CN106565599A - 2-aminomethylpyridylnicotinamides and preparation method and application thereof - Google Patents

2-aminomethylpyridylnicotinamides and preparation method and application thereof Download PDF

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CN106565599A
CN106565599A CN201610463182.5A CN201610463182A CN106565599A CN 106565599 A CN106565599 A CN 106565599A CN 201610463182 A CN201610463182 A CN 201610463182A CN 106565599 A CN106565599 A CN 106565599A
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pyridine
amino
methylene
nicotiamide
unsubstituted
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黄文龙
钱海
潘渺博
邱倩倩
强浩
石炜
崔建
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China Pharmaceutical University
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a compound as shown in the general formula (I) and salt thereof. The compound has the effect of high reversal of tumor multidrug resistance (MDR). The activity is far higher than that of verapamil, and the cytotoxicity is small. The invention further relates to a preparation method of the compound and a pharmaceutic preparation containing the compound. (Please see the specification for the formula)

Description

2- aminomethyl-pyridine base nicotinamide compounds and its preparation method and application
Technical field
The invention belongs to medicinal chemistry art, and in particular to a class P- glycoprotein inhibitors, its preparation method and such Application of the compound in multidrug-resistance reversal agent.
Background technology
Tumor is one of principal disease of threat human health and life.Chemotherapy is sent out as the main method for the treatment of tumor Wave irreplaceable effect.However, due to the appearance of tumor cell multidrug resistance (Multidrug resistance, MDR), So that the curative effect of chemicalses is substantially reduced.So-called MDR refers to tumor patient after chemotherapeutic drug therapy is received, tumor cell pair A kind of chemotherapeutics produce drug resistance, while to other not in contact with crossing, or the structurally and functionally even a completely different chemotherapy of mechanism Medicine also produces cross resistance, so as to reduction that clinical efficacy occur or invalid phenomenon.Research shows that 90% tumor is suffered from Person's chemotherapy of tumors is unsuccessfully caused by the generation by tumor multi-medicine drug-resistant.Therefore, the medicine of reversion MDR is found to suppress multiple medicines resistance to The generation of medicine has become urgent problem in oncotherapy.
The generation of tumor multi-medicine drug-resistant is related to number of mechanisms, P- glycoproteins (P- wherein in tumor cell membrane Glycoprotein, P-gp) overexpression be considered as multidrug resistance produce main reason.The P-gp of overexpression is sharp With ATP hydrolyze release energy will pump out into the medicine in tumor cell it is extracellular, so as to cause antitumor in tumor cell The concentration of medicine is less than valid density, causes the generation of multidrug resistance.Find so far from first MDR reversal agents verapamil In more than 30 years, the research of P-gp inhibitor becomes the Main way of MDR reversal agents research.The research of P-gp inhibitor experienced three In generation, with verapamil etc. as representative, this generation inhibitor has serious Cardiovascular Toxicity to the first generation, it is difficult to for clinic；The It is secondary that with verapamil derivant etc. as representative, the inhibitor activity of this generation has significantly enhancing, and toxic and side effects decrease, But most compounds have obvious inhibitory action to P450 enzymes, which has limited their clinical practice.Third generation inhibitor is not only P-gp inhibitory activity is improve, and overcomes the side effect that second filial generation inhibitor disturbs P450 enzymes.Although third generation P-gp presses down The research of preparation once brought hope for reverse multiple drug resistance of tumor, but did not had MDR reversal agents list marketing yet so far.
In recent years, researcher finds that erlotinib, Ah handkerchief is a series of of representative for Buddhist nun and Mo Tesaini with gefitinib Tyrosine kinase inhibitor has the activity of reverse multiple drug resistance of tumor, and this has also researched and proposed one newly for MDR reversal agents Direction.
The present invention replaces the apokoinou construction 2- aminomethyl-pyridine base nicotiamide of Buddhist nun and Mo Tesaini as reversion MDR based on Ah handkerchief The common backbone of activity, replaces with reference to distinct fragrance amine, completes design and the synthetic work of the compound with novel structure, Obtain a series of with higher active compound.The compound that the present invention is obtained compared with verapamil, Ah handkerchief are for Buddhist nun not only With stronger MDR Reversal activities, and almost no cytotoxicity.Therefore the logical formula (I) compound and its pharmaceutical salts have The effect that potential prevention and treatment tumor multi-medicine drug-resistant occurs.
The content of the invention
Present invention is primarily targeted at providing a class mother nucleus structure for the new of 2- aminomethyl-pyridine base nicotinoyl amine structures Multidrug resistance reversing agent, its cytotoxicity is less, and Reversal activity is higher, for improving the curative effect of antitumor drug.
The purpose of the present invention is also in one class 2- aminomethyl-pyridine base nicotinoyl amine structure class tumor multi-drug resistance reversal of offer The preparation method of agent.
Detailed description is as follows：
The present invention has synthesized the compound described in a series of general structures (I) or its pharmaceutically useful salt：
Wherein：
A rings are selected from：Substituted or unsubstituted phenyl, naphthyl, aromatic condensed ring, fragrant heterocyclic radical, the substituent group is taken from：Halogen Element, haloalkyl, replacement or unsubstituted C1-C5Alkyl, replacement or unsubstituted C1-C5Alkoxyl, replacement or unsubstituted C1-C5Alkyl Alkoxyl；Aromatic rings include an aromatic rings and a cycloaliphatic ring thickening, the such as ring of saturation or fractional saturation, such as tetrahydric naphthalene ring；
N represents integer 0～2；
R1It is H, halogen, haloalkyl, halogenated alkoxy, replacement or unsubstituted C1-C5Alkyl, replacement or unsubstituted C1-C5 Alkoxyl, replacement or unsubstituted aromatic radical, aromatic heterocyclic；
R2It is H, replaces or unsubstituted C1-C5Alkyl, replacement or unsubstituted aromatic radical, aromatic heterocyclic.
The compound of preferred formula (I) is：
Wherein：
A rings are selected from：It is unsubstituted or be up to three replacement phenyl ring, naphthalene, pyrrolidine, ketopyrrolidine, piperidines, piperidones, Piperazine, morpholine, imidazolidine, pyrazolidine, pyrroles, indole, pyrazoles, indole azoles, triazole, benzotriazole, imidazoles, benzimidazole, thiophene Azoles, benzothiazole, furan, benzofuran, oxazole, benzoxazoles, isoxazole, tetrazolium, pyridine, pyrimidine, three pyridines, quinoline, isoquinoline Quinoline, quinazoline, indoline, dihydroindolone, benzo tetrahydrofuran, tetrahydroquinoline, tetrahydroisoquinoline, fluorenes；
N represents integer 0～2；
R1It is selected from：H、F、Cl、-OCF3, replace or unsubstituted C1-C5Alkyl, replacement or unsubstituted C1-C5Alkoxyl, replacement Or unsubstituted aromatic radical, aromatic heterocyclic；
R2It is H, replaces or unsubstituted C1-C5Alkyl, replacement or unsubstituted aromatic radical, aromatic heterocyclic.
