereof is selected from the group consisting of hydrochloride, hydrobromide, sulphate, acetate, lactate, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulphonic acid or methanesulphonate.
5. The derivative of formula V according to claim 4, wherein the pharmaceutically acceptable salt thereof is selected from hydrochloride, acetate, sulfate, tartrate or malate.
6. A process for the preparation of a derivative of formula V according to claim 1, comprising the steps of the following scheme:
taking an aminopyridine compound 2 as an initial raw material, carrying out Suzuki coupling on the aminopyridine compound 2 and boron ester 3a to prepare a compound 4a, and then reacting with hydroxylamine under an alkaline condition to prepare a compound V;
in the above reaction scheme, A of the compound 3a is pyrazolyl
Wherein, N atom in pyrazolyl A is connected with X, X, N is consistent with the selection range of corresponding group in compound V structural formula; said R in Compound 21、R2、R3The selection range of the corresponding groups in the structural formula of the compound V is kept consistent.
7. A process for the preparation of a derivative of formula V according to claim 1, comprising the steps of the following scheme:
taking an aminopyridine compound 2 as a starting material, carrying out Buchwald-Hartwig coupling on the aminopyridine compound 2 and an ester compound 3b to prepare a compound 4b, and then reacting with hydroxylamine under an alkaline condition to prepare a compound V;
in the above reaction scheme, A of the compound 3b is an amino group (-NH)2) X, n is consistent with the selection range of the corresponding group in the compound V structural formula; r of Compound 21、R2、R3The selection range of the corresponding groups in the structural formula of the compound V is kept consistent.
8. A composition comprising a derivative of formula V according to any one of claims 1 to 5 and a pharmaceutically acceptable excipient.
9. Use of a derivative of formula V according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of tumours.
10. The use according to claim 9, wherein the tumor is selected from liver cancer, lung cancer, breast cancer, esophageal cancer, stomach cancer, nasopharyngeal cancer, ovarian cancer, bladder cancer, rectal cancer, skin cancer and lymphoma.
11. Use according to claim 9, wherein the tumor is selected from liver cancer, lung cancer, rectal cancer, lymphoma.
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| CN105622577A (en) * | 2014-11-29 | 2016-06-01 | 江苏先声药业有限公司 | Novel crystallographic form of ceritinib and preparation method of novel crystallographic form |
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| CN105622577A (en) * | 2014-11-29 | 2016-06-01 | 江苏先声药业有限公司 | Novel crystallographic form of ceritinib and preparation method of novel crystallographic form |
| CN105820113A (en) * | 2015-01-07 | 2016-08-03 | 爱技特科技（北京）有限公司 | Method for preparing Crizotinib chiral intermediate |
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