CN108314676A - The aminopyridine analog derivative and its antitumor application thereof of the segment containing hydroxamic acid - Google Patents
The aminopyridine analog derivative and its antitumor application thereof of the segment containing hydroxamic acid Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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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
- C07D213/04—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 having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—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 having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The present invention provides a kind of aminopyridine analog derivative of the segment containing hydroxamic acid shown in Formula V and its pharmaceutically acceptable salts, and its in the application of anti-tumor aspect,
Description
Technical field
The present invention relates to organic chemistry and medicinal chemistry arts, and in particular to the aminopyridines of the segment containing hydroxamic acid spread out
Biology and its antitumor application thereof.
Background technology
Tumour is polygenes, multi-path interaction as a result, as people are to science of heredity, biochemistry and oncogene
The understanding such as signal transduction deepen continuously, and research and develop the antitumor inhibitor of multiple target point, multi-path to treat drug resistance of tumor
And recurrence, will be the developing direction of antitumor drug research from now on.
In recent years, with the continuous improvement of Protocols in Molecular Biology and to Tumorigenesis from cell, molecular level
The further rapid development of the technologies such as understanding and combinatorial chemistry, Structure-ba sed drug design and computer science, tumour life
Object treatment has had significant progress, enters the molecular targeted therapy epoch.It is logical that targeted anticancer medicine can target specificity
Road prevents tumour growth and reduces the toxicity to normal cell.However, there are weak curative effects for single target spot antitumor drug, it is also easy to produce
The problems such as drug resistance, is insufficient for the demand of prevention malignant tumour.
The research and development of multiple target point antineoplastic are becoming a new hot spot at present, research and develop novel multiple target point unimolecule
Antitumor drug can be better than single target spot inhibitor in terms for the treatment of, break away from the drug resistance that single target treatment is brought, and can avoid
The defect of drug combination represents oncotherapy and the new developing direction of drug development, it may have huge social and economic benefit.
C-Met is the important member of receptor tyrosine kinase family.C-Met is as the key in tumor signal network path
Node can be handed over other tumor related genes (such as integrin family, dead associated receptor, other receptor tyrosine kinases)
Interaction is shared and crosslinking activation downstream signaling pathway, induced cell proliferation resist apoptosis, promote cell migration, invasion, blood vessel
Generate etc..
C-Met inhibitor can be generated with targeted inhibition tumor cell proliferation and new vessels, especially inhibit tumour cell point
It dissipates, move, invading, migrating, shifting this tumor development critical process, fundamentally blocking tumour cell route of transmission.It uses
The Patients with Non-small-cell Lung and list that small molecule c-Met inhibitor assists or monotherapy protein tyrosine kinase inhibitor is invalid
The patient with breast cancer of clonal antibody drug ineffective has been achieved for extraordinary clinical effectiveness.Existing Pfizer exploitation at present
ALK kinases and c-Met kinase inhibitor PF-2341066 (Crizotinib) in 2011 by FDA ratify list, for controlling
Treat advanced Non-small cell lung (NSCLC) patient of anaplastic lymphoma kinase (ALK) gene of abnormal expression.Exelixis is public
The c-Met kinases and VEGFR2 inhibitor Cs abozantinib for taking charge of exploitation were ratified to list in 2012 by FDA, for treating treatment
Progressive stage, the medullary carcinoma of thyroid gland of transfer (MTC) patient.Separately there is a c-Met inhibitor more than ten to be in clinical investigation phase, faces
Bed result of study provides strong evidence for c-Met as the reliability of anti-tumor target.
Histon deacetylase (HDAC) (Histone deacetylase, HDAC) is the oncotherapy developed in recent years
Important target spot.The study found that hdac inhibitor can express out good antimetabolic and anti-angiogenic life in testing in vitro and in vivo
It is Viability.Since the 1990s, people have obtained the different hdac inhibitor of various structures, at present there are many
Hdac inhibitor enters clinical experimental stage.Research has shown that they can inhibit the proliferation of kinds of tumor cells, induction tumour thin
Born of the same parents break up and (or) apoptosis, are a kind of antitumor drugs with wide application prospect.
Histon deacetylase (HDAC) inhibitor can be divided into four classes by structure：Benzamides, hydroxamic acid, fatty acid and
Cyclic peptide.SAHA (also known as Vorinostat), belongs to hydroxamic acid, is the non-selective histone deacetylase of first listing
Change enzyme inhibitor, be used for other medicines treatment when or treatment after cannot still cure deteriorate or Relapse rate in the case of turn
Shifting property T-cell lymphoma,cutaneous (CTCL).
It is well known that tumour be polygenes, multi-path interaction a kind of complex disease, single target spot, unipath inhibit
It is often also easy to produce drug resistance, the antitumor inhibitor of multiple target point multi-path can break away from the drug resistance that single target treatment may be brought and ask
Topic, avoids the defect of drug combination, represents the developing direction of oncotherapy and drug development.C-Met and HDAC is anti-at present swollen
Tumor research hot topic target spot, simple c-Met inhibitor and hdac inhibitor have been successfully applied to clinic, pass through marketed drug
Structure and its target proteins carry out analysis and Computer-Aided Drug Design, and the present invention is by two targeted integrations of c-Met and HDAC
Get up, by many experiments and screening active ingredients, obtains a batch while there is the chemical combination of c-Met and HDAC dual restraining activities
Object, and find its with preferable antitumor activity and toxicity it is relatively low, have further investigation value.
Technical problem to be solved by the invention is to provide a kind of and entirely different pyridine derivatives of the prior art, tools
Body is a kind of aminopyridines of the segment containing hydroxamic acid, which has good protein kinase inhibiting activity
With histon deacetylase (HDAC) inhibitory activity, i.e. c-Met/HDAC dual restraining activities, it is shown that preferable antitumor action.
Invention content
There is provided one kind having protein kinase c-Met and/or DNA methylase inhibitor kinases for an object of the present invention
Aminopyridine analog derivative of the segment containing hydroxamic acid of HDAC inhibitory activity and preparation method thereof.