The preferred present invention has the compound or pharmaceutically acceptable salt thereof of logical formula (I), and the compound is selected from：
N- (3- (methoxyl group) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide (I-1)；
2- ((pyridine -4- methylene) amino)-N- (3,4,5- (trimethoxy) phenyl) nicotiamide mesylate (I-2)；
2- ((pyridine -4- methylene) amino)-N- (4- (trifluoromethoxy) phenyl) nicotiamide (I-3)；
N- (4- (tert-butyl group) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide mesylate (I-4)；
N- ([1,1 '-xenyl] -4- bases) -2- ((pyridine -4- methylene) amino) nicotiamide (I-5)；
N- (thiadiazoles -2- bases of 5- (3- (methoxyl group) phenyl) -1,3,4-) -2- ((pyridine -4- methylene) amino) nicotinoyl Amine (I-6)；
N- (4- (piperidin-1-yl) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide (I-7)；
N- (4- morpholinyl phenyls) -2- ((pyridine -4- methylene) amino) nicotiamide (I-8)；
N- (4- (4- methylpiperazine-1-yls) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide (I-9)；
N- (naphthalene -1- bases) -2- ((pyridine -4- methylene) amino) nicotiamide (I-10)；
2- ((pyridine -4- methylene) amino)-N- (1,2,3,4- naphthane -1- bases) nicotiamide (I-11)；
N- (1H- benzimidazolyl-2 radicals-yl) -2- ((pyridine -4- methylene) amino) nicotiamide (I-12)；
N- (pyridine -4- methylene) -2- ((pyridine -4- methylene) amino) nicotiamide mesylate (I-13)；
N- (3,4- (dimethoxy) phenethyl) -2- ((pyridine -4- methylene) amino) nicotiamide mesylate (I-14)；
2- ((pyridine -4- methylene) amino)-N- (2- (thiophene -2- bases) ethyl) nicotiamide (I-15)；
N, N- dibenzyl -2- ((pyridine -4- methylene) amino) nicotiamide (I-16)；
N- (4- (morpholinyl ethyl) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide (I-17)；
N- (4- (2- (4- methylpiperazine-1-yls) ethyl) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide (I- 18)；
N- (4- (2- (piperidin-1-yl) ethyl) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide (I-19)；
N- (4- (2- (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-yl) ethyl) phenyl) -2- ((pyridine -4- Methylene) amino) nicotiamide (I-20)；
N- (3,4- dimethoxy-benzyl)-N- methyl -2- ((pyridine -4- methylene) amino) nicotiamide (I-21)；
N- (4- (2- ((3,4- dimethoxy-benzyl) (methyl) amino) ethylphenyl) -2- ((pyridine -4- methylene) ammonia Base) nicotiamide (I-22)；
N, N- bis- (3,4- dimethoxy-benzyl) -2- ((pyridine -4- methylene) amino) nicotiamide (I-23)；
N- (9H- fluorenes -2- bases) -2- ((pyridine -4- methylene) amino) nicotiamide (I-24)；
N- (2- benzoyloxy phenyls) -2- ((pyridine -4- methylene) amino) nicotiamide (I-25).
On the other hand, the invention provides a kind of compound or pharmaceutically acceptable salt thereof is being prepared for treating tumor multiple medicines The purposes of drug resistance.
Another aspect of the present invention is related to a kind of pharmaceutical composition, and it contains described in the logical formula (I) for the treatment of effective dose Compound or its pharmaceutically useful salt and its pharmaceutically useful carrier, diluent or excipient；And the pharmaceutical composition is swollen in treatment Purposes in tumor multidrug resistance.
Detailed description of the invention
Unless otherwise stated, the term in specification and claims has following implications.
“C1-C5Alkyl " is it can be mentioned that such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, tertiary fourth Base, amyl group, isopentyl, neopentyl etc..
“C1-C6Alkyl " it can be mentioned that as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, Amyl group, isopentyl, neopentyl, hexyl etc..
" heteroaromatic " it can be mentioned that such as 5-13 unit (monocyclic, bicyclic or tricyclic) heterocyclic radical, constitute heterocycle atom except Outside containing carbon atom, also 1 to 4 hetero atom of N, S, O, preferred 5-6 membered aromatic heterocycles etc. are selected from containing one or two.Specifically Ground, aromatic heterocycle include pyrrolidine, ketopyrrolidine, piperidines, piperidones, piperazine, morpholine, imidazolidine, pyrazolidine, pyrroles, indole, Pyrazoles, indole azoles, triazole, benzotriazole, imidazoles, benzimidazole, thiazole, benzothiazole, furan, benzofuran, oxazole, benzo Oxazole, isoxazole, tetrazolium, pyridine, pyrimidine, three pyridines, quinoline, isoquinolin, quinazoline, indoline, dihydroindolone, benzo four Hydrogen furan, tetrahydroquinoline, tetrahydroisoquinoline, fluorenes etc..
" pharmaceutical composition " to be represented and lead to compound or its pharmaceutically useful salt described in formula (I) containing one or more present invention, Or the mixture of its prodrug and other chemical constituents, for example pharmaceutically useful carrier of other chemical constituents and excipient.Drug regimen The purpose of thing is the absorption for promoting organism to active component, and beneficial to active component biological activity is played in vivo.
The structure of part of compounds is：
According to the present invention, pharmaceutically acceptable salt includes the addition salts formed with following acid：Hydrochloric acid, hydrobromic acid, sulphuric acid, Citric acid, methanesulfonic acid, tartaric acid, phosphoric acid, lactic acid, acetone acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, succinic acid and Similar known acceptable acid is into salt.
The preparation method of 2- aminomethyl-pyridines base nicotiamide structural compounds of the present invention, method is as follows：
With compound 2 under the catalysis of copper oxide, reaction generates 2- ((pyridine -4- methylene) amino) nicotinic acid to compound 1 I.e. compound 3, further replaces amine Jing condensation reactions to generate target compound with various fragrance.
The following is the pharmacological experiment data of part of compounds of the present invention：
1st, the cytotoxicity of compound
Amycin (Doxorubicin) is positive control.K562 (human leukemia cell), K562/A02 be (adriamycin-resistant Human leukemia cell), K562/A02 cells are formed by the induction of sensitive K562 cells contacting increasing concen-trations amycin.Two Cell strain respectively with the culture medium of RPMI 1640 that is containing 10% calf serum and adding final concentration of 1mg/L amycin 37 DEG C, 5%CO2Cultivate under conditions of saturated humidity, and drug-resistant cell strain is cultivated 14 days under conditions of without amycin before testing.Take The cell of exponential phase, with 1 × 104Individual/ml density is inoculated in 96 well culture plates, in 37 DEG C of 5%CO2Under the conditions of cultivate After 24h, the test-compound and amycin of a series of Concentraton gradient are separately added into, continue to be incubated after 48h, MTT is added per hole (5mg/ml) 4h, is further cultured for, is centrifuged, board-washing machine sucks culture fluid, add 150 μ L DMSO dissolvings, shaking table to shake 20min per hole, Then it is measured with wavelength 570nm in microplate reader, cell growth inhibiting is calculated respectively up to concentration when 50%, with IC50Value Represent.
16 compounds are determined respectively to K562 cells and the cytotoxicity of K562/A02 cells, as shown in table 1, are changed Compound is less to the cytotoxicity of two plants of cells for Buddhist nun compared with verapamil, Ah handkerchief, and majority of compounds does not have cytotoxicity (IC50100 μM of ＞).
The part of compounds of table 1 is to K562 cells and the cytotoxicity of K562/A02 cells
2nd, reverse effect of the compound to adriamycin-resistant human leukemia cell
Verapamil (Verapamil) is positive control.K562 and the cell strains of K562/A02 two are respectively with containing 10% calf Serum and the final concentration of 1mg/L amycin of addition the culture medium of RPMI 1640 is in 37 DEG C, 5%CO2Under conditions of saturated humidity Culture, and drug-resistant cell strain is cultivated 14 days under conditions of without amycin before testing.Take the logarithm the cell of trophophase, with 1 × 104Individual/ml density is inoculated in 96 well culture plates, in 37 DEG C of 5%CO2Under the conditions of cultivate 24h after, be separately added into final concentration of 1 μM Test-compound and a series of Concentraton gradient amycin, continue be incubated 48h after, per hole add MTT (5mg/ml), be further cultured for 4h, centrifugation, board-washing machine sucks culture fluid, and 150 μ L DMSO dissolvings, shaking table shaking 20min, then in microplate reader are added per hole It is measured with wavelength 570nm, cell growth inhibiting is calculated respectively up to concentration when 50%, with IC50Value represent, reversal index with IC50(ADR)/IC50(ADR+ inversion agent) is represented.
