CN103664876A - Quinoline derivative and usage thereof - Google Patents

Quinoline derivative and usage thereof Download PDF

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Publication number
CN103664876A
CN103664876A CN201310535587.1A CN201310535587A CN103664876A CN 103664876 A CN103664876 A CN 103664876A CN 201310535587 A CN201310535587 A CN 201310535587A CN 103664876 A CN103664876 A CN 103664876A
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phenyl
benzamide
quinolyl
alkyl
group
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CN103664876B (en
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吉民
张曙光
李锐
王义成
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SUZHOU SOUTHEAST PHARMACEUTICALS CO Ltd
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SUZHOU SOUTHEAST PHARMACEUTICALS CO Ltd
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    • 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
    • C07D401/02—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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/38—Nitrogen atoms
    • 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
    • C07D401/02—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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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

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Abstract

The invention discloses a quinoline derivative and a usage thereof, a compound with a structure as shown in a formula (I) and or a pharmaceutically acceptable salt of the compound. The compound or the pharmaceutically acceptable salt thereof disclosed by the invention can be applied to the field of preparation of drugs for preventing or treating tumors.

Description

Quinoline derivatives and uses thereof
Technical field
The invention belongs to pharmaceutical chemistry field, be specifically related to a kind of synthetic technology of preparing of Wnt signal pathway inhibitor, i.e. quinoline derivatives and uses thereof.
Background technology
Wnt signal path is a conservative signal path on evolving, and most important to fetal development, growth, migration and differentiation that can regulating cell.The Wnt part of secretion and cell surface receptor Fzd family or LRPS/LRP6 receptors bind form mixture, and receptor complex causes that β-catenin is in intracellular accumulation.When Wnt signal path activates, Wnt is combined with acceptor Fzd, Dsh albumen in activating cells, the Dsh albumen of phosphorylation reaches signal in cell, suppresses APC, GSK-3 β, Axin, the kinase whose activity of mixture that CK1 α forms, causes that β-catenin is in intracellular accumulation, and the transcription factor that enters nucleus and T cytokine (TCF)-lymphocyte enhancement factor family forms mixture, activate transcribing of downstream gene.β-catenin is Wnt signal to the signal of interest molecule in nucleus transmittance process, and the key of Wnt signal transduction is in endochylema, whether to have constitutionally stable, solubility β-catenin, and β-catenin is the by-pass cock of Wnt signal.β-catenin can participate in sticking of cell with E-cadherin effect.GSK-3 β plays an important role in insulin signaling conduction and carbohydrate metabolism process.APC is relevant with stretching, extension, the polarity migration of cell.Therefore, Wnt signal path is not single path, but forms complicated network, and the growth stimulation of whole cell is played to important regulating and controlling effect.Do not having under the state of Wnt signal, the mixture that APC albumen, GSK-3 β, Axin and CK1 α form can pass through aminoterminal phosphorylation fast degradation β-catenin.
Wnt signal path not only plays an important role in fetal development regulation process, and closely related with the generation of tumour.The abnormal activation of Wnt signal makes cell and iuntercellular adhesive function disappearance, and to the induction of human tumor with developed certain effect, what wherein play a crucial role is that β-catenin level is out of control, can cause the generation of the cancers such as colorectal carcinoma.Survivin and cyclinD1 interact in Wnt signal path inducible protein Wnt-1, downstream effect albumen WISP-1 and cell, may accelerate cell cycle, cell proliferation and apoptosis inhibit, this and colorectal carcinoma have a substantial connection.In adenoma of colon and colorectal carcinoma, extensively there is APC and β-catenin sudden change, this significant sudden change is not only confined to the tumour of gastrointestinal tissue's origin, in the tumour of Endometrial Carcinomas, prostate cancer, thyroid carcinoma and some mesenchymal cells origin, also finds that there is the abnormal of the Wnt signal components such as β-catenin, APC and Axin.
The activation of Wnt signal path, plays keying action for the stable propagation that maintains the multiple human stem cells such as intestinal stem cell, hemopoietic stem cell, skin progenitor cell.APC is first found mankind Wnt signal path genes involved, and APC expression deletion in 80% colorectal carcinoma.Be similar to human diseases, induction APC, β-catenin sudden change, also can cause the generation of a large amount of polyps of mouse model Small Intestine fine hair crypts and colorectal carcinoma.
Summary of the invention
The object of this invention is to provide the quinoline derivatives that a kind of propagation to tumour cell has inhibition ability,
Another object of the present invention is to provide a kind of composition that contains above-mentioned quinoline derivatives.
A further object of the invention is to provide above-mentioned quinoline derivatives in purposes pharmaceutically.
Object of the present invention can reach by following measures:
Quinoline derivatives of the present invention is compound or its pharmacy acceptable salt of formula (1) structure,
Figure BDA0000407223010000011
Wherein:
R is selected from hydrogen, alkyl, haloalkyl, halogen ,-NR 1r 2or-CH 2nR 3r 4, R 1or R 2independently selected from hydrogen, alkyl or cycloalkyl, R 3or R 4independently selected from hydrogen, alkyl or cycloalkyl, or R 3and R 4be connected and form the heterolipid cyclic group replacing arbitrarily, its substituting group is alkyl or hydroxyalkyl;
Ar is selected from the phenyl of any replacement, any replacement-R '-Ph group; wherein R ' is five yuan or hexa-member heterocycle; Ph is phenyl, and its substituting group is selected from halogen, nitro, alkyl, alkoxyl group, cyano group, sulfydryl, hydroxyl, amino, ester group, alkyl sulphonyl or haloalkyl.
In a kind of preferred version, R is selected from hydrogen, C 1～6alkyl, halogen ,-NR 1r 2or-CH 2nR 3r 4, R 1or R 2independently selected from hydrogen or C 1～6alkyl, R 3or R 4select independently C 1～6alkyl, or R 3and R 4be connected and form the heterolipid cyclic group replacing arbitrarily, its substituting group is C 1～6alkyl or C 1～6hydroxyalkyl.
In a kind of preferred version, R is hydrogen, alkyl ,-NR 1r 2,-CH 2nR 3r 4, R 1or R 2independently selected from hydrogen, alkyl, R 3or R 4select independently C1-4 alkyl, or R 3or R 4form altogether substituted or non-substituted heterolipid cyclic group, wherein substituting group methyl, ethyl, methylol or hydroxyethyl.