Another object of the present invention is to disclose the aminopyridine analog derivative of the above-mentioned segment containing hydroxamic acid antitumor
Application in aspect.
Hydroxamic acid compound of the present invention, be a kind of segment containing hydroxamic acid aminopyridine analog derivative with
And its pharmaceutically acceptable salt, the derivative are shown in Formula V：
In Formula V,
R1、R2And R3It is independent to be selected from hydrogen or halogen；
A is pyrazolylOr amino (- NH-)；
X is piperidylN in the piperidyl X is connected with carbochain；Or X is methylene (- CH2-)；
N is expressed as 0~6.
The aminopyridine analog derivative of the segment containing hydroxamic acid shown in present invention Formula V as described above, it is preferable that Formula V
In,
R1、R2And R3It is independent to be selected from hydrogen or halogen；
A is pyrazolyl
X is piperidylN in the piperidyl X is connected with carbochain；
N is expressed as 0~6.
The aminopyridine analog derivative of the segment containing hydroxamic acid shown in present invention Formula V as described above, it is preferable that Formula V
In,
R1、R2And R3It is independent to be selected from hydrogen or halogen；
A is pyrazolylX is methylene (- CH2-)；
N is expressed as 0~6.
The aminopyridine analog derivative of the segment containing hydroxamic acid shown in present invention Formula V as described above, it is preferable that Formula V
In,
R1、R2And R3It is independent to be selected from hydrogen or halogen；
A is amino (- NH-), and X is methylene (- CH2-)；
N is expressed as 0~6.
It is further preferred that the aminopyridine analog derivative of the segment containing hydroxamic acid shown in Formula V as described above, preferably
Ground, in Formula V,
R1、R2And R3It is independent to be selected from hydrogen or halogen；
A is amino (- NH-), and X is methylene (- CH2-)；N is 4~6.
For convenience of understanding the present invention, preferred following specific compounds and its salt from the compound of Formula V structure, but this
Invention is not limited to following compounds：
V-1 7- (4- (4- (6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridin-3-yl) -1H- pyrroles
Azoles -1- bases) piperidin-1-yl)-N- hydroxyl heptamides,
V-2 6- (4- (4- (6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridin-3-yl) -1H- pyrroles
Azoles -1- bases) piperidin-1-yl)-N- hydroxyl hexanamides,
V-3 5- (4- (4- (6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridin-3-yl) -1H- pyrroles
Azoles -1- bases) piperidin-1-yl)-N- hydroxyvaleramides,
V-4 3- (4- (4- (6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridin-3-yl) -1H- pyrroles
Azoles -1- bases) piperidin-1-yl)-N- hydroxypropanamides,
V-5 2- (4- (4- (6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridin-3-yl) -1H- pyrroles
Azoles -1- bases) piperidin-1-yl)-N- hydroxyl acetamides,
V-6 4- (4- (6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridin-3-yl) -1H- pyrazoles -1-
Base) N- hydroxy piperidine -1- formamides,
V-7 7- (4- (- 3 base of 6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) -1H- pyrazoles -1-
Base)-N- hydroxyl heptamides,
V-8 6- (4- (- 3 base of 6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) -1H- pyrazoles -1-
Base)-N- hydroxyl hexanamides,
V-9 5- (4- (- 3 base of 6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) -1H- pyrazoles -1-
Base)-N- hydroxyvaleramides,
V-10 4- (4- (- 3 base of 6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) -1H- pyrazoles -1-
Base)-N- hydroxybutyrate amides,
V-11 7- (4- (- 3 base of 6- amino -5- (1- phenyl ethoxies) pyridine) -1H- pyrazol-1-yls)-N- hydroxyl oenanthyl
Amine,
V-12 7- (4- (- 3 base of 6- amino -5- (1- (the chloro- 3- fluorophenyls of 2-) ethyoxyl) pyridine) -1H- pyrazol-1-yls) -
N- hydroxyl heptamides,
V-13 7- (4- (- 3 base of 6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 6-) ethyoxyl) pyridine) -1H- pyrazoles -1-
Base)-N- hydroxyl heptamides,
V-14 7- ((6- amino -5- (1- (2,6- bis- chloro- 3- fluorophenyls) ethyoxyl) pyridin-3-yl) amino)-N- hydroxyls
Heptamide,
V-15 6- ((6- amino -5- (1- (2,6- bis- chloro- 3- fluorophenyls) ethyoxyl) pyridin-3-yl) amino)-N- hydroxyls
Caproamide,
V-16 5- ((6- amino -5- (1- (2,6- bis- chloro- 3- fluorophenyls) ethyoxyl) pyridin-3-yl) amino)-N- hydroxyls
Pentanamide,
Its structural formula is shown in Table 1：
1 preferred compound of table is numbered and corresponding structural formula
The compound of the Formula V structure can obtain the salt of the compound of Formula V structure with inorganic acid, organic acid at salt
Form substance, the salt are hydrochloride, hydrobromate, sulfate, disulfate, acetate, lactate, tartrate, tan
Hydrochlorate, citrate, trifluoroacetate, malate, maleate, succinate, p-methyl benzenesulfonic acid or mesylate.
Preferably, the salt form substance of the compound of Formula V structure, the salt are selected from hydrochloride, hydrobromate, hydrogen sulfate
Salt, malate, maleate, succinate, p-methyl benzenesulfonic acid or mesylate.
It is highly preferred that the salt form substance of the compound of Formula V structure, the salt is selected from hydrochloride, acetate, sulfuric acid
Salt, tartrate or malate.
According to the salt form of the compound of above-mentioned Formula V structure, by the Formula V structure compound with it is corresponding inorganic
Acid, organic acid are obtained at salt, and the inorganic acid or organic acid are selected from acid, hydrobromic acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, tan
Acid, citric acid, trifluoracetic acid, malic acid, maleic acid, succinic acid, p-methyl benzenesulfonic acid or methanesulfonic acid.