34 compounds are determined respectively under 1 μM of concentration, and drug-fast reverse of leukaemia of adriamycin-resistant is lived Property such as table 2, as a result shows, compound is respectively provided with Reversal activity, and the Reversal activity of compound significantly more than positive reference substance Verapamil (verapamil).Wherein, the reversal index of I-18 is 26.9, much stronger than the verapamil that reversal index is 1.5. Experimental result is shown in Table 2.
Table 2 adds (1 μM) of inversion agent to reduce K562/A02 to amycin IC50The effect of (μM)
Above pharmacology data shows, the logical formula (I) compound of the present invention have compared with positive control drug verapamil compared with The effect of strong reverse multiple drug resistance of tumor, and majority of compounds almost no cytotoxicity.
Present invention additionally comprises pharmaceutical preparation, said preparation comprising the logical formula (I) compound or pharmaceutically acceptable salt thereof as activating agent and Pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier refers to one or more inert, atoxic solids or liquid Implant, diluent, auxiliary agent etc., they inversely do not have an effect with reactive compound or patient.
The dosage form of the present composition can be tablet, capsule, pill, suppository, soft capsule, oral liquid, suspensoid, injection The dosage form commonly used on the pharmaceuticss such as liquid.Medicine for oral use and capsule contain traditional excipient such as implant, diluent, lubrication Agent, dispersant and binding agent.Can be prepared according to method known in the art.
The dosage of above activating agent will be different because of formula.
Usually, it has therefore proved that favourable amount, to reach results needed, formula (I) compound of administration per kg body weight 24h Total amount is for about 0.01-80mg, preferred total amount about 0.1-40mg/kg.If necessary, it is administered in the form of single dose several times.
However, if necessary, above-mentioned consumption can be deviateed, i.e., this depends on the type and body weight of experimenter to be treated, individual Type and administration time or interval of the body to the behavior of medicine, the property of disease and seriousness, preparation and administration.
By the following examples the invention will be further described.
Specific embodiment：
With reference to embodiment, the invention will be further described.It should be noted that following embodiments are only for It is bright, and it is not intended to limit the present invention.The various change that those skilled in the art's training centre of the invention is made all should be Within protection domain required by the application claim.
Embodiment 1
The preparation of 2- ((pyridine -4- methylene) amino) nicotinic acid (3)
2- chlorine apellagrins (25.3mmol), copper oxide (catalytic amount), potassium carbonate (25.3mmol) are added to the round bottom of 100ml and burn In bottle, stirring at normal temperature 20min adds 4- methylamino pyridines (50.6mmol), 110 DEG C of heating 2h.Ethyl acetate stirring is added afterwards To room temperature, sucking filtration, filter cake is first washed 2 times with ethyl acetate, and water (20ml) dissolving, 4N hydrochloric acid is adjusted to pH 5～6, stands and separates out, and takes out Filter, filter cake drying, obtains crude product, and ethanol hot beating is further purified, sucking filtration, obtains pale solid 5.16g, and yield 89% melts Point：197-199℃.
1H NMR (300MHz, DMSO-d6)δppm：8.61 (d, J=5.8Hz, 1.0H, ArH), 8.48 (s, 2H, ArH), 8.19 (dd, J=4.7,1.9Hz, 1H, ArH), 8.11 (dd, J=7.7,1.9Hz, 1H, ArH), 7.29 (d, J=4.7Hz, 2H, ArH), 6.64 (dd, J=7.7,4.8Hz, 1.0Hz ,-NH-), 4.73 (d, J=5.8Hz, 2H ,-NHCH 2 -)；13C NMR (75MHz, DMSO-d6)δ：170.78,159.02,151.33,150.46,149.05,136.60,122.79,114.11, 106.62,43.63；ESI-MS m/z：230.2[M+H]+；Anal.calcd.For C12H11N3O2：C, 62.87；H, 4.84；N, 18.33；Found：C, 62.56；H, 4.94；N, 18.52.
Embodiment 2
The preparation of N- (3- (methoxyl group) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide (I-1)
Compound 3 (6mmol), 3- aminoanisoles (5mmol), EDCI (7.2mmol), HOBT (7.2mmol) is dissolved in In DMF, reaction 16h is stirred at room temperature, adds 50ml water, ethyl acetate (30ml × 3) extraction to merge organic in backward reactant liquor Phase, saturated sodium carbonate solution (20ml × 2) saturated aqueous common salt (20ml × 2) washing, anhydrous sodium sulfate drying is filtered, and filtrate subtracts Press and solvent is evaporated off, residue Jing column chromatographies (methylene chloride/methanol, 50: 1, v/v), purification obtains 0.88g white solids, yield 53%, fusing point：113-115℃.
1H NMR (300MHz, DMSO-d6)δppm：10.59 (s, 1H ,-CONH-), 9.23 (s, 1H, ArH), 8.87 (d, J =5.4Hz, 2H, ArH), 8.41 (d, J=7.0Hz, 1H, ArH), 8.07 (d, J=5.4Hz, 3H, ArH), 7.45 (s, 1H, ArH), 7.32 (d, J=6.9Hz, 2H, ArH), 6.97 (d, J=5.7Hz, 1H, ArH), 6.74 (d, J=6.9Hz, 1H ,- NH-), 5.03 (s, 2H ,-NHCH 2 -), 3.76 (s, 3H ,-OCH3)；13C NMR (75MHz, DMSO-d6)δ：162.25, 160.12,158.75,151.41,150.46,149.05,140.25,134.99,130.08,122.79,116.75,111.08, 110.71,109.81,107.01,56.08,42.72；ESI-MS m/z：335.2[M+H]+；Anal.calcd.For C19H18N4O2：C, 68.25；H, 5.43；N, 16.67；Found：C, 68.03；H, 5.50；N, 16.76.
Embodiment 3
2- ((pyridine -4- methylene) amino)-N- (3,4,5- (trimethoxy) phenyl) nicotiamide mesylate (I-2) Prepare
Compound I-1 in preparation method class example 2, by compound c (6mmol) 3,4,5- (trimethoxy) aniline (5mmol) compound I-2 is obtained, obtains white solid 1.21g, yield 61%, fusing point：216-218℃.
1H NMR (300MHz, DMSO-d6)δppm：10.32 (s, 1H ,-CONH-), 8.83 (d, J=6.1Hz, 3H, ArH), 8.20 (d, J=7.3Hz, 1H, ArH), 8.10 (d, J=4.1Hz, 1H, ArH), 7.97 (d, J=5.9Hz, 2H, ArH), 7.20 (s, 2H, ArH), 6.85-6.67 (m, 1H ,-NH-), 4.94 (s, 2H ,-NHCH 2 -), 3.78 (s, 6H ,-OCH3), 3.65 (s, 3H ,-OCH3), 2.37 (s, 6H ,-CH3)；13C NMR (75MHz, DMSO-d6)δ：162.22,155.04,151.12,149.22, 144.38,140.57,137.08,133.41,125.26,116.37,108.08,101.24,60.70,56.83,43.29, 38.57,36.02；ESI-MS m/z：395.2[M+H]+；Anal.calcd.For C23H28N4O10S2：C, 47.25；H, 4.83； N, 9.58；S, 10.97；Found：C, 47.27；H, 4.70；N, 9.71；S, 10.82.
Embodiment 4
The preparation of 2- ((pyridine -4- methylene) amino)-N- (4- (trifluoromethoxy) phenyl) nicotiamide (I-3)
Compound I-1 in preparation method class example 2, by compound c (6mmol) and 4- (trifluoromethoxy) aniline (5mmol) compound I-3 is obtained, obtains faint yellow solid 1.36g, yield 70%, fusing point：125-127℃.