In a kind of preferred version, R is selected from hydrogen, C 1～4alkyl ,-NR 1r 2or-CH 2nR 3r 4, R 1or R 2independently selected from hydrogen or C 1～4alkyl, R 3or R 4select independently C 1～4alkyl, or R 3and R 4be connected and form the hexa-atomic heterolipid cyclic group replacing arbitrarily, its substituting group is C 1～4alkyl.
In a kind of preferred version, R is selected from hydrogen, methyl ,-N (CH 3) 2,
Figure BDA0000407223010000021
In a kind of preferred version, Ar be selected from the phenyl of any replacement, replace arbitrarily-R '-Ph group, wherein R ' be pyrrole ring, Ph is phenyl, its substituting group is selected from that halogen, nitre are plain, C 1～6alkyl, C 1～6alkoxyl group, cyano group, thin base, hydroxyl, amino, ester group, methyl sulphonyl or C 1～6haloalkyl.
In a kind of preferred version, Ar be selected from the phenyl of any replacement, replace arbitrarily-R '-Ph group, wherein R ' is pyrrole ring, Ph is phenyl, its substituting group is selected from halogen, C 1～4alkyl, C 1～4alkoxyl group, methyl sulphonyl or C 1～4haloalkyl.
In a kind of preferred version, Ar be selected from the phenyl of any replacement, replace arbitrarily-R '-Ph group, wherein R ' is pyrrole ring, Ph is phenyl, its substituting group is selected from halogen, methyl, methoxyl group, methylsulfonyl methoxycarbonyl or chloro methyl.
In a kind of preferred version, when R is hydrogen, Ar be selected from the phenyl of any replacement, replace arbitrarily-R '-Ph group, wherein R ' is pyrrole ring, Ph is phenyl, its substituting group is selected from halogen, C 1～6alkyl, C 1～6alkoxyl group or methyl sulphonyl;
When R is C 1~ 6during alkyl, Ar is selected from the phenyl of any replacement, and its substituting group is selected from halogen, C 1～6alkyl or methyl sulphonyl;
When R is-NR 1r 2and R 1or R 2independently selected from C 1～6during alkyl, Ar is selected from the phenyl of any replacement, and its substituting group is selected from halogen, C 1～6alkyl or C 1～6haloalkyl;
When R is-CH 2nR 3r 4and R 3or R 4select independently C 1～6during alkyl, Ar is selected from the phenyl of any replacement, and its substituting group is selected from halogen, C 1～6alkyl, methyl sulphonyl or C 1～6haloalkyl;
When R is-CH 2nR 3r 4and R 3and R 4be connected and form the hexa-atomic heterolipid cyclic group replacing arbitrarily, its substituting group is C 1～4during alkyl, Ar be selected from the phenyl of any replacement, replace arbitrarily-R '-Ph group, wherein R ' is pyrrole ring, Ph is phenyl, its substituting group is selected from halogen, C 1～6alkyl, C 1～6alkoxyl group, methyl sulphonyl or C 1～6haloalkyl.
Further, compound of the present invention can be selected from lower group one or more:
4-methoxyl group-N-{3-[6-(pipecoline base)-2-quinolyl] phenyl } benzamide;
The chloro-N-{3-[6-of 4-(pipecoline base)-2-quinolyl] phenyl } benzamide;
The chloro-N-{3-[6-of 2-(pipecoline base)-2-quinolyl] phenyl }-4-methylsulfonyl benzamide;
2,5-dimethyl-N-{3-[2-(6-toluquinoline base)] phenyl }-1-phenyl-1H-pyrrole-3-carboxamide;
The chloro-N-{3-[6-of 3-(pipecoline base)-2-quinolyl] phenyl } benzamide;
2,5-dimethyl-1-phenyl-N-[3-(2-quinolyl) phenyl]-1H-pyrrole-3-carboxamide;
The chloro-4-of 2-(methylsulfonyl)-N-[3-(2-quinolyl)-phenyl] benzamide;
4-methoxyl group-N-[3-(2-quinolyl)-phenyl] benzamide;
The chloro-N-[3-of 4-(2-quinolyl)-phenyl] benzamide;
The chloro-N-[3-of 3-(2-quinolyl)-phenyl] benzamide;
4-chloromethyl-N-[3-(2-quinolyl)-phenyl] benzamide;
2,5-dimethyl-1-phenyl-N-{3-[2-(6-toluquinoline base)] phenyl }-1H-pyrrole-3-carboxamide;
The chloro-N-{3-[2-of 2-(6-toluquinoline base)] phenyl }-4-(methylsulfonyl) benzamide;
The chloro-N-{3-[2-of 4-(6-toluquinoline base)] phenyl } benzamide;
The chloro-N-{3-[2-of 3-(6-toluquinoline base)] phenyl } benzamide;
4-chloromethyl-N-{3-[2-(6-toluquinoline base)] phenyl } benzamide;
The chloro-4-of 2-(methylsulfonyl)-N-{3-{2-[6-(piperidines-1-methyl)] quinolyl } phenyl } benzamide;
The chloro-N-{3-{2-[6-of 4-(piperidines-1-methyl)] quinolyl } phenyl } benzamide;
The chloro-N-{3-{2-[6-of 3-(piperidines-1-methyl)] quinolyl } phenyl } benzamide;
4-chloromethyl-N-{3-{2-[6-(piperidines-1-methyl)] quinolyl } phenyl } benzamide;
4-methoxyl group-N-{3-{2-[6-(piperidines-1-methyl)] quinolyl } phenyl } benzamide;
The bromo-N-{3-{2-[6-of 4-(piperidines-1-methyl)] quinolyl } phenyl } benzamide;
The chloro-4-of 2-(methylsulfonyl)-N-{3-{2-[6-(N, N-dimethyl)] quinolyl } phenyl } benzamide;
The chloro-N-{3-{2-[6-of 4-(N, N-dimethyl)] quinolyl } phenyl } benzamide;
4-chloromethyl-N-{3-{2-[6-(N, N-dimethyl)] quinolyl } phenyl } benzamide;
The bromo-N-{3-{2-[6-of 4-(N, N-dimethyl)] quinolyl } phenyl } benzamide;
The fluoro-N-{3-{2-[6-of 3-(N, N-dimethyl)] quinolyl } phenyl } benzamide;
The chloro-4-of 2-(methylsulfonyl)-N-{3-{2-[6-(diethylin)] quinolyl } phenyl } benzamide;
The chloro-N-{3-{2-[6-of 4-(diethylin)] quinolyl } phenyl } benzamide;
The chloro-N-{3-{2-[6-of 3-(diethylin)] quinolyl } phenyl } benzamide;
4-chloromethyl-N-{3-{2-[6-(diethylin)] quinolyl } phenyl } benzamide;
The bromo-N-{3-{2-[6-of 4-(diethylin)] quinolyl } phenyl } benzamide;
The chloro-4-of 2-(methylsulfonyl)-N-{3-{2-[6-(morpholinyl)] quinolyl } phenyl } benzamide;
The chloro-N-{3-{2-[6-of 4-(morpholinyl)] quinolyl } phenyl } benzamide;
4-chloromethyl-N-{3-{2-[6-(morpholinyl)] quinolyl } phenyl } benzamide;
The chloro-N-{3-{2-[6-of 3-(morpholinyl)] quinolyl } phenyl } benzamide;
Or the bromo-N-{3-{2-[6-of 4-(morpholinyl)] quinolyl } phenyl } benzamide.