The preparation method of the aminopyridine analog derivative of the above-mentioned segment containing hydroxamic acid, this method include shown in route one
Step：
Route one is starting material with aminopyridines 2, and compound is made by Suzuki couplings with boron ester 3a
Then compound V is made in 4a with azanol reaction under alkaline condition；
It reacts and leads in method shown in above-mentioned route one, the A of compound 3a is pyrazolylWherein, pyrazolyl A
Middle N atoms connect X, and X, n are consistent to the selection range of corresponding group in compound V structure formula；It is described in compound 2
R1、R2、R3It is consistent to the selection range of corresponding group in compound V structure formula.
In preparation method shown in above-mentioned route one, involved raw material, 2 ﹑ compounds 3a of compound and hydroxylamine hydrochloride etc.
It can be bought by commercial channel or be prepared according to the method for document WO2006021881 reports.
Method (route one), further, a kind of experiment condition of preferred implementation presented below are led to regard to above-mentioned synthesis.
Aminopyridines 2 (10mmol) and pyrazoles boron ester 3 (12mmol) are dissolved in 60ml glycol dimethyl ethers,
The aqueous sodium carbonate 20ml of 2M is added, is passed through inert gas, [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride is added
(0.5mmol), is warming up to 90 DEG C of reaction 6h, and filtrate is concentrated to give grease, directly fed intake without purifying by filtering.In grease
30mL methanol is added, ice bath stirring sequentially adds KOH (80mmol), hydroxylamine hydrochloride (40mmol) and 3mL water.Ice bath reacts 3h,
Reaction solution hydrochloric acid tune pH to 4-5, vacuum rotary steam remove solvent.Solid recrystallized from acetonitrile or ethyl acetate/methanol (2:1-5:
1) column chromatography obtains V class target compounds.
Preparation method shown in above-mentioned route one can further include the compound of Formula V structure and inorganic acid (or nothing
Machine alkali), organic acid (or organic base) reaction, the salt of the cooling compound that Formula V structure is precipitated.
The preparation method of the aminopyridine analog derivative of another kind segment containing hydroxamic acid, this method include shown in route two
The step of：
Route two is starting material with aminopyridines 2, is passed through with carbamate compound 3b
Compound 4b is made in Buchwald-Hartwig couplings, and compound V is then made with azanol reaction under alkaline condition；
It reacts and leads in method shown in above-mentioned route two, the A of compound 3b is amino (- NH2), X, n and compound V structure formula
In the selection range of corresponding group be consistent；The R of compound 21、R2、R3To the selection of corresponding group in compound V structure formula
Range is consistent.
In preparation method shown in above-mentioned route one, involved raw material, 2 ﹑ compounds 3b of compound and hydroxylamine hydrochloride etc.
It can be bought by commercial channel or be prepared according to the method for document WO2006021881 reports.
Lead to method, further, a kind of experiment condition of preferred implementation presented below with regard to being synthesized shown in above-mentioned route two.
Aminopyridines 2 (10mmol) and urethane compounds 3a (15mmol) are dissolved in 40mlDMF
In, cuprous iodide (15mmol) is added and potassium carbonate (30mmol) is warming up to 110 DEG C of reaction 5h, filtrate is concentrated to give oil by filtering
Shape object directly feeds intake without purifying.30mL methanol is added in grease, ice bath stirring sequentially adds KOH (80mmol), hydrochloric acid
Azanol (40mmol) and 3mL water.Ice bath reacts 3h, reaction solution hydrochloric acid tune pH to 4-5, and vacuum rotary steam removes solvent.Solid is used
Recrystallized from acetonitrile or ethyl acetate/methanol (2:1-5:1) column chromatography obtains V class target compounds.
Above-mentioned preparation method can further include the compound and inorganic acid (or inorganic base), organic acid of Formula V structure
(or organic base) reacts, the salt of the cooling compound that Formula V structure is precipitated.
Pharmacological testing shows compound of the present invention, has stronger inhibiting effect to c-Met kinases and HDAC kinases
(embodiment 17), wherein V-1~V-16 compounds show c-Met apparent inhibitory activity, part of compounds such as V-5, V-6
C-Met inhibitory activity be better than positive control drug PF-2341066；In addition, part of compounds such as V-7 ﹑ V-9, V-10 ﹑ V-11 ﹑ V-
The HDAC inhibitory activity of 12 ﹑ V-13 is better than positive control drug SAHA.
Pharmacological testing shows compound of the present invention, there is stronger induction to break up and resist more plants of tumour cells
Proliferation activity (embodiment 18).The part of compounds of the present invention tested has preferable anti-tumour cell proliferative activity, V-
1, V-5 is suitable with positive control SAHA and PF-2341066 to the inhibitory activity of HCT116；V-7, V-9 live to the inhibition of HCT116
Property be better than PF-2341066；V-7, V-9 are suitable with positive control SAHA to the inhibitory activity of Hut78；The suppression of V-5, V-9 to A549
System activity is suitable with positive control PF-2341066；V-7 is better than PF-2341066 to the inhibitory activity of A549；V-3、V-4、V-5、
V-7, V-9 are suitable with positive control PF-2341066 to the inhibitory activity of H1993；V-1 is better than the inhibitory activity of H1993
PF2341066.Thus illustrate that the aminopyridine analog derivative of the segment provided by the invention containing hydroxamic acid is thin for kinds of tumors
Born of the same parents all have good inhibitory activity.
V-7 is better than PF-2341066 to the inhibitory activity of A549；V-3, V-4, V-5, V-7, V-9 live to the inhibition of H1993
Property is suitable with positive control PF-2341066；V-1 is better than PF2341066 to the inhibitory activity of H1993
Pharmacological testing shows preferred compound V-7 of the present invention, weaker to the inhibitory activity of normal cell, has more
Low toxic side effect (embodiment 19), indicating has lower toxic side effect when it is used as antitumor drug, be easy to conduct
Tumour medicine uses.