1H NMR (300MHz, DMSO-d6)δppm：10.46 (s, 1H ,-CONH-), 8.47-8.08 (m, 3H, ArH), 8.13 (d, J=8.9Hz, 2H, ArH), 7.84 (d, J=8.9Hz, 2H, ArH), 7.38 (d, J=8.6Hz, 2H, ArH), 7.29 (d, J =5.2Hz, 2H, ArH), 6.70 (dd, J=7.5,4.9Hz, 1H ,-NH-), 4.68 (d, J=5.8Hz, 2H ,-NHCH 2 -)；13C NMR (75MHz, DMSO-d6)δppm：162.25,158.75,151.41,150.12,149.05,135.41,134.99, 123.35,122.79,117.70,110.71,109.81,43.75；ESI-MS m/z：389.2[M+H]+； Anal.calcd.For C19H15F3N4O2：C, 58.76；H, 3.89；F, 14.68；N, 14.43；Found：C, 58.66；H, 3.95；F, 14.72；N, 14.30.
Embodiment 5
The preparation of N- (4- (tert-butyl group) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide mesylate (I-4)
Compound I-1 in preparation method class example 2, is made by compound c (6mmol) and 4- (tert-butyl group) aniline (5mmol) Compound I-4 is obtained, white solid 1.05g, yield 58%, fusing point is obtained：141-143℃.
1H NMR (300MHz, DMSO-d6)δppm：10.39 (s, 1H ,-CONH-), 8.84 (d, J=5.7Hz, 3H, ArH), 8.24 (d, J=7.2Hz, 1H, ArH), 8.11 (d, J=4.5Hz, 1H, ArH), 7.98 (d, J=5.6Hz, 2H, ArH), 7.67 (d, J=8.2Hz, 2H, ArH), 7.39 (d, J=8.2Hz, 2H, ArH), 6.86-6.77 (m, 1H ,-NH-), 4.96 (s, 2H ,- NHCH 2-), 2.38 (s, 6H ,-SO3CH3), 1.29 (s, 9H ,-CH3)；13C NMR (75MHz, DMSO-d6)δppm：162.22, 158.25,149.22,146.62,144.38,141.77,135.54,125.93,123.86,120.49,116.37,108.08, 43.29,38.57,34.58,31.36；ESI-MS m/z：361.3[M+H]+；Anal.calcd.For C24H30N4O7S2：C, 52.35；H, 5.49；N, 10.17；S, 11.64；Found：C, 51.68；H, 5.32；N, 10.21；S, 11.55..
Embodiment 6
The preparation of N- ([1,1 '-xenyl] -4- bases) -2- ((pyridine -4- methylene) amino) nicotiamide (I-5)
Compound I-1 in preparation method class example 2, by compound c (6mmol) and (1,1 '-biphenyl) -4- amine (5mmol) Prepared compound I-5, obtains white solid 1.49g, yield 78%, fusing point：190-192℃.
1H NMR (300MHz, DMSO-d6)δppm：10.40 (s, 1H ,-CONH-), 8.51 (s, 3H, ArH), 8.17 (s, 2H, ArH), 7.77 (m, 7H, ArH), 7.46 (s, 2H, ArH), 7.31 (s, 2H, ArH), 6.71 (s, 1H ,-NH-), 4.72 (s, 2H ,-NHCH 2-)；13C NMR (75MHz, DMSO-d6)δppm：162.25,158.75,151.41,150.46,149.05, 140.35,137.21,135.09,128.91,127.88,127.44,123.66,122.79,110.71,109.81,43.66； ESI-MS m/z：381.2[M+H]+；Anal.calcd.For C24H20N4O：C, 75.77；H, 5.30；N, 14.73；Found：C, 75.67；H, 5.36；N, 14.56.
Embodiment 7
N- (thiadiazoles -2- bases of 5- (3- (methoxyl group) phenyl) -1,3,4-) -2- ((pyridine -4- methylene) amino) nicotinoyl The preparation of amine (I-6)
Compound I-1 in preparation method class example 2, by compound c (6mmol) and 5- (3- (methoxyl group) phenyl) -1,3, 4- thiadiazoles -2- amine (5mmol) is obtained compound I-6, obtains white solid 1.36g, yield 65%, fusing point：221-223℃.
1H NMR (300MHz, DMSO-d6)δppm：8.78-8.40 (m, 3H, ArH), 8.21 (s, 1H, ArH), 7.48 (s, 5H, ArH), 7.10 (s, 1H, ArH), 6.69 (s, 1H ,-NH-), 4.74 (s, 2H ,-NHCH 2-), 3.84 (s, 3H ,-CH3)；13C NMR (75MHz, DMSO-d6)δppm：170.42,169.48,161.96,158.75,154.43,151.41,150.46, 149.05,134.99,133.18,129.14,122.79,120.11,116.14,110.71,109.81,56.08,43.70； ESI-MS m/z：419.2[M+H]+；Anal.calcd.For C21H18N6O2S：C, 60.27；H, 4.34；N, 20.08；S, 7.66；Found：C, 60.15；H, 4.28；N, 20.24；S, 7.57.
Embodiment 8
The preparation of N- (4- (piperidin-1-yl) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide (I-7)
Compound I-1 in preparation method class example 2, by compound c (6mmol) and 4- (piperidin-1-yl) aniline (5mmol) Prepared compound I-7, obtains white solid 1.42g, yield 73%, fusing point：217-219℃.
1H NMR (300MHz, DMSO-d6)δppm：10.09 (s, 1H ,-CONH-), 8.51-8.11 (m, 3H, ArH), 8.09 (d, J=6.6Hz, 2H, ArH), 7.53 (d, J=8.9Hz, 2H, ArH), 7.28 (d, J=4.9Hz, 2H, ArH), 6.91 (d, J =8.9Hz, 2H, ArH), 6.67 (dd, J=7.4,4.9Hz, 1H ,-NH-), 4.67 (d, J=5.8Hz, 2H ,-NHCH 2-), 3.08 (d, J=5.3Hz, 4H ,-NCH2-), 1.74-1.37 (m, 6H ,-CH2-)；13C NMR (75MHz, DMSO-d6)δppm： 162.25,158.75,151.41,150.46,149.05,147.22,134.99,129.23,122.79,118.56,110.71, 109.81,49.59,43.57,25.09,23.43；ESI-MS m/z：388.3[M+H]+；Anal.calcd.For C22H25N5O： C, 71.29；H, 6.50；N, 18.07；Found：C, 71.35；H, 6.44；N, 18.01.
Embodiment 9
The preparation of N- (4- morpholinyl phenyls) -2- ((pyridine -4- methylene) amino) nicotiamide (I-8)
Compound I-1 in preparation method class example 2, by compound c (6mmol) and 4- morpholine aniline (5mmol) preparedization Compound I-8, obtains white solid 1.54g, yield 79%, fusing point：215-217℃.
1H NMR (300MHz, DMSO-d6)δppm：10.10 (s, 1H ,-CONH-), 8.63-8.33 (m, 3H, ArH), 8.10 (d, J=7.2Hz, 2H, ArH), 7.58 (d, J=8.8Hz, 2H, ArH), 7.29 (d, J=4.6Hz, 2H, ArH), 6.94 (d, J =8.8Hz, 2H, ArH), 6.67 (dd, J=7.2,5.0Hz, 1H ,-NH-), 4.68 (d, J=5.7Hz, 2H ,-NHCH 2-), 3.74 (s, 4H ,-OCH2-), 3.15 (s, 4H ,-NCH2-)；13C NMR (75MHz, DMSO-d6)δppm：166.06,156.93, 150.91,149.77,149.37,147.67,136.90,130.79,121.94,115.11,111.17,66.05,48.75, 42.83；ESI-MS m/z：390.3[M+H]+；Anal.calcd.For C22H23N5O2：C, 67.85；H, 5.95；N, 17.98； Found：C, 67.91；H, 6.02；N, 17.76.
Embodiment 10
The preparation of N- (4- (4- methylpiperazine-1-yls) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide (I-9)
Compound I-1 in preparation method class example 2, by compound c (6mmol) and 4- (4- methylpiperazine-1-yls) aniline (5mmol) compound I-9 is obtained, obtains faint yellow solid 1.45g, yield 72%, fusing point：220-222℃.