The invention also discloses a kind of pharmaceutical composition, it take compound of the present invention or its pharmacy acceptable salt is activeconstituents or main active ingredient, is aided with pharmaceutically acceptable auxiliary material.
Compound of the present invention or its pharmacy acceptable salt can be applicable to, in preparation prevention or treatment cancer drug, particularly be applied to prevention or the treatment of the solid tumor cancers such as colorectal carcinoma, liver cancer, prostate cancer, cervical cancer or mammary cancer.
Compound of the present invention can also, as raw material, be prepared into the spendable medicine that is used for the treatment of the tumours such as liver cancer, colorectal carcinoma clinically.
Form administration by compound of the present invention with prodrug.Prodrug refers to the compound of the pharmacological action just having after transforming in organism.Can use prodrug to change physicochemical property or the pharmacokinetics aspect character of the compounds of this invention.When compound of the present invention contains, can connect while changing the suitable group of character group or substituted radical, form prodrug.
1. chemistry
Unless otherwise indicated, the following term using in specification sheets and claim has implication discussed below:
" alkyl " represents the saturated fatty alkyl of 1-20 carbon atom, comprise side chain and the straight chain group (digital scope of mentioning in the application's book, for example " 1-20 " refers to this group, it is now alkyl, can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms etc., until comprise 20 carbon atoms).Alkyl containing 1-4 carbon atom is called low alkyl group.When low alkyl group does not have substituting group, be called the low alkyl group of unsubstituted.More preferably, alkyl is the medium sized alkyl that has 1-10 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl, amyl group etc.Preferably, alkyl is the low alkyl group that has 1-4 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be that replace or unsubstituted.When being substituted alkyl, this substituting group preferably one or more, more preferably 1-3,1 or 2 substituting group most preferably, they are independently preferably from following group: halogen, hydroxyl, lower alkoxy, aryl, aryloxy, hetero-aromatic ring, heterolipid cyclic group and ester group.
" cycloalkyl " represents to be all the monocycle of carbon or the ring condensing (" condensing " encircled each ring meaning in system and shared with other ring in system a pair of carbon atom adjoining) group, contain 3-10 carbon atom, preferably 5,6 or 7 carbon atoms, most preferably 5 or 6 carbon atoms.The example of cycloalkyl (being not limited to) is hexanaphthene, pentamethylene, hexanaphthene, cyclohexadiene etc.Cycloalkyl can for replace with unsubstituted.When being substituted, substituting group is preferably one or more following groups that are selected from separately, comprising: alkyl, aryl, heteroaryl, heterolipid cyclic group, hydroxyl, alkoxyl group, aryloxy, cyano group, halogen, carbonyl etc.
" heterolipid cyclic group " represents monocycle or fused rings group, has 5-18 annular atoms in ring, preferred 5-12 annular atoms, and more preferably 5-9 annular atoms, wherein one or two annular atoms is selected from the heteroatoms of N, O or S, and all the other annular atomses are C.These rings can have one or more pair of key, but these rings do not have the π-electron system of total conjugated.The limiting examples of unsubstituted heterolipid cyclic group has piperidino-(1-position only), morpholine subbase, Piperazino, pyrrolidino etc.Heterolipid cyclic group can be that replace or unsubstituted.When being substituted, that substituting group is preferably is one or more, more preferably one, two or three, and then more preferably one or two, independently selected from following group, comprise alkyl, halogen, hydroxyl, alkoxyl group, carbonyl, three alkylhalide groups etc.Preferred hetero-aromatic ring base is optionally replaced by one or two substituting group, and substituting group is independently by replacements such as halogen, low alkyl group, three alkylhalide groups.Preferably, the hexa-atomic heterolipid cyclic group in the present invention is selected from piperidyl or morpholinyl.
" hydroxyl " expression-OH group.
" hydroxyalkyl " represents the substituent alkyl of have-OH, and wherein the concept of alkyl as mentioned above.
The unsubstituted alkyl of " alkoxyl group " expression-O-() and-the unsubstituted cycloalkyl of O-(), wherein the definition of alkyl and cycloalkyl is as above.Representative example includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group etc.
" sulfydryl " expression-SH group.
" ester group " expression-C (O) O-R ' group, wherein R ' define the same, but R ' can not be hydrogen.
" halogen " represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine, bromine or iodine.
" trihalogenmethyl " expression-CX 3group, wherein X is halogen as defined above.
" cyano group " expression-CN group.
" amino " expression-NH 2group.
" nitro " expression-NO 2group.
" haloalkyl " represents that alkyl is replaced by one or more identical or different halogen atoms, and preferably low alkyl group is replaced by one or more identical or different halogen atoms as defined above, and wherein alkyl defines as above, for example-CH 2cl ,-CH 2br ,-CF 3deng." halogenated alkoxy " represents that alkoxyl group is replaced by one or more identical or different halogen atoms, and wherein alkoxyl group defines as above, for example-OCH 2cl ,-OCH 2br ,-OCF 3deng.