Pharmacological testing shows that acute toxicity is low (embodiment 20) in compound Mice Body of the present invention.Compound V-5,
The LD that V-7, V-9, V-13 mouse single gavage50Respectively 1.2g/kg, 1.6g/kg, 1.3g/kg and 1.9g/kg.
Pharmacological evaluation shows that compound of the present invention has the advantages that：
1) compound of the present invention has good c-Met and HDAC dual restraining activities, thin to human body kinds of tumors
Born of the same parents have good inhibitory activity.
2) compound of the present invention is while effectively inhibiting tumour cell, table weak to the inhibiting effect of normal cell
Reveal preferable selection inhibitory activity, there is good antitumor potential applicability in clinical practice.
3) acute toxicity preliminary experiment shows that safety is higher in compound Mice Body of the present invention, and toxicity is smaller.
Compound of the present invention can be applied to by approach such as oral, injections in the form of compositions needs tumour to control
The mammal (including people) for the treatment of.
The composition includes the compound or its pharmaceutically acceptable salt and pharmaceutically of the Formula V structure of therapeutically effective amount
Acceptable carrier.
The carrier refers to the carrier of pharmaceutical field routine, such as：Diluent, excipient such as water etc.；Adhesive is such as fine
The plain derivative of dimension, gelatin, polyvinylpyrrolidone etc.；Filler such as starch etc.；Burst apart agent such as calcium carbonate, sodium bicarbonate；In addition,
Other adjuvants such as flavouring agent and sweetener can also be added in the composition.
The composition of the present invention can be prepared into conventional solid pharmaceutical preparation, such as tablet, capsule, for taking orally；It can also
The dosage forms such as injection are prepared into for injecting.
It is prepared by the various dosage forms method that pharmaceutical field routine may be used of the composition of the present invention, wherein it is active at
The content of the compound of fraction V structure is 0.1%~99.5% (weight ratio) of composition weight.
The compound of Formula V structure of the present invention clinically can be by oral or injection system to mammal
(including people) is administered, wherein especially best with oral way.Dosage is daily 0.0001mg/kg~200mg/kg bodies
Weight.For optimal dose depending on individual, dosage is smaller when usually starting, and is then gradually increased dosage.
The invention has the advantages that by many experiments and screening active ingredients, obtain a collection of structure novel contains hydroxamic acid
The aminopyridine analog derivative of segment, while acting on two target spots of c-Met and HDAC, the compound and its pharmaceutical formulation pair
In disease caused by therapeutic gene abnormal expression, such as：Tumour, disease of immune system, hereditary disease have fine curative effect.
Therefore, the compound of Formula V structure of the present invention and its salt can be used for preparing antitumor drug, and the tumour is
Solid tumor and blood tumor, such as liver cancer, lung cancer, breast cancer, cancer of the esophagus, gastric cancer, nasopharyngeal carcinoma, oophoroma, carcinoma of urinary bladder, the carcinoma of the rectum, skin
Skin cancer and lymthoma.
It is highly preferred that the tumour is selected from liver cancer, lung cancer, the carcinoma of the rectum, lymthoma.
The aminopyridine analog derivative of a kind of segment containing hydroxamic acid provided by the present invention, it is preferable that table is crossed to c-Met
The tumour cell Non-small cell lung carcinoma cell (A549, H1993 cell strain) reached, the white blood of T lymphocytes that HDAC is overexpressed
Sick cell (Hut78 cell strains) and human colon cancer cell (HCT116 cell strains) have apparent Inhibit proliferaton activity, for design gram
The novel c-Met/HDAC inhibitor for taking single target spot drug resistance provides possibility.
In conclusion there is smaller toxic side effect, more when compound of the present invention is applied as antitumor drug
It is easy to use as antitumor drug, is equivalent to the prior art, the present invention has the progress of novelty, creativeness and science.
Specific implementation mode
With reference to embodiment, the present invention is described in further detail, but the embodiment invented is without being limited thereto, this
It invents claimed technical scope and is subject to claims.
Embodiment 1
7- (4- (4- (6 amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) 3- yls) pyrazol-1-yl) piperazine
The synthesis of pyridine -1- base-N- hydroxyls heptamides (V-1) and its hydrochloride
The bromo- 3- of 5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) -2-aminopyridine (0.5g, 1.3mmol), 1- (4- piperazines
Pyridine -1- (7- cognac oil) -4- pyrazoles pinacol boron esters (0.68g, 1.5mmol), KOH (0.58g, 10.4mmol), hydrochloric acid hydroxyl
Amine (0.36g, 5.3mmol) is raw material, and leading to method Scheme 1 according to V class compound synthesis synthesizes V-1, obtains target compound
0.35g, yield 45%.
ESI-MS[M+H]+:m/z 593.22
1H NMR(400MHz,DMSO-d6)δppm:δ7.78(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)
Compound V-1 (0.20g, 0.3mmol) is dissolved in isopropanol, concentrated hydrochloric acid is added dropwise, white solid is precipitated, through filtering
Target compound hydrochloride 0.17g, yield 90% is made.
Embodiment 2
6- (4- (4- (6 amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) 3- yls) pyrazol-1-yl) piperazine
The synthesis of pyridine -1- base-N- hydroxyl hexanamides (V-2)
The bromo- 3- of 5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) -2-aminopyridine (0.5g, 1.3mmol), 1- (4- piperazines
Pyridine -1- (6- ethyl hexanoates) -4- pyrazoles pinacol boron esters (0.65g, 1.5mmol), KOH (0.58g, 10.4mmol), hydrochloric acid hydroxyl
Amine (0.36g, 5.3mmol) is raw material, and leading to method Scheme 1 according to V class compound synthesis synthesizes V-2, obtains target compound
0.39g, yield 52%.
ESI-MS[M+H]+:m/z 579.21
1H NMR(400MHz,DMSO-d6)δppm:δ10.49(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).