1H NMR (300MHz, DMSO-d6)δppm：10.11 (s, 1H ,-CONH-), 8.69-8.29 (m, 3H, ArH), 8.17-7.95 (m, 2H, ArH), 7.55 (d, J=8.9Hz, 2H, ArH), 7.28 (d, J=5.7Hz, 2H, ArH), 6.92 (d, J =8.9Hz, 2H, ArH), 6.66 (dd, J=7.6,4.9Hz, 1H ,-NH-), 4.67 (d, J=5.9Hz, 2H ,-NHCH 2-), 3.24-2.98 (m, 4H, ArNCH2-), 2.47-2.32 (m, 4H ,-NCH2-), 2.20 (s, 3H ,-NCH3)；13C NMR (75MHz, DMSO-d6)δppm：162.25,158.75,151.41,150.46,149.05,147.22,134.99,129.23,122.79, 118.56,110.71,109.81,52.65,50.29,46.06,43.72；ESI-MSm/z：403.3[M+H]+； Anal.calcd.For C23H26N6O：C, 68.63；H, 6.51；N, 20.88；Found：C, 68.77；H, 6.45；N, 20.76.
Embodiment 11
The preparation of N- (naphthalene -1- bases) -2- ((pyridine -4- methylene) amino) nicotiamide (I-10)
Compound I-1 in preparation method class example 2, by compound c (6mmol) and naphthylamines (5mmol) compound I- is obtained 10, obtain yellow solid 1.26g, yield 71%, fusing point：197-199℃.
1H NMR (300MHz, DMSO-d6)δppm：10.49 (s, 1H ,-CONH-), 8.71 (s, 1H, ArH), 8.56-8.31 (m, 3H, ArH), 8.22 (s, 1H, ArH), 8.08-7.80 (m, 3H, ArH), 7.58 (d, J=4.1Hz, 4H, ArH), 7.30 (s, 2H, ArH), 6.75 (s, 1H ,-NH-), 4.70 (s, 2H ,-NHCH 2-)；13C NMR (75MHz, DMSO-d6)δppm：161.63, 158.75,151.41,150.46,149.05,135.45,134.99,134.48,128.65,127.86,126.45,126.13, 125.65,123.19,122.79,120.36,110.71,109.81,43.55；ESI-MS m/z：355.2[M+H]+； Anal.calcd.For C22H18N4O：C, 74.56；H, 5.12；N, 15.81；Found：C, 74.47；H, 5.09；N, 15.92.
Embodiment 12
The preparation of 2- ((pyridine -4- methylene) amino)-N- (1,2,3,4- naphthane -1- bases) nicotiamide (I-11)
Compound I-1 in preparation method class example 2, by compound c (6mmol) and 1,2,3,4- naphthane -1- amine (5mmol) compound I-11 is obtained, obtains white solid 1.15g, yield 64%, fusing point：144-146℃.
1H NMR (300MHz, DMSO-d6)δppm：8.87-8.54 (m, 4H, ArH), 8.11-8.03 (m, 2H, ArH), 7.33 (s, 2H, ArH), 7.33-7.16 (m, 4H, ArH), 6.59 (s, 1H ,-NH-), 5.26 (s, 1H ,-NHCH-), 4.71 (s, 2H ,-NHCH 2-), 2.78 (s, 2H ,-CH2Ar), 1.98 (s, 2H ,-CH2-), 1.82 (s, 2H ,-CH2-)；C13NMR (75MHz, DMSO-d6)δppm：163.54,159.01,151.73,150.46,149.05,139.10,138.43,135.30,129.38, 127.18,126.55,122.79,112.15,108.92,52.97,43.57,30.59,20.98；ESI-MS m/z：359.3[M +H]+；Anal.calcd.For C22H22N4O：C, 73.72；H, 6.19；N, 15.63；Found：C, 73.67；H, 6.23；N, 15.61.
Embodiment 13
The preparation of N- (1H- benzimidazolyl-2 radicals-yl) -2- ((pyridine -4- methylene) amino) nicotiamide (I-12)
Compound I-1 in preparation method class example 2, by compound c (6mmol) and 1H- benzimidazolyl-2 radicals-amine (5mmol) Prepared compound I-12, obtains white solid 1.41g, yield 82%, fusing point：239-241℃.
1H NMR (300MHz, DMSO-d6)δppm：12.46 (s, 1H, ArNH), 9.75 (s, 1H ,-CONH-), 8.75- 8.26 (m, 3H), 8.33-7.99 (m, 2H, ArH), 7.42 (d, J=2.6Hz, 4H, ArH), 7.23-6.94 (m, 2H, ArH), 6.72-6.45 (m, 1H ,-NH-), 4.77 (d, J=5.1Hz, 2H ,-NHCH 2-)；13C NMR (75MHz, DMSO-d6)δppm： 171.30,158.75,151.41,150.53,149.05,136.92,135.12,122.79,121.76,121.04,113.30, 112.06,110.71,109.81,43.69；ESI-MSm/z：345.2[M+H]+；Anal.calcd.For C19H16N6O：C, 66.27；H, 4.68；N, 24.40；Found：C, 66.41；H, 4.53；N, 24.49.
Embodiment 14
The preparation of N- (pyridine -4- methylene) -2- ((pyridine -4- methylene) amino) nicotiamide mesylate (I-13)
Compound I-1 in preparation method class example 2, is made by compound c (6mmol) and N- pyridines -4- methylene amine (5mmol) Compound I-13 is obtained, white solid 1.14g, yield 71%, fusing point is obtained：101-103℃.
1H NMR (300MHz, DMSO-d6)δppm：9.69 (d, J=1.8Hz, 1H ,-CONH-), 9.26 (s, 1H, ArH), 8.91-8.84 (m, 4H, ArH), 8.35 (d, J=7.2Hz, 1H, ArH), 8.08-7.96 (m, 5H, ArH), 6.87 (d, J= 3.1Hz, 1H ,-NH-), 4.95 (s, 2H ,-NHCH 2-), 4.78 (s, 2H ,-NHCH 2-), 2.42 (s, 9H ,-SO3CH3)；13C NMR (75MHz, DMSO-d6)δppm：168.60,159.23.152.05,150.46,149.05,135.63,122.79,113.69, 108.16,44.99,43.54,37.85；ESI-MS m/z：320.2[M+H]+；Anal.calcd.For C21H25N5O10S3：C, 41.79；H, 4.17；N, 11.60；S, 15.93；Found：C, 41.72；H, 4.33；N, 11.58；S, 15.82.
Embodiment 15
N- (3,4- (dimethoxy) phenethyl) -2- ((pyridine -4- methylene) amino) nicotiamide mesylate (I-14) Preparation
Compound I-1 in preparation method class example 2, by compound c (6mmol) and N- (3,4- dimethoxy) phenethylamine (5mmol) compound I-14 is obtained, obtains white solid 1.47g, yield 75%, fusing point：185-187℃.
1H NMR (300MHz, DMSO-d6)δppm：9.80 (s, 1H ,-CONH-), 9.07 (t, J=5.0Hz, 1H, ArH), 8.88 (d, J=6.4Hz, 2H, ArH), 8.30 (d, J=6.7Hz, 1H, ArH), 8.14-8.03 (m, 1H, ArH), 7.99 (d, J =6.4Hz, 2H, ArH), 6.95 (dd, J=7.3,6.0Hz, 1H ,-NH-), 6.86 (t, J=5.7Hz, 2H, ArH), 6.76 (dd, J=8.1,1.5Hz, 1H, ArH), 5.03 (s, 2H ,-NHCH 2-), 3.71 (d, J=4.6Hz, 6H ,-OCH3), 3.50 (dd, J=12.9,6.7Hz, 2H ,-NHCH 2-), 2.81 (t, J=7.3Hz, 2H, ArCH2-), 2.41 (s, 9H ,-SO3CH3)；13C NMR (75MHz, DMSO-d6)δppm：166.35,159.23,152.05,150.37,149.05,147.86,135.63,132.91, 122.79,122.42,113.35,108.16,56.83,43.56,43.35,37.85,35.88；ESI-MS m/z：393.3[M+ H]+；Anal.calcd.For C25H32N4O12S3：C, 44.37；H, 4.77；N, 8.28；S, 14.21；Found：C, 44.28；H, 4.82；N, 8.31；S, 14.19.