" optionally " or " optionally " mean subsequently described event or environment can but needn't occur, this explanation comprises the occasion that this event or environment occur and do not occur.For example, " heteroaryl is optionally replaced by one or two substituting group " mean heteroaryl substituting group can but need not to be one, this explanation comprises the situation that situation that heteroaryl is replaced by substituting group and heterocyclic radical are replaced by two substituting groups.The statement " replacing arbitrarily " represents " replacement " or " not replacing " two kinds of situations, and " replacement " wherein also comprises monosubstituted and polysubstituted situation.
" alkyl sulphonyl " refers to the sulphonyl ester group with alkyl substituent, i.e. " alkyl-SO 2-" group.
" halogen " comprises fluorine, chlorine, bromine or iodine, preferably adopts fluorine, chlorine or bromine.
" pharmacy acceptable salt " represents to retain the biological effectiveness of parent compound and those salt of character.This class salt comprises:
(1) with sour salify, free alkali by parent compound reacts and obtains with mineral acid or organic acid, mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acid comprises acetic acid, trifluoroacetic acid, propionic acid, vinylformic acid, caproic acid, pentamethylene propionic acid, hydroxyethanoic acid, pyruvic acid, oxalic acid, (D) or (L) oxysuccinic acid, fumaric acid, toxilic acid, phenylformic acid, hydroxy-benzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methylsulfonic acid, ethyl sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, tosic acid, Whitfield's ointment, tartrate, citric acid, lactic acid, styracin, dodecyl sulphate, glyconic acid, L-glutamic acid, aspartic acid, stearic acid, amygdalic acid, succsinic acid or propanedioic acid etc.
(2) salt that is present in that acid proton in parent compound is replaced by metal ion or is generated with organic bases ligand compound, metal example is alkalimetal ion, alkaline-earth metal ions or aluminum ion for example, organic bases such as thanomin, diethanolamine, trolamine, Trometamol, N-METHYL-ALPHA-L-GLUCOSAMINE etc.
2. general synthetic method
The total preparation of compound of mentioning in the present invention is:
Take to nitro bromobenzyl is starting raw material, obtain product 2 with secondary amine generation substitution reaction, then take iron oxide hydroxide as catalyzer, hydrazine hydrate is that reductive agent obtains reduzate 3, compound 3 obtains amide product 4 with ethoxy propylene acyl chloride reaction, compound 4 obtains product 5 at sulfuric acid catalysis ShiShimonoseki ring, compound 5 obtains bromination product 6 with tribromo oxygen phosphorus reaction, under tetra-triphenylphosphine palladium catalysis, there is linked reaction with m-nitro boric acid and obtain product 7 in compound 6, then take iron oxide hydroxide as catalyzer, hydrazine hydrate is that reductive agent obtains reduzate 8, last and corresponding acyl chloride reaction obtains target compound.
Figure BDA0000407223010000051
3. biological assessment method
At present a lot of for the screening method of inhibition tumor cell proliferation mechanism, mtt assay is one of them.MTT chemistry 3-(4,5-dimethylthiazole-2)-2 by name, 5-phenylbenzene tetrazole bromine salt, is commonly called as tetrazolium bromide, is a kind of dyestuff of yellow color.In viable cell plastosome succinodehydrogenase can metabolism the exogenous colourless MTT of reduction, simultaneously under the effect of cytochrome C, generate blue (or bluish voilet) water-fast formazan (Formazan), and be deposited in cell, in dead cell, not containing succinodehydrogenase, MTT is not reduced.With measuring its absorbance value at 490nm wavelength place by microplate reader after DMSO Rong Xie formazan.Under normal conditions, formazan growing amount is directly proportional to viable count, therefore can infer the number that viable cell according to optical density(OD) OD value.The method has been widely used in screening anti-tumor medicine, cell toxicity test and tumor radiosensitivity mensuration etc.Although mtt assay repeatability is not fine, can be improved by increasing multiple hole count, and can be analyzed by statistical test.Mtt assay carries out cell cultures cell on 96 orifice plates, testing drug inhibition tumor cell proliferation activity, the cell quantity needing is few, adds the quantity of tested medicine many, be easy to carry out dose-effect relationship investigation, also can point out to a certain extent the restraining effect of medicine to tumor cell proliferation.
Beneficial effect of the present invention: the invention provides a class and show the quinoline derivatives propagation of tumour cell to inhibition ability, a kind of composition that contains above-mentioned quinoline derivatives is provided.Provide above-mentioned quinoline derivatives in purposes pharmaceutically.Propagation to human hepatoma cell strain (SMMC7721), human colon cancer cell strain (HCT116) has significant restraining effect.Above-mentioned these compounds can be applicable to the preparation of antitumor drug.
Embodiment
Provide following preparation and embodiment, make those skilled in the art can more clearly understand and implement the present invention.They can not be construed as limiting the scope of the invention, and are only its illustration and representative.
Synthetic example
Embodiment 1
Synthesizing of intermediate 8
Figure BDA0000407223010000061
2-methyl isophthalic acid-(4-nitrobenzyl) piperidines (2a)
In 500mL there-necked flask, add successively nitro bromobenzyl (21.5g, 0.1mol), methylene dichloride (200mL), stirs it is dissolved, and reaction solution is cooled to 0 ℃ with ice-water bath, then drip pipecoline (9.9g, 0.1mol), triethylamine (17.5g), the mixing solutions of methylene dichloride (50mL).After dropwising, reaction solution is warming up to after room temperature to stirring reaction 5h.After reaction finishes, reaction solution is poured in 400mL saturated sodium carbonate solution, stirred 0.5h, separate organic layer, methylene dichloride 3 * 100mL extraction for water layer, merges organic layer, water and saturated nacl aqueous solution washing successively, anhydrous magnesium sulfate drying.Filter, solvent evaporated in vacuo, obtains yellow oil 19.1g, yield 81.6%.