Embodiment 3
5- (4- (4- (6 amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) 3- yls) pyrazol-1-yl) piperazine
The synthesis of pyridine -1- base-N- hydroxyvaleramides (V-3)
The bromo- 3- of 5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) -2-aminopyridine (0.5g, 1.3mmol), 1- (4- piperazines
Pyridine -1- (5- ethyl valerates) -4- pyrazoles pinacol boron esters (0.64g, 1.5mmol), KOH (0.58g, 10.4mmol), hydrochloric acid hydroxyl
Amine (0.36g, 5.3mmol) is raw material, and leading to method Scheme 1 according to V class compound synthesis synthesizes V-3, obtains target compound
0.37g, yield 51%.
ESI-MS[M+H]+:m/z 565.20
1H NMR(400MHz,DMSO-d6)δppm:δ10.50(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).
Embodiment 4
4- (4- (4- (6 amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) 3- yls) pyrazol-1-yl) piperazine
The synthesis of pyridine -1- base-N- hydroxypropanamides (V-4)
The bromo- 3- of 5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) -2-aminopyridine (0.5g, 1.3mmol), 1- (4- piperazines
Pyridine -1- (ethyl 3--propanoate) -4- pyrazoles pinacol boron esters (0.59g, 1.5mmol), KOH (0.58g, 10.4mmol), hydrochloric acid hydroxyl
Amine (0.36g, 5.3mmol) is raw material, and leading to method Scheme 1 according to V class compound synthesis synthesizes V-4, obtains target compound
0.31g, yield 45%.
ESI-MS[M+H]+:m/z 537.16
1H NMR(400MHz,DMSO-d6)δppm: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).
Embodiment 5
2- (4- (4- (6 amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) 3- yls) pyrazol-1-yl) piperazine
The synthesis of pyridine -1- base-N- hydroxyl acetamides (V-5)
The bromo- 3- of 5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) -2-aminopyridine (0.5g, 1.3mmol), 1- (4- piperazines
Pyridine -1- (2- ethyl acetate) -4- pyrazoles pinacol boron esters (0.56g, 1.5mmol), KOH (0.58g, 10.4mmol), hydrochloric acid hydroxyl
Amine (0.36g, 5.3mmol) is raw material, and leading to method Scheme 1 according to V class compound synthesis synthesizes V-5, obtains target compound
0.36g, yield 53%.
ESI-MS[M+H]+:m/z 523.15
1H NMR(400MHz,DMSO-d6)δppm:δ10.49(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).
Embodiment 6
4- (4- (6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) 3- yls) pyrazol-1-yl) piperidines -
The synthesis of 1- base-N- hydroxyformamides (V-6)
The bromo- 3- of 5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) -2-aminopyridine (0.5g, 1.3mmol), 1- (4- piperazines
Pyridine -1- (1- Ethyl formates) -4- pyrazoles pinacol boron esters (0.54g, 1.5mmol), KOH (0.58g, 10.4mmol), hydrochloric acid hydroxyl
Amine (0.36g, 5.3mmol) is raw material, and leading to method Scheme 1 according to V class compound synthesis synthesizes V-6, obtains target compound
0.31g, yield 47%.
ESI-MS[M+H]+:m/z 509.15
1H NMR(400MHz,DMSO-d6)δppm: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)
Embodiment 7
7- (4 (6- amino -5 (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) -3- bases)-N- hydroxyl heptamides (V-
And its synthesis of hydrochloride 7)
The bromo- 3- of 5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) -2-aminopyridine (0.5g, 1.3mmol), 1- (7- heptan
Acetoacetic ester) -4- pyrazoles pinacol boron esters (0.53g, 1.5mmol), KOH (0.58g, 10.4mmol), hydroxylamine hydrochloride (0.36g,
It is 5.3mmol) raw material, leading to method Scheme 1 according to V class compound synthesis synthesizes V-7, obtains target compound 0.37g, yield
56%.
ESI-MS[M+H]+:m/z 510.15
1H NMR(400MHz,DMSO-d6)δppm:δ10.43(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).
Compound V-7 (0.51g, 1mmol) is dissolved in isopropanol, concentrated hydrochloric acid is added dropwise, white solid is precipitated, is made through filtering
Obtain target compound hydrochloride 0.49g, yield 90%.
Embodiment 8
6- (4 (6- amino -5 (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) -3- bases)-N- hydroxyl hexanamides (V-
And its synthesis of sulfate 8)
The bromo- 3- of 5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) -2-aminopyridine (0.5g, 1.3mmol), 1- (6- oneself
Acetoacetic ester) -4- pyrazoles pinacol boron esters (0.50g, 1.5mmol), KOH (0.58g, 10.4mmol), hydroxylamine hydrochloride (0.36g,
It is 5.3mmol) raw material, leading to method Scheme 1 according to V class compound synthesis synthesizes V-8, obtains target compound 0.33g, yield
51%.
ESI-MS[M+H]+:m/z 496.13
1H NMR(400MHz,DMSO-d6)δppm:δ 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)
Compound V-8 (0.30g, 0.6mmol) is dissolved in isopropanol, dilute sulfuric acid is added dropwise, white solid is precipitated, through filtering
Target compound sulfate 0.32g, yield 90% is made.
Embodiment 9
5- (4 (6- amino -5 (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) -3- bases)-N- hydroxyvaleramides (V-
And its synthesis of tartrate 9)
The bromo- 3- of 5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) -2-aminopyridine (0.5g, 1.3mmol), 1- (5- penta
Acetoacetic ester) -4- pyrazoles pinacol boron esters (0.48g, 1.5mmol), KOH (0.58g, 10.4mmol), hydroxylamine hydrochloride (0.36g,
It is 5.3mmol) raw material, leading to method Scheme 1 according to V class compound synthesis synthesizes V-9, obtains target compound 0.33g, yield
53%.
ESI-MS[M+H]+:m/z 482.15
1H NMR(400MHz,DMSO-d6)δppm:δ10.49(s,1H),δ8.03(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).