Embodiment 16
The preparation of 2- ((pyridine -4- methylene) amino)-N- (2- (thiophene -2- bases) ethyl) nicotiamide (I-15)
Compound I-1 in preparation method class example 2, by compound c (6mmol) and N- (2- (thiophene -2- bases) ethamine (5mmol) compound I-15 is obtained, obtains yellow solid 1.26g, yield 74%, fusing point：130-132℃.
1H NMR (300MHz, DMSO-d6)δppm：8.92-8.62 (m, 2H, ArH ,-CONH-), 8.47 (d, J=5.6Hz, 2H, ArH), 8.10 (dd, J=4.7,1.5Hz, 1H, ArH), 7.93 (dd, J=7.6,1.5Hz, 1H, ArH), 7.49-7.14 (m, 3H, ArH), 7.05-6.80 (m, 2H, ArH), 6.62 (dd, J=7.6,4.9Hz, 1H ,-NH-), 4.67 (d, J=5.9Hz, 2H ,-NHCH 2-), 3.66-3.40 (m, 2H ,-NHCH 2-), 3.08 (t, J=6.9Hz, 2H, ArCH2-)；13C NMR (75MHz, DMSO-d6)δppm：166.35,159.23,152.05,150.46,149.05,137.22,135.63,125.95,125.50, 124.70,122.79,113.69,108.16,43.60,40.44,32.51；ESI-MS m/z：339.2[M+H]+ .Anal.calcd.For C18H18N4OS：C, 63.88；H, 5.36；N, 16.56；Found：C, 63.75；H, 5.39；N, 16.61.
Embodiment 17
The preparation of N, N- dibenzyl -2- ((pyridine -4- methylene) amino) nicotiamide (I-16)
Compound I-1 in preparation method class example 2, is obtained by compound c (6mmol) and N, N- dibenzyl amine (5mmol) Compound I-16, obtains white solid 1.39g, yield 68%, fusing point：197-199℃.
1H NMR (300MHz, DMSO-d6)δppm：8.42 (s, 2H, ArH), 8.00 (d, J=4.2Hz, 1H, ArH), 7.50 (d, J=6.9Hz, 1H, ArH), 7.42-7.06 (m, 12H, ArH), 6.90 (s, 1H, ArH), 6.63-6.49 (m, 1H ,-NH-), 4.59 (d, J=5.5Hz, 6H ,-NHCH 2-)；13C NMR (75MHz, DMSO-d6)δppm：175.92,157.02,150.74, 150.46,149.05,137.34,135.40,128.60,127.89,122.79,115.39,108.71,50.13,43.69； ESI-MS m/z：409.3[M+H]+；Anal.calcd.For C26H24N4O：C, 76.45；H, 5.92；N, 13.72；Found：C, 76.51；H, 5.87；N, 13.65.
Embodiment 18
The preparation of N- (4- (morpholinyl ethyl) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide (I-17)
Compound I-1 in preparation method class example 2, by compound c (6mmol) and 4- (2- morpholinyl ethyls) aniline (5mmol) compound I-17 is obtained, obtains white solid 1.49g, yield 71.4%, fusing point：183-185℃.
1H NMR (300MHz, DMSO-d6)δppm：10.23 (s, 1H ,-CONH-), 8.47 (dd, J=9.2,4.9Hz, 3H, ArH), 8.11 (ddd, J=9.2,6.2,1.5Hz, 2H, ArH), 7.61 (d, J=8.4Hz, 2H, ArH), 7.24 (dd, J= 15.3,7.0Hz, 4H, ArH), 6.68 (dd, J=7.6,4.9Hz, 1H ,-NH-), 4.68 (d, J=5.9Hz, 2H ,-NHCH 2-), 3.63-3.50 (m, 4H ,-OCH2-), 2.79-2.59 (m, 2H, ArCH2-), 2.49-2.27 (m, 6H ,-NCH2-)；13C NMR (75MHz, DMSO-d6)δppm：162.25,158.75,151.41,150.46,149.05,138.07,135.10,128.59, 122.79,121.26,110.71,109.81,67.08,56.15,53.07,43.63,33.42；ESI-MS m/z：418.3[M+ H]+；Anal.calcd.For C24H27N5O2：C, 69.04；H, 6.52；N, 16.77；Found：C, 68.89；H, 6.60；N, 16.72.
Embodiment 19
N- (4- (2- (4- methylpiperazine-1-yls) ethyl) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide (I- 18) preparation
Compound I-1 in preparation method class example 2, by compound c (6mmol) and 4- (2- (4- methylpiperazine-1-yls) second Base) the prepared compound I-18 of aniline (5mmol), obtain white solid 1.35g, yield 63%, fusing point：157-161℃.
1H NMR (300MHz, DMSO-d6)δppm：10.22 (s, 1H ,-CONH-), 8.47 (s, 3H, ArH), 8.11 (dd, J =17.6,5.5Hz, 2H, ArH), 7.61 (d, J=7.9Hz, 2H, ArH), 7.24 (dd, J=17.6,6.1Hz, 4H, ArH), 6.80-6.58 (m, 1H ,-NH-), 4.68 (d, J=5.5Hz, 2H ,-NHCH 2-), 2.68 (d, J=7.9Hz, 2H, ArCH2-), 2.43 (m, 10H ,-NCH2-), 2.14 (s, 3H ,-NCH3)；13C NMR (75MHz, DMSO-d6)δppm：162.25,158.75, 151.41,150.46,149.05,138.07,135.10,128.59,122.79,121.26,110.71,109.81,56.15, 54.39,53.95,46.06,43.63,33.42；ESI-MS m/z：431.3[M+H]+；Anal.calcd.For C25H30N6O： C, 69.74；H, 7.02；N, 19.52；Found：C, 69.68；H, 7.11；N, 19.34.
Embodiment 20
The system of N- (4- (2- (piperidin-1-yl) ethyl) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide (I-19) It is standby
Compound I-1 in preparation method class example 2, by compound c (6mmol) and 4- (2- (base of piperidines -1) ethyl) aniline (5mmol) compound I-19 is obtained, obtains white solid 1.41g, yield 67%, fusing point：167-170℃.
1H NMR (300MHz, DMSO-d6)δppm：10.24 (s, 1H ,-CONH-), 8.46 (s, 3H, ArH), 8.11 (d, J =16.2,5.4Hz, 2H, ArH), 7.61 (d, J=8.0Hz, 2H, ArH), 7.25 (dd, J=18.6,6.1Hz, 4H, ArH), 6.78-6.48 (m, 1H ,-NH-), 4.68 (d, J=5.3Hz, 2H ,-NHCH 2-), 2.68 (d, J=7.6Hz, 2H, ArCH2-), 2.36 (m, 6H ,-NCH2-), 2.18 (m, 4H ,-NCH2CH 2-), 1.37 (m, 2H ,-CH2-)；13C NMR (75MHz, DMSO-d6)δ ppm：162.25,158.75,151.41,150.46,149.05,138.07,135.10,128.59,122.79,121.26, 110.71,109.81,56.15,54.39,53.95,46.06,43.63,33.42；ESI-MS m/z：416.3[M+H]+； Anal.calcd.For C25H29N5O：C, 72.26；H, 7.03；N, 16.85；Found：C, 72.18；H, 7.99；N, 16.77.