1H-NMR(DMSO-d 6,500MHz)δ(ppm):1.06(s,3H,-CH 3),1.26-1.29(m,2H,1×2-methyl-piperidine-CH 2),1.38-1.39(m,2H,1×2-methylpiperidine-CH 2),1.58-1.63(m,2H,1×2-methylpiperidine-CH 2),1.98-2.03(m,1H,0.5×2-methylpiperidine-CH 2),2.36(s,1H,0.5×2-methyl-piperidine-CH 2),2.58-2.62(m,1H,0.5×2-methylpiperidine-CH 2),3.28-3.32(m,2H,-CH 2-),7.59(d,J=8.55Hz,2H,2×Ar-H),8.17(d,J=8.65Hz,2H,2×Ar-H);TOF-MS?m/z:235.2[M+H] +.
1-(4-nitrobenzyl) piperidines (2b)
Specific experiment operation is synthetic with compound 2a's, adds nitro bromobenzyl (21.5g, 0.1mol), and piperidines (8.5g, 0.1mol), obtains yellow oil 18.9g, yield 85.9%.
IR(KBr,cm -1):3078.49,2926.51,2861.14,1603.96,1514.25,1448.45,1344.55,1316.39,1152.70,1105.01,1041.17,996.92,847.60,741.21.
N-ethyl-N-(4-nitrobenzyl) ethamine (2c)
Specific experiment operation is synthetic with compound 2a's, adds nitro bromobenzyl (21.5g, 0.1mol), and diethylamine (7.3g, 0.1mol), obtains yellow oil 18.4g, yield 88.5%.
1H-NMR(DMSO-d 6,500MHz)δ(ppm):0.95-0.98(m,6H,2×2-diethylamine-CH 3),2.44-2.50(m,4H,2×2-diethylamine-CH 2),3.64(s,2H,-CH 2-),7.58(d,J=8.65Hz,2H,2×Ar-H),8.16(d,J=8.65Hz,2H,2×Ar-H);TOF-MS?m/z:209.0[M+H] +.
4-(4-nitrobenzyl) morpholine (2d)
Specific experiment operation is synthetic with compound 2a's, adds nitro bromobenzyl (21.5g, 0.1mol), and morpholine (8.7g, 0.1mol), obtains yellow solid 19.4g, yield 87.4%, mp76-78 ℃.
IR(KBr,cm -1):3078.49,2969.51,2936.67,2862.95,2818.07,1606.37,1516.96,1445.11,1342.47,1208.73,1117.27,1008.54,912.62,869.27,806.78,744.28.
4-[(2-methyl piperidine-1-yl) methyl] aniline (3a)
In 500mL there-necked flask, add successively compound 2a (18g, 0.077mol), methyl alcohol (200mL), stirring is dissolved it, adds iron oxide hydroxide (1.8g), and reaction solution is warming up to after reflux temperature, drip 80% hydrazine hydrate (15mL), after dropwising, stirring reaction 5h.After reaction finishes, suction filtration while hot, methanol wash filter cake, vacuum-drying solvent, obtains yellow solid 15.1g, yield 96.2%, mp50-51 ℃.
1H-NMR(DMSO-d 6,500MHz)δ(ppm):1.07(s,3H,-CH 3),1.18-1.24(m,2H,1×2-methyl-piperidine-CH 2),1.28-1.35(m,1H,0.5×2-methylpiperidine-CH 2),1.42-1.44(m,1H,0.5×2-methylpiperidine-CH 2),1.56-1.58(m,2H,1×2-methylpiperidine-CH 2),1.82-1.87(m,1H,?0.5×2-methylpiperidine-CH 2),1.98-2.03(m,1H,0.5×2-methylpiperidine-CH 2),2.23-2.24(m,1H,0.5×2-methylpiperidine-CH 2),3.71-3.73(m,2H,-CH 2-),4.84(s,2H,-NH 2),6.48(d,J=8.35Hz,2H,2×Ar-H),6.89(d,J=8.25Hz,2H,2×Ar-H);TOF-MS?m/z:205.2[M+H] +.
4-(piperidines-1-methyl) aniline (3b)
Specific experiment operation is synthetic with compound 3a's, adds compound 7b (18g, 0.078mol), and 80% hydrazine hydrate (15mL), obtains faint yellow solid 14.4g, yield 96.8%.mp75-77℃。
IR(KBr,cm -1):3454.76,3417.63,3311.47,3186.14,2931.38,2851.95,2791.07,1633.16,1613.24,1518.04,1432.51,1342.34,1290.59,1101.20,1036.27,990.78,867.83,821.30,787.03.
4-[(diethylamine) methyl] aniline (3c)
Specific experiment operation is synthetic with compound 3a's, adds compound 7c (18g, 0.086mol), and 80% hydrazine hydrate (18mL), obtains yellow oil 14.9g, yield 96.7%.
1H-NMR(DMSO-d 6,500MHz)δ(ppm):0.99-1.04(m,6H,2×2-diethylamine-CH 3),2.45-2.52(m,4H,2×2-diethylamine-CH 2),3.45(s,2H,-CH 2-),6.32(d,J=7.68Hz,2H,2×Ar-H),7.09(d,J=7.92Hz,2H,2×Ar-H);TOF-MS?m/z:179.1[M+H] +.
4-(morpholine methyl) aniline (3d)
Specific experiment operation is synthetic with compound 3a's, adds compound 7d (18g, 0.081mol), and 80% hydrazine hydrate (18mL), obtains white solid 15.2g, yield 97.4%, mp101-102 ℃.
IR(KBr,cm -1):3351.42,3326.62,2968.32,2858.31,2804.34,1636.58，1515.18,1453.82,1394.06,1351.05,1281.20,1172.13,1107.25,1062.39,1005.20,912.24,860.01,825.41.
(E)-3-oxyethyl group-N-{4-[(2-methyl piperidine-1-yl) methyl] phenyl } acrylamide (4a)
In 500mL there-necked flask, add successively compound 3a (15.3g, 0.075mol), pyridine (8.9g, 0.1125mol), anhydrous tetrahydro furan (200mL), stirring makes its dissolving, reaction solution is bathed and is cooled to-10 ℃ with cryosel, then drip the mixing solutions of 3-ethoxy propylene acyl chlorides (15.1g, 0.1125mol) and anhydrous tetrahydro furan (50mL).After dropwising, at this temperature, continue stirring reaction 2h.Reaction solution is warming up to after room temperature, and stirring is spent the night.After reaction finishes, reaction solution is poured in 1L saturated sodium carbonate solution, stirred 0.5h, the solid that suction filtration is separated out, vacuum-drying, obtains brown solid 18.6g, yield 82.1%, mp110-112 ℃.