Compound V-9 (0.30g, 0.6mmol) is dissolved in isopropanol, tartaric acid is added, white solid is precipitated, through filtering
Target compound tartrate 0.32g, yield 85% is made.
Embodiment 10
4- (4 (6- amino -5 (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) -3- bases)-N- hydroxybutyrate amides (V-
And its synthesis of malate 10)
The bromo- 3- of 5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) -2-aminopyridine (0.5g, 1.3mmol), 1- (4- fourths
Acetoacetic ester) -4- pyrazoles pinacol boron esters (0.46g, 1.5mmol), KOH (0.58g, 10.4mmol), hydroxylamine hydrochloride (0.36g,
It is 5.3mmol) raw material, leading to method Scheme 1 according to V class compound synthesis synthesizes V-10, obtains target compound 0.33g, yield
54%.
ESI-MS[M+H]+:m/z 468.10
1H NMR(400MHz,DMSO-d6)δppm:δ10.49(s,1H),δ8.03(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)
Compound V-10 (0.30g, 0.6mmol) is dissolved in isopropanol, malic acid is added, white solid is precipitated, is passed through
Target compound malate 0.31g, yield 86% is made in filter.
Embodiment 11
The conjunction of 7- (4- (6- amino -5 (1- (3- fluorophenyls) ethyoxyl) pyridine) -3- bases)-N- hydroxyls heptamide (V-11)
At
The bromo- 3- of 5- (1- phenyl ethoxies) -2-aminopyridine (0.5g, 1.7mmol), 1- (7- cognac oil) -4- pyrazoles
Pinacol boron ester (0.70g, 2.0mmol), KOH (0.76g, 13.6mmol), hydroxylamine hydrochloride (0.47g, 6.8mmol) are raw material,
Lead to method Scheme 1 according to V class compound synthesis and synthesize V-11, obtains target compound 0.35g, yield 49%.
ESI-MS[M+H]+:m/z 424.30
1H NMR(400MHz,DMSO-d6)δppm:δ10.43(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)
Embodiment 12
7- (4- (6- amino -5 (1- (the chloro- 3- fluorophenyls of 2-) ethyoxyl) pyridine) -3- bases)-N- hydroxyls heptamide (V-12)
Synthesis
The bromo- 3- of 5- (1- (the chloro- 3- fluorophenyls of 2-) ethyoxyl) -2-aminopyridine (0.5g, 1.4mmol), 1- (7- enanthic acid second
Ester) -4- pyrazoles pinacol boron esters (0.59g, 1.7mmol), KOH (0.63g, 11.2mmol), hydroxylamine hydrochloride (0.37g,
It is 5.6mmol) raw material, leading to method Scheme 1 according to V class compound synthesis synthesizes V-12, obtains target compound 0.34g, yield
51%.
ESI-MS[M+H]+:m/z 476.22
1H NMR(400MHz,DMSO-d6)δppm:δ10.43(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)
Embodiment 13
7- (4- (6- amino -5 (1- (the chloro- 3- fluorophenyls of 6-) ethyoxyl) pyridine) -3- bases)-N- hydroxyls heptamide (V-13)
And its synthesis of acetate
The bromo- 3- of 5- (1- (the chloro- 3- fluorophenyls of 6-) ethyoxyl) -2-aminopyridine (0.5g, 1.4mmol), 1- (7- enanthic acid second
Ester) -4- pyrazoles pinacol boron esters (0.59g, 1.7mmol), KOH (0.63g, 11.2mmol), hydroxylamine hydrochloride (0.37g,
It is 5.6mmol) raw material, leading to method Scheme 1 according to V class compound synthesis synthesizes V-13, obtains target compound 0.34g, yield
51%.
ESI-MS[M+H]+:m/z 476.22
1H NMR(400MHz,DMSO-d6)δppm:δ10.43(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)
Compound V-13 (0.30g, 0.6mmol) is dissolved in isopropanol, glacial acetic acid is added dropwise, white solid is precipitated, is passed through
Target compound acetate 0.26g, yield 80% is made in filter.
Embodiment 14
N- hydroxyls -7- (8- chloro-quinazoline -4- amino) heptamides (V-14) and its synthesis
The bromo- 3- of 5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) -2-aminopyridine (0.5g, 1.3mmol), 7- amino
Cognac oil (0.26g, 1.5mmol), KOH (0.58g, 10.4mmol), hydroxylamine hydrochloride (0.36g, 5.3mmol) are raw material, are pressed
Lead to method Scheme 2 according to V class compound synthesis and synthesize V-14, obtains target compound 0.18g, yield 31%.
ESI-MS[M+H]+:m/z 459.20
1H NMR(400MHz,DMSO-d6)δppm:δ10.43(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)
Compound V-14 (0.30g, 0.7mmol) is dissolved in isopropanol, concentrated hydrochloric acid is added dropwise, white solid is precipitated, is passed through
Target compound hydrochloride 0.27g, yield 85% is made in filter.
Embodiment 15
The synthesis of V-15N- hydroxyls -7- (5- Fluquinconazole quinoline -4- amino) heptamide
The bromo- 3- of 5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) -2-aminopyridine (0.5g, 1.3mmol), 7- amino
Cognac oil (0.24g, 1.5mmol), KOH (0.58g, 10.4mmol), hydroxylamine hydrochloride (0.36g, 5.3mmol) are raw material, are pressed
Lead to method Scheme 2 according to V class compound synthesis and synthesize V-15, obtains target compound 0.16g, yield 28%.
ESI-MS[M+H]+:m/z 445.13
1H NMR(400MHz,DMSO-d6)δppm:δ10.43(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)
Embodiment 16
The synthesis of V-16N- hydroxyls -7- (2- chloro-quinazoline -4- amino) heptamide
The bromo- 3- of 5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) -2-aminopyridine (0.5g, 1.3mmol), 7- amino
Cognac oil (0.22g, 1.5mmol), KOH (0.58g, 10.4mmol), hydroxylamine hydrochloride (0.36g, 5.3mmol) are raw material, are pressed
Lead to method Scheme 2 according to V class compound synthesis and synthesize V-16, obtains target compound 0.16g, yield 28%.