Embodiment 21
N- (4- (2- (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-yl) ethyl) phenyl) -2- ((pyridine -4- Methylene) amino) nicotiamide (I-20) preparation
Compound I-1 in preparation method class example 2, by compound c (6mmol) and 4- (2- (6,7- dimethoxys-dihydro Isoquinolin -2 (1H) base) ethyl) the prepared compound I-20 of aniline (5mmol), white solid 1.59g is obtained, yield 60.7% melts Point：188-190℃.
1H NMR (300MHz, DMSO-d6)δppm：10.24 (s, 1H ,-CONH-), 8.47 (d, J=5.0Hz, 3H, ArH), 8.25-7.93 (m, 2H, ArH), 7.63 (d, J=8.4Hz, 2H, ArH), 7.26 (dd, J=15.1,6.7Hz, 4H, ArH), 6.75-6.50 (m, 3H ,-NH-), 4.68 (d, J=5.8Hz, 2H ,-NHCH 2-), 3.70 (s, 6H ,-OCH3), 3.54 (s, 2H, ArCH 2N-), 2.98-2.55 (m, 8H ,-CH2-)；13C NMR (75MHz, DMSO-d6)δppm：162.25,158.75,151.41, 150.46,149.41,149.05,148.19,138.07,135.10,128.59,128.14,126.93,122.79,121.26, 112.58,111.35,110.71,109.81,56.73,54.70,51.36,43.63,33.42,28.76；ESI-MS m/z： 524.3[M+H]+；Anal.calcd.For C31H33N5O3：C, 71.11；H, 6.35；N, 13.37；Found：C, 71.06；H, 6.52；N, 14.01.
Embodiment 22
The preparation of N- (3,4- dimethoxy-benzyl)-N- methyl -2- ((pyridine -4- methylene) amino) nicotiamide (I-21)
Compound I-1 in preparation method class example 2, by compound c (6mmol) and 1- (3,4- dimethoxy-benzyl)-N first Base methylamine (5mmol) is obtained compound I-21, obtains white solid 1.27g, yield 65%, fusing point：201-203℃.
1H NMR (300MHz, DMSO-d6)δppm：9.09 (m, 1H ,-CONH-), 8.86 (d, J=6.4Hz, 2H, ArH), 8.30 (d, J=6.7Hz, 1H, ArH), 8.12-8.04 (m, 1H, ArH), 7.99 (d, J=6.4Hz, 2H, ArH), 6.95 (dd, J =7.3,6.0Hz, 1H ,-NH-), 6.88 (t, J=5.7Hz, 2H, ArH), 6.72 (dd, J=8.1,1.5Hz, 1H, ArH), 5.05 (s, 2H ,-NHCH 2-), 4.52 (dd, J=12.9,6.6Hz, 2H ,-NCH2Ar), 3.70 (d, J=4.6Hz, 6H ,- OCH3), 3.16 (s, 3H ,-NCH3)；13C NMR (75MHz, DMSO-d6)δppm：174.92,157.41,151.02,150.41, 149.05,148.71,135.67,129.36,122.79,121.65,116.83,113.92,112.97,107.92,56.83, 52.33,43.63,35.13；ESI-MS m/z：493.2[M+H]+；Anal.calcd.For C22H24N4O3：C, 67.33；H, 6.16；N, 14.28；Found：C, 67.36；H, 6.14；N, 14.34.
Embodiment 23
N- (4- (2- ((3,4- dimethoxy-benzyl) (methyl) amino) ethyl) phenyl) -2- ((pyridine -4- methylene) ammonia Base) nicotiamide (I-22) preparation
Compound I-1 in preparation method class example 2, by compound c (6mmol) and 4- (2- ((3,4- dimethoxy-benzyl) (methyl) amino) ethyl) the prepared compound 1-22 of aniline (5mmol), obtain white solid 1.48g, yield 58%, fusing point：167- 169℃。
1H NMR (300MHz, DMSO-d6)δppm：10.22 (s, 1H ,-CONH-), 8.57 (d, J=5.0Hz, 4H, ArH), 8.25-7.93 (m, 2H, ArH), 7.63 (d, J=8.4Hz, 4H, ArH), 7.26 (dd, J=15.1,6.7Hz, 4H, ArH), 6.78-6.70 (m, 1H ,-NH-), 4.88 (d, J=5.8Hz, 2H ,-NHCH 2-), 3.68 (s, 6H ,-OCH3), 3.54 (s, 2H ,- NCH2Ar), 2.68 (d, J=7.6Hz, 2H ,-NCH2-), 2.14-2.08 (m, 5H ,-CH2- ,-NCH3)；13C NMR (75MHz, DMSO-d6)δppm：162.25,158.75,151.41,150.35,148.94,138.07,135.10,130.17,128.59, 122.79,121.31,113.68,112.88,110.71,109.81,63.66,57.57,56.83,43.63,43.02, 32.37；ESI-MS m/z：355.2[M+H]+；Anal.calcd.For C30H33N5O3：C, 70.43；H, 6.50；N, 13.69； Found：C, 70.48；H, 6.50；N, 14.01.
Embodiment 24
The preparation of N, N- bis- (3,4- dimethoxy-benzyl) -2- ((pyridine -4- methylene) amino) nicotiamide (I-23)
Compound I-1 in preparation method class example 2, by compound c (6mmol) and 2- (3,4- dimethoxy-benzyl) amine (5mmol) compound I-23 is obtained, obtains white solid 1.25g, yield 45%, fusing point：167-170℃.
1H NMR (300MHz, DMSO-d6)δppm：9.12 (m, 1H, ArH), 8.89 (d, J=6.4Hz, 2H, ArH), 8.28 (d, J=7.3Hz, 1H, ArH), 8.14-8.03 (m, 1H, ArH), 7.99 (d, J=6.4Hz, 2H, ArH), 6.93 (dd, J= 7.3,6.0Hz, 2H, ArH), 6.82 (d, J=6.4Hz, 4H, ArH), 6.72 (s, 1H ,-NH-), 5.03 (s, 2H ,-NHCH 2-), 3.68 (d, J=4.6Hz, 12H ,-OCH3), 3.45 (m, 4H ,-NCH2-), 2.81 (m, 4H ,-CH2Ar)；13C NMR (75MHz, DMSO-d6)δppm：172.80,157.02,150.94,150.26,149.05,147.93,135.40,132.48,122.79, 122.39,115.39,114.25,113.75,108.71,56.83,45.88,43.63,33.64；ESI-MS m/z：557.3[M +H]+；Anal. calcd.For C32H36N4O5：C, 69.05；H, 6.52；N, 10.06；Found：C, 69.03；H, 6.49；N, 10.02.
Embodiment 25
The preparation of N- (9H- fluorenes -2- bases) -2- ((pyridine -4- methylene) amino) nicotiamide (I-24)
Compound I-1 in preparation method class example 2, by compound c (6mmol) and 9H- fluorenes -2- amine (5mmol) preparedization Compound 13, obtains white solid 1.19g, yield 61%, fusing point：189-192℃.
1H NMR (300MHz, DMSO-d6)δppm：10.38 (s, 1H ,-CONH-), 8.53 (s, 3H, ArH), 8.16 (s, 3H, ArH), 7.94-7.51 (m, 4H, ArH), 7.33 (s, 4H, ArH), 6.71 (s, 1H ,-NH-), 4.71 (s, 2H ,- NHCH2-), 3.93 (s, 2H ,-CH2-)；13C NMR (75MHz, DMSO-d6)δppm：162.25,158.75,151.41, 150.46,149.05,142.40,141.89,140.13,138.87,136.28,134.99,125.84,124.88,122.79, 119.82,119.06,118.54,117.99,110.71,109.81,43.63,38.34；ESI-MS m/z：393.2[M+H]+； Anal. calcd.For C25H20N4O：C, 76.51；H, 5.14；N, 14.28；Found：C, 76.22；H, 5.32；N, 14.29.