1H-NMR(CDCl 3,500MHz)δ(ppm):1.14-1.16(m,3H,-CH 3),1.21-1.31(m,1H,0.5×2-methyl-piperidine-CH 2),1.32-1.36(m,3H,-CH 2 CH 3 ),1.42-1.53(m,2H,1×2-methylpiperidine-CH 2),1.63-1.65(m,2H,1×2-methylpiperidine-CH 2),1.93-1.98(m,2H,1×2-methylpiperidine-CH 2),2.30-2.33(m,1H,0.5×2-methylpiperidine-CH 2),2.70-2.74(m,1H,0.5×2-methylpiperidine-CH 2),3.18-3.22(m,2H,-CH 2-),3.90-3.96(m,2H,- CH 2 CH 3),5.34(d,1H,J=12.05Hz,-COCH=),7.13(s,1H,Ar-H),7.24-7.26(m,1H,Ar-H),7.44(d,J=7.85Hz,2H,2×Ar-H),7.61(d,J=12.05Hz,1H,-OCH=);TOF-MS?m/z:303.1[M+H] +.
(E)-3-oxyethyl group-N-[4-(piperidin-1-yl-methyl) phenyl] acrylamide (4b)
Specific experiment operation is synthetic with compound 4a's, adds compound 3b (14.25g, 0.075mol), and 3-ethoxy propylene acyl chlorides (15.1g, 0.1125mol), obtains yellow solid 18.9g, yield 87.5%.mp109-111℃。
IR(KBr,cm -1):3313.97,2932.79,2844.83,1664.56,1636.52,1526.24,1411.11,1340.98,1166.18,1013.68,996.45,953.09,846.40,793.38.
(E)-N-{4-[(diethylin) methyl] phenyl }-3-ethoxy propylene acid amides (4c)
Specific experiment operation is synthetic with compound 4a's, adds compound 3c (13.35g, 0.075mol), and 3-ethoxy propylene acyl chlorides (15.1g, 0.1125mol), obtains brown color solid 18.5g, yield 89.8%, mp114-116 ℃.
1H-NMR(CDCl 3,500MHz)δ(ppm):1.03-1.06(m,6H,2×2-diethylamine-CH 3),1.33-1.35(m,3H,-CH 2 CH 3 ),2.50-2.54(m,4H,2×2-diethylamine-CH 2),3.54(s,2H,-CH 2-),3.91-3.95(m,2H,- CH 2 CH 3),5.33(d,J=12.08Hz,1H,-COCH=),7.26-7.29(m,2H,2×Ar-H),7.44(d,J=7.8Hz,2H,2×Ar-H),7.62(d,J=12Hz,1H,-OCH=);TOF-MS?m/z:277.1[M+H] +.
(E)-3-oxyethyl group-N-[4-(piperidin-1-yl-methyl) phenyl] acrylamide (4d)
Specific experiment operation is synthetic with compound 4a's, adds compound 3d (14.4g, 0.075mol), and 3-ethoxy propylene acyl chlorides (15.1g, 0.1125 mol), obtains faint yellow solid 19.8g, yield 91.0%, mp134-135 ℃.
IR(KBr,cm -1):3257.68,2968.36,2857.67,1676.26,1605.84,1532.56,1409.51,1354.30,1323.16,1149.21,1119.11,1008.96,967.42,913.68,864.24,817.63,790.55.
(E)-N-[4-(dimethylamino) phenyl]-3-ethoxy propylene acid amides (4e)
Specific experiment operation is synthetic with compound 4a's, adds 4-(N, N-dimethyl) aniline (10.2g, 0.075mol), and 3-ethoxy propylene acyl chlorides (15.1g, 0.1125mol), obtains brown solid 15.5g, yield 88.6%, mp143-144 ℃.
IR(KBr,cm -1):3295.37,3258.31,2981.19,2891.25,1656.91,1611.80,1524.98,1474.99,1343.40,1235.91,1152.14,1012.74,959.09,812.89,710.11.
(E)-3-oxyethyl group N-phenyl-acrylamide (4f)
Specific experiment operation is synthetic with compound 4a's, adds aniline (6.98g, 0.075mol), and 3-ethoxy propylene acyl chlorides (15.1g, 0.1125mol), obtains brown solid 13.2g, yield 92.3%, mp137-138 ℃.
1H-NMR(CDCl 3,500MHz)δ(ppm):1.33-1.36(m,3H,-CH 2 CH 3 ),3.92-3.96(m,2H,- CH 2 CH 3),5.32(d,J=12.05Hz,1H,-COCH=),7.07-7.10(m,1H,1×Ar-H),7.29-7.32(m,2H,2×Ar-H),7.50(d,J=7.85Hz,2H,2×Ar-H),7.59(d,J=12Hz,1H,-OCH=);TOF-MS?m/z:192.0[M+H] +.
(E)-3-oxyethyl group N-(p-methylphenyl)-acrylamide (4g)
Specific experiment operation is synthetic with compound 4a's, adds monomethylaniline (8.02g, 0.075mol), and 3-ethoxy propylene acyl chlorides (15.1g, 0.1125mol), obtains gray solid 13.9g, yield 90.3%, mp165-167 ℃.
IR(KBr,cm -1):3298.59,3258.96,2981.64,1663.67,1621.99,1514.31,1471.18,1407.27,1359.01,1292.50,1245.81,1162.71,1016.43,861.88,816.91.
2-hydroxyl-6-[(2-methyl piperidine) methyl] quinoline (5a)
In 500mL there-necked flask, add the vitriol oil (30mL), with cryosel, bathe and be cooled to-10 ℃, then add compound 4a (12.08g, 0.04mol) in batches.After adding, reaction solution is warming up to after room temperature to stirring reaction 5h.After reaction finishes, reaction solution is poured in 1L saturated sodium carbonate solution, stirred 0.5h, the solid that suction filtration is separated out, vacuum-drying, obtains yellow solid 7.6g, yield 74.2%, mp179-181 ℃.