ESI-MS[M+H]+:m/z 431.12
1H NMR(400MHz,DMSO-d6)δppm:δ10.43(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)
Embodiment 17
The inhibitory activity of compound on tumor kinases is tested：
Select the 08-151 kits test compound that Carna produces to c-Met suppression enzymes IC50Value, test operation is with reference to examination
Agent box specification carries out.
Select the K340-100 kits test compound that Biovision produces to HDAC suppression enzymes IC50Test, experimental implementation
It is carried out with reference to kit specification.
Experimental result is shown in Table 2.
External inhibitory activity experimental result of 2 the compounds of this invention of table to c-Met and HDAC
In table 2, what NT was referred to is not detect activity.
From upper table 2 as it can be seen that the compounds of this invention shows and positive control drug PF-2341066 comparable inhibition work c-Met
Property, the c-Met inhibitory activity of part of compounds such as V-5, V-6 are better than positive control drug；In addition, the compounds of this invention is to HDAC
With stronger inhibitory activity, part of compounds such as V-7 ﹑ V-9, V-10 ﹑ V-11 ﹑ V-12 ﹑ V-13 HDAC inhibitory activity be better than
Positive control drug SAHA.
Embodiment 18
This example is embodiment 1, embodiment 3, embodiment 4, embodiment 5, embodiment 7, the compound prepared by embodiment 9
Extracorporeal anti-tumor cell proliferation test.Wherein, selected tumour sensitive cells is HCT116 (human colon cancer cell), A549
(human lung adenocarcinoma cell), Hut78 (T lymphocytic leukemia cells), H1993 (human lung cancer non-small cell)；Select SAHA and PF-
02341066 is control drug.(unit is concrete outcome such as table 3：μM)：
External inhibitory activity of 3 part of compounds of the present invention of table to tumour cell
From upper table 3 as it can be seen that the part of compounds of the present invention tested has preferable anti-tumour cell proliferative activity,
In, V-1, V-5 are suitable with positive control SAHA and PF-2341066 to the inhibitory activity of HCT116；V-7, V-9 are to HCT116's
Inhibitory activity is better than PF-2341066；V-7, V-9 are suitable with positive control SAHA to the inhibitory activity of Hut78；V-5, V-9 couple
The inhibitory activity of A549 is suitable with positive control PF-2341066；V-7 is better than PF-2341066 to the inhibitory activity of A549；V-3、
V-4, V-5, V-7, V-9 are suitable with positive control PF-2341066 to the inhibitory activity of H1993；Inhibitory activity of the V-1 to H1993
Better than PF2341066.Thus illustrate that the hydroxamic acid compound of the invention containing aminopyridines is equal for kinds of tumor cells
With good inhibitory activity.
Embodiment 19
The external inhibitory activity of normal cell of compound measures：
This example be embodiment 7 prepared by compound to normal cell MRC-5 (human embryonic lung cell), (people liver is thin by HL-7702
Born of the same parents), the external inhibitory activity test of HEK-293 (embryonic kidney cells).Concrete outcome is as follows：
External inhibitory activity (the IC of 4 the compounds of this invention of table and control drug to normal cell50,μM)
As seen from Table 4, the compounds of this invention V-7 is relative to control drug Cabozantinib, the inhibition to normal cell
Activity is weaker, has lower toxic side effect, and indicating has lower toxic side effect when it is used as antitumor drug, be easy to
It is used as tumour medicine.
Embodiment 20
Acute toxicity test：Using Zhang Juntian chief editors'《Modern pharmacology experimental method》(Beijing Medical University, China's consonance
Combined publication society of medical university, 1998 publish) report method, preliminary screening, through with Bliss methods statistics (《Practical drug system
Agent technology》, People's Health Publisher publishes for 1999), the LD that compound V-5, V-7, V-9, V-13 mouse single gavages50Point
It Wei not 1.2g/kg, 1.6g/kg, 1.3g/kg and 1.9g/kg.
Embodiment 21
Preparation method：Any compounds of active constituent V-1 to V-17 are mixed with sucrose, cornstarch, adds water to moisten, stirs
It mixes uniformly, dry, pulverize sieving, calcium stearate is added, be uniformly mixed, tabletting.Every weight 290mg, active component content are
100mg。
Embodiment 22
Injection：Any compound 15mg selected from V-1 to V-17
Water for injection 80mg
Preparation method：Any compounds of active constituent V-1 to V-17 are dissolved in water for injection, are uniformly mixed, are filtered, it will
The solution obtained is aseptically sub-packed in ampoule bottle, every bottle of 95mg, and active component content is 15mg/ bottles.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, it is other it is any without departing from the spirit and principles of the present invention made by changes, modifications, substitutions, combinations, simplifications,
Equivalent substitute mode is should be, is included within the scope of the present invention.
Claims (14)
1. a kind of aminopyridine analog derivative of segment containing hydroxamic acid and its pharmaceutically acceptable salt, which is formula
Shown in V：
In Formula V,
R1、R2And R3It is independent to be selected from hydrogen or halogen；
A is pyrazolylOr amino (- NH-)；
X is piperidylN in the piperidyl X is connected with carbochain；Or X is methylene (- CH2-)；
N is expressed as 0~6.
2. derivative shown in Formula V according to claim 1, in Formula V：
R1、R2And R3It is independent to be selected from hydrogen or halogen；
A is pyrazolylX is piperidylN in the piperidyl X is connected with carbochain；
N is expressed as 0~6.
3. derivative shown in Formula V according to claim 1, in Formula V：
R1、R2And R3It is independent to be selected from hydrogen or halogen；
A is pyrazolylX is methylene (- CH2-)；
N is expressed as 0~6.
4. derivative shown in Formula V according to claim 1, in Formula V：
R1、R2And R3It is independent to be selected from hydrogen or halogen；
A is amino (- NH-), and X is methylene (- CH2-)；
N is expressed as 0~6.