Embodiment 26
The preparation of N- (2- benzoyloxy phenyls) -2- ((pyridine -4- methylene) amino) nicotiamide (I-25)
Compound I-1 in preparation method class example 2, by compound c (6mmol) and 2- (aminophenyl) (phenyl) ketone (5mmol) compound 13 is obtained, obtains white solid 1.37g, yield 67%, fusing point：177-179℃.
1H NMR (300MHz, DMSO-d6)δppm：10.59 (s, 1H ,-CONH-), 8.45 (s, 2H, ArH), 8.26 (s, 1H, ArH), 8.09 (s, 1H, ArH), 7.64 (d, J=15.3Hz, 6H, ArH), 7.58-7.50 (m, 2H, ArH), 7.47 (d, J =7.3Hz, 2H, ArH), 7.38 (d, J=7.1Hz, 1H, ArH), 7.21 (s, 1H, ArH), 6.57 (d, J=4.9Hz, 1H ,- NH-), 4.61 (d, J=5.4Hz, 2H ,-NHCH 2-)；13C NMR (75MHz, DMSO-d6)δppm：196.06,162.50, 158.75,151.41,150.46,149.05,141.29,136.25,134.99,132.50,131.68,129.97,129.24, 128.60,124.88,124.35,122.79,110.71,109.81,43.63；ESI-MS m/z：409.2[M+H]+； Anal.calcd.For C25H20N4O2：C, 73.51；H, 4.94；N, 13.72；Found：C, 73.44；H, 4.96；N, 13.85.
Embodiment 27
Tablet containing activating agent I-11：
Supplementary material is mixed according to a conventional method, is pelletized, be dried, tabletting.

Claims (6)

1. compound described in general structure (I) or its pharmaceutically useful salt：
Wherein A rings are selected from：Substituted or unsubstituted aromatic radical, aromatic heterocyclic；
Wherein n represents integer 0～2；
Wherein R1It is H, halogen, haloalkyl, halogenated alkoxy, replacement or unsubstituted C1-C5Alkyl, replacement or unsubstituted C1-C5 Alkoxyl, replacement or unsubstituted aromatic radical, aromatic heterocyclic, alicyclic heterocyclic base, cycloalkyl；
Wherein R2It is H, replaces or unsubstituted C1-C5Alkyl, replacement or unsubstituted aromatic radical, aromatic heterocyclic.
2. the compound of general structure defined in claim 1 (I) or its pharmaceutically useful salt：
Wherein A rings are selected from：Substituted or unsubstituted phenyl, naphthyl, aromatic condensed ring, fragrant heterocyclic radical, the substituent group is selected from：Halogen Element, haloalkyl, replacement or unsubstituted C1-C5Alkyl, replaces or unsubstituted C1-C5Alkoxyl, replaces or unsubstituted C1-C5Alkyl Alkoxyl；Aromatic rings include an aromatic rings and a cycloaliphatic ring thickening, the such as ring of saturation or fractional saturation, such as tetrahydric naphthalene ring；
Wherein n represents integer 0～2；
Wherein R1It is H, F, Cl ,-OCF3, replace or unsubstituted C1-C5Alkyl, replacement or unsubstituted C1-C5Alkoxyl, replacement or not Substituted aromatic base, aromatic heterocyclic, alicyclic heterocyclic base, cycloalkyl；
Wherein R2It is H, replaces or unsubstituted C1-C5Alkyl, replacement or unsubstituted aromatic radical, aromatic heterocyclic.
3. the compound of general structure defined in claims 1 or 2 (I) or its pharmaceutically useful salt：
Wherein A rings are selected from：It is unsubstituted or be up to three replacement phenyl ring, naphthalene, pyrrolidine, ketopyrrolidine, piperidines, piperidones, Piperazine, morpholine, imidazolidine, pyrazolidine, pyrroles, indole, pyrazoles, indole azoles, triazole, benzotriazole, imidazoles, benzimidazole, thiophene Azoles, benzothiazole, furan, benzofuran, oxazole, benzoxazoles, isoxazole, tetrazolium, pyridine, pyrimidine, three pyridines, quinoline, isoquinoline Quinoline, quinazoline, indoline, dihydroindolone, benzo tetrahydrofuran, tetrahydroquinoline, tetrahydroisoquinoline, fluorenes；
Wherein n represents integer 0～2；
Wherein R1It is selected from：H、F、Cl、-OCF3, replace or unsubstituted C1-C5Alkyl, replacement or unsubstituted C1-C5Alkoxyl, replacement Or unsubstituted aromatic radical, aromatic heterocyclic, alicyclic heterocyclic base, cycloalkyl；
Wherein R2It is H, replaces or unsubstituted C1-C5Alkyl, replacement or unsubstituted aromatic radical.
4. the compound of general structure (I) or its pharmaceutically useful salt according to defined in claim 1-3 any one, are selected from：
N- (3- (methoxyl group) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide；
2- ((pyridine -4- methylene) amino)-N- (3,4,5- (trimethoxy) phenyl) nicotiamide mesylate；
2- ((pyridine -4- methylene) amino)-N- (4- (trifluoromethoxy) phenyl) nicotiamide；
N- (4- (tert-butyl group) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide mesylate；
N- ([1,1 '-xenyl] -4- bases) -2- ((pyridine -4- methylene) amino) nicotiamide；
N- (thiadiazoles -2- bases of 5- (3- (methoxyl group) phenyl) -1,3,4-) -2- ((pyridine -4- methylene) amino) nicotiamide；
N- (4- (piperidin-1-yl) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide；
N- (4- morpholinyl phenyls) -2- ((pyridine -4- methylene) amino) nicotiamide；
N- (4- (4- methylpiperazine-1-yls) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide；
N- (naphthalene -1- bases) -2- ((pyridine -4- methylene) amino) nicotiamide；
2- ((pyridine -4- methylene) amino)-N- (1,2,3,4- naphthane -1- bases) nicotiamide；
N- (1H- benzimidazolyl-2 radicals-yl) -2- ((pyridine -4- methylene) amino) nicotiamide；
N- (pyridine -4- methylene) -2- ((pyridine -4- methylene) amino) nicotiamide mesylate；
N- (3,4- (dimethoxy) phenethyl) -2- ((pyridine -4- methylene) amino) nicotiamide mesylate；
2- ((pyridine -4- methylene) amino)-N- (2- (thiophene -2- bases) ethyl) nicotiamide；
N, N- dibenzyl -2- ((pyridine -4- methylene) amino) nicotiamide；
N- (4- (morpholinyl ethyl) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide；
N- (4- (2- (4- methylpiperazine-1-yls) ethyl) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide；
N- (4- (2- (piperidin-1-yl) ethyl) phenyl) -2- ((pyridine -4- methylene) amino) nicotiamide；
N- (4- (2- (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-yl) ethyl) phenyl) -2- ((pyridine -4- methylenes Base) amino) nicotiamide；
N- (3,4- dimethoxy-benzyl)-N- methyl -2- ((pyridine -4- methylene) amino) nicotiamide；
N- (4- (2- ((3,4- dimethoxy-benzyl) (methyl) amino) ethylphenyl) -2- ((pyridine -4- methylene) amino) cigarettes Amide；
N, N- bis- (3,4- dimethoxy-benzyl) -2- ((pyridine -4- methylene) amino) nicotiamide；
N- (9H- fluorenes -2- bases) -2- ((pyridine -4- methylene) amino) nicotiamide；
N- (2- benzoyloxy phenyls) -2- ((pyridine -4- methylene) amino) nicotiamide.
5. the logical formula (I) compound or its pharmaceutically useful salt of claim 1-4 definition is preparing treatment multi-drug resistance of the tumor Application in medicine.
6. a kind of pharmaceutical composition, it is characterised in that the chemical combination described in the claim 1-4 any one containing therapeutically effective amount Thing and pharmaceutically acceptable adjuvant.
CN201610463182.5A 2016-06-20 2016-06-20 2-aminomethylpyridylnicotinamides and preparation method and application thereof Pending CN106565599A (en)

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