1H-NMR(CDCl 3,500MHz)δ(ppm):1.09-1.10(m,3H,-CH 3),1.23-1.28(m,2H,1×2-methyl-piperidine-CH 2),1.30-1.32(m,1H,0.5×2-methylpiperidine-CH 2),1.34-1.38(m,1H,0.5×2-methylpiperidine-CH 2),1.57-1.59(m,2H,1×2-methylpiperidine-CH 2),1.90-1.95(m,1H,0.5×2-methylpiperidine-CH 2),2.31(s,1H,0.5×2-methylpiperidine-CH 2),2.59-2.62(m,1H,0.5×2-methylpiperidine-CH 2),3.13-3.18(m,2H,-CH 2-),6.46(d,J=9.5Hz,1H,Ar-H),7.25(d,J=8.3Hz,1H,Ar-H),7.42(d,J=8.3Hz,1H,Ar-H),7.53(s,1H,Ar-H),7.87(d,J=9.5Hz,1H,Ar-H),11.65(s,1H,-OH);TOF-MS?m/z:257.1[M+H] +.
2-hydroxyl-6-(piperidine methyl) quinoline (5b)
Specific experiment operation is synthetic with compound 5a's, adds compound 4b (11.52g, 0.04mol), and sulfuric acid (30mL), obtains off-white color solid 7.54g, yield 77.9%, mp197-199 ℃.
IR(KBr,cm -1):3440.91,2930.35,2851.01,1666.45,1601.85,1564.31,1475.01,1434.02,1367.63,1287.64,1167.91,1112.39,1038.43,993.48,908.10,831.22,783.89; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):1.39-1.48(m,6H,3×piperidine-CH 2),2.31-2.51(m,4H,2×piperidine-CH 2),3.32-3.43(m,2H,-CH 2-),6.47(d,J=9.48Hz,1H,Ar-H),7.24(d,J=8.31Hz,1H,Ar-H),7.42(d,J=8.25Hz,1H,Ar-H),7.53(s,1H,Ar-H),7.88(d,J=9.51Hz,1H,Ar-H),11.69(s,1H,-OH);TOF-MS?m/z:243.2[M+H] +,265.2[M+Na] +.
2-hydroxyl-6-(diethylamine methyl) quinoline (5c)
Specific experiment operation is synthetic with compound 5a's, adds compound 4c (11.04g, 0.04mol), and sulfuric acid (30mL), obtains yellow solid 6.77g, yield 73.6%, mp154-155 ℃.
1H-NMR(DMSO-d 6,300MHz)δ(ppm):0.95-0.99(m,6H,2×2-diethylamine-CH 3),2.42-2.51(m,4H,2×2-diethylamine-CH 2),3.53(s,2H,-CH 2-),6.47(d,J=9.51Hz,1H,Ar-H),7.24(d,J=8.4Hz,1H,Ar-H),7.43(d,J=8.4Hz,1H,Ar-H),7.55(s,1H,Ar-H),7.88(d,J=9.54Hz,1H,Ar-H),11.67(s,1H,-OH);TOF-MS?m/z:231.1[M+H] +,253.1[M+Na] +.
2-hydroxyl-6-(morpholine methyl) quinoline (5d)
Specific experiment operation is synthetic with compound 5a's, adds compound 4d (11.6g, 0.04mol), and sulfuric acid (30mL), obtains off-white color solid 7.2g, yield 73.8%, mp229-231 ℃.
IR(KBr,cm -1):3146.51,2955.12,2861.32,1651.50,1564.74,1499.96,1454.57,1429.59,1373.88,1286.17,1159.14,1112.35,1008.37,911.75,860.18; 1H-NMR(DMSO-d 6,500MHz)δ(ppm):2.35-2.50(m,4H,2×morpholine-CH 2),3.48(s,2H,-CH 2-),3.55-3.57(s,4H,2×morpholine-CH 2),6.47(d,J=9.55Hz,1H,Ar-H),7.26(d,J=8.35Hz,1H,Ar-H),7.43(d,J=8.35Hz,1H,Ar-H),7.55(s,1H,Ar-H),7.88(d,J=9.45Hz,1H,Ar-H),11.68(s,1H,-OH);TOF-MS?m/z:245.2[M+H] +,267.2[M+Na] +.
2-hydroxyl-6-(N, N-dimethyl) quinoline (5e)
Specific experiment operation is synthetic with compound 5a's, adds compound 4e (9.36g, 0.04mol), and sulfuric acid (30mL), obtains brown solid 5.42g, yield 72.1%, mp243-244 ℃.
IR(KBr,cm -1):3140.78,2984.12,2895.30,2817.66,1656.89,1618.52,1505.34,1425.84,1360.37,1199.17,1114.28,1067.67,969.01,905.17,840.04,814.73,754.36,686.12,583.02; 1H-NMR(DMSO-d 6,500MHz)δ(ppm):2.88(s,6H,-N(CH 3) 2),6.42(d,J=9.5Hz,1H,Ar-H),6.91(d,J=2.5Hz,1H,Ar-H),7.09(d,J=8.9Hz,1H,Ar-H),7.18(d,J=8.9Hz,1H,Ar-H),7.77(d,J=9.5Hz,1H,Ar-H),11.42(s,1H,-OH);TOF-MS?m/z:189.1[M+H] +,211.1[M+Na] +.
2-hydroxyquinoline (5f)
Specific experiment operation is synthetic with compound 5a's, adds compound 4f (7.64g, 0.04mol), and sulfuric acid (30mL), obtains yellow solid 4.21g, yield 72.7%, mp200-201 ℃.
1H-NMR(CDCl 3,500MHz)δ(ppm):6.79(d,J=9.45Hz,1H,Ar-H),7.30-7.33(m,1H,Ar-H),7.42(d,J=8.2Hz,1H,Ar-H),7.57-7.60(m,1H,Ar-H),7.64(d,J=7.9Hz,1H,Ar-H),7.93(d,J=9.4Hz,1H,Ar-H),11.43(s,1H,-OH);TOF-MS?m/z:146.0[M+H] +,168.0[M+Na] +.
2-hydroxyl-6-toluquinoline (5g)
Specific experiment operation is synthetic with compound 5a's, adds compound 4g (8.2g, 0.04mol), and sulfuric acid (30mL), obtains white solid 4.66g, yield 73.4%, mp244-245 ℃.