5. derivative shown in Formula V according to claim 1, in Formula V：
R1、R2And R3It is independent to be selected from hydrogen or halogen；
A is amino (- NH-), and X is methylene (- CH2-)；N is 4~6.
6. derivative and its salt shown in Formula V according to claim 1, Formula V is selected from lower structure：
V-1 7- (4- (4- (6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridin-3-yl) -1H- pyrazoles -1-
Base) piperidin-1-yl)-N- hydroxyl heptamides,
V-2 6- (4- (4- (6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridin-3-yl) -1H- pyrazoles -1-
Base) piperidin-1-yl)-N- hydroxyl hexanamides,
V-3 5- (4- (4- (6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridin-3-yl) -1H- pyrazoles -1-
Base) piperidin-1-yl)-N- hydroxyvaleramides,
V-4 3- (4- (4- (6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridin-3-yl) -1H- pyrazoles -1-
Base) piperidin-1-yl)-N- hydroxypropanamides,
V-5 2- (4- (4- (6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridin-3-yl) -1H- pyrazoles -1-
Base) piperidin-1-yl)-N- hydroxyl acetamides,
V-6 4- (4- (6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridin-3-yl) -1H- pyrazol-1-yls)
N- hydroxy piperidine -1- formamides,
V-7 7- (4- (- 3 base of 6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) -1H- pyrazol-1-yls) -
N- hydroxyl heptamides,
V-8 6- (4- (- 3 base of 6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) -1H- pyrazol-1-yls) -
N- hydroxyl hexanamides,
V-9 5- (4- (- 3 base of 6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) -1H- pyrazol-1-yls) -
N- hydroxyvaleramides,
V-10 4- (4- (- 3 base of 6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyoxyl) pyridine) -1H- pyrazol-1-yls) -
N- hydroxybutyrate amides,
V-11 7- (4- (- 3 base of 6- amino -5- (1- phenyl ethoxies) pyridine) -1H- pyrazol-1-yls)-N- hydroxyl heptamides,
V-12 7- (4- (- 3 base of 6- amino -5- (1- (the chloro- 3- fluorophenyls of 2-) ethyoxyl) pyridine) -1H- pyrazol-1-yls)-N- hydroxyls
Base heptamide,
V-13 7- (4- (- 3 base of 6- amino -5- (1- (bis- chloro- 3- fluorophenyls of 6-) ethyoxyl) pyridine) -1H- pyrazol-1-yls)-N-
Hydroxyl heptamide,
V-14 7- ((6- amino -5- (1- (2,6- bis- chloro- 3- fluorophenyls) ethyoxyl) pyridin-3-yl) amino)-N- hydroxyl oenanthyl
Amine,
V-15 6- ((6- amino -5- (1- (2,6- bis- chloro- 3- fluorophenyls) ethyoxyl) pyridin-3-yl) amino)-N- hydroxyl hexanoyls
Amine,
V-16 5- ((6- amino -5- (1- (2,6- bis- chloro- 3- fluorophenyls) ethyoxyl) pyridin-3-yl) amino)-N- hydroxypentanoyls
Amine.
7. derivative shown in the Formula V according to claim 1-5 any one, pharmaceutically acceptable salt is selected from hydrochloric acid
Salt, hydrobromate, sulfate, acetate, lactate, tartrate, tannate, citrate, trifluoroacetate, malic acid
Salt, maleate, succinate, p-methyl benzenesulfonic acid or mesylate.
8. derivative shown in Formula V according to claim 6, pharmaceutically acceptable salt be selected from hydrochloride, acetate,
Sulfate, tartrate or malate.
9. the preparation method of derivative shown in the Formula V according to claim 1-5 any one, this method include following road
Step shown in line：
It is starting material with aminopyridines 2, compound 4a is made by Suzuki couplings with boron ester 3a, then in alkali
Compound V is made with azanol reaction under the conditions of property；
In above-mentioned reaction equation, the A of compound 3a is pyrazolylWherein, in pyrazolyl A N atoms connect X, X, n with
The selection range of corresponding group is consistent in compound V structure formula；The R in compound 21、R2、R3With compound V structure
The selection range of corresponding group is consistent in formula.
10. the preparation method of derivative, this method include following shown in the Formula V according to claim 1-5 any one
Step shown in route：
It is starting material with aminopyridines 2, passes through Buchwald-Hartwig with carbamate compound 3b
Compound 4b is made in coupling, and compound V is then made with azanol reaction under alkaline condition；
In above-mentioned reaction equation, the A of compound 3b is amino (- NH2), the selection model of X, n and corresponding group in compound V structure formula
It encloses and is consistent；The R of compound 21、R2、R3It is consistent to the selection range of corresponding group in compound V structure formula.
11. composition, the composition can comprising derivative and pharmacy shown in the Formula V described in claim 1-5 any one
Receive auxiliary material.
12. purposes of the derivative in preparing tumor shown in the Formula V described in claim 1-5 any one.
13. purposes according to claim 11, wherein the tumour is selected from liver cancer, lung cancer, breast cancer, cancer of the esophagus, stomach
Cancer, nasopharyngeal carcinoma, oophoroma, carcinoma of urinary bladder, the carcinoma of the rectum, cutaneum carcinoma and lymthoma.
14. purposes according to claim 12, wherein the tumour is selected from liver cancer, lung cancer, the carcinoma of the rectum, lymthoma.
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| CN110128411A (en) * | 2019-05-22 | 2019-08-16 | 北京凯恩梅格医药科技有限公司 | A kind of bis- target spot inhibitor of c-Met/HDAC and its synthetic method and application |
| CN111187222A (en) * | 2020-01-16 | 2020-05-22 | 山东大学 | Substituted pyrimidine derivative and preparation method and application thereof |
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| CN111187222B (en) * | 2020-01-16 | 2021-09-24 | 山东大学 | Substituted pyrimidine derivative and preparation method and application thereof |
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