IR(KBr,cm -1):3134.00,3092.37,2914.73,2865.81,1660.66,1607.36,1566.22,1500.95,1429.48,1381.01,1280.30,1173.58,1137.87,955.55,879.96,861.39,806.12,690.00,599.27; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):2.32(s,3H,-CH 3),7.46(d,J=7.9Hz,1H,Ar-H),7.17-7.32(m,2H,2×Ar-H),7.42(s,1H,Ar-H),7.81(d,J=9.36Hz,1H,Ar-H),11.64(s,1H,-OH);TOF-MS?m/z:160.1[M+H] +.
The bromo-6-[(2-methyl piperidine of 2-) methyl] quinoline (6a)
In 500mL there-necked flask, compound 5a (12.8g, 0.05mol) successively, chloroform (200mL), stirs and makes its dissolving.Then add tribromo oxygen phosphorus (21.53g, 0.075mol).After adding, reaction solution is warming up to after reflux temperature to stirring reaction 8h.After reaction finishes, reaction solution is poured in 1L saturated sodium carbonate solution, stirred 0.5h, separate organic layer, methylene dichloride 3 * 150mL extraction for water layer, merges organic layer, anhydrous magnesium sulfate drying, suction filtration, solvent evaporated in vacuo, obtains white solid 12.9g, yield 81.6%, mp62-63 ℃.
1H-NMR(DMSO-d 6,300MHz)δ(ppm):1.12-1.13(m,3H,-CH 3),1.27-1.45(m,4H,2×2-methyl-piperidine-CH 2),1.62(s,2H,1×2-methylpiperidine-CH 2),1.96-2.03(m,1H,0.5×2-methylpiperidine-CH 2),2.38(s,1H,0.5×2-methylpiperidine-CH 2),2.62-2.66(m,1H,0.5×2-methylpiperidine-CH 2),3.30-3.35(m,2H,-CH 2-),7.67(d,J=8.58Hz,1H,Ar-H),7.78(d,J=8.79Hz,1H,Ar-H),7.91(d,J=8.34Hz,2H,2×Ar-H),8.31(d,J=8.58Hz,1H,Ar-H);TOF-MS?m/z:319.1[M+H] +.
The bromo-6-of 2-(piperidine methyl) quinoline (6b)
Specific experiment operation is synthetic with compound 6a's, adds compound 5b (12.1g, 0.05mol), and tribromo oxygen phosphorus (21.53g, 0.075mol), obtains off-white color solid 12.4g, yield 81.9%, mp83-85 ℃.
IR(KBr,cm -1):3440.62,2940.25,2916.82,2850.23,2780.95,1578.37,1562.36,1493.03,1453.86,1398.05,1331.42,1295.77,1124.44,1110.07,1084.21,1036.24,992.78,896.49,846.08,808.33,785.64,749.37;? 1H-NMR(DMSO-d 6,500MHz)δ(ppm):1.39-1.42(m,2H,piperidine-CH 2),1.49-1.53(m,4H,2×piperidine-CH 2),2.36(s,4H,2×piperidine-CH 2),3.59(s,2H,-CH 2-),7.66(d,J=8.55Hz,1H,Ar-H),7.24(d,?J=8.6Hz,1H,Ar-H),7.89-7.92(m,2H,2×Ar-H),8.30(d,J=8.6Hz,1H,Ar-H);TOF-MS?m/z:305.1[M+H] +.
The bromo-6-of 2-(diethylamine methyl) quinoline (6c)
Specific experiment operation is synthetic with compound 6a's, adds compound 5c (11.5g, 0.05mol), and tribromo oxygen phosphorus (21.53g, 0.075mol), obtains brown oil 11.8g, yield 80.9%.
1H-NMR(DMSO-d 6,300MHz)δ(ppm):0.97-1.02(m,6H,2×2-diethylamine-CH 3),2.46-2.53(m,4H,2×2-diethylamine-CH 2),3.68(s,2H,-CH 2-),7.66(d,J=8.58Hz,1H,Ar-H),7.77-7.80(m,1H,Ar-H),7.92(d,J=8.55Hz,2H,2×Ar-H),8.31(d,J=8.52Hz,1H,Ar-H);TOF-MS?m/z:293.1[M+H] +.
The bromo-6-of 2-(morpholine methyl) quinoline (6d)
Specific experiment operation is synthetic with compound 6a's, adds compound 5d (12.2g, 0.05mol), and tribromo oxygen phosphorus (21.53g, 0.075mol), obtains white solid 12.7g, yield 83.2%, mp69-72 ℃.
IR(KBr,cm -1):3146.51,2955.12,2861.32,1651.50,1564.74,1499.96,1454.57,1429.59,1373.88,1286.17,1159.14,1112.35,1008.37,911.75,860.18; 1H-NMR(DMSO-d 6,500MHz)δ(ppm):2.39-2.41(m,4H,2×morpholine-CH 2),3.58-3.60(m,4H,2×morpholine-CH 2),3.65(s,2H,-CH 2-),7.68(d,J=8.55Hz,1H,Ar-H),7.79(d,J=8.75Hz,1H,Ar-H),7.92-7.94(m,2H,2×Ar-H),8.31(d,J=8.55Hz,1H,Ar-H);TOF-MS?m/z:307.1[M+H] +.
The bromo-6-of 2-(N, N-dimethyl) quinoline (6e)
Specific experiment operation is synthetic with compound 6a's, adds compound 5e (9.4g, 0.05mol), and tribromo oxygen phosphorus (21.53g, 0.075mol), obtains yellow solid 9.15g, yield 73.2%, mp80-81 ℃.
IR(KBr,cm -1):2923.61,2809.33,1618.73,1567.39,1511.55,1450.88,1366.90,1263.24,1151.14,1129.57,1085.18,934.56,844.78,813.40,633.51; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):3.03(s,6H,-N(CH 3) 2),6.95(d,J=2.79Hz,1H,Ar-H),7.43-7.49(m,2H,2×Ar-H),7.77(d,J=9.33Hz,1H,Ar-H),8.03(d,J=8.61Hz,1H,Ar-H);TOF-MS?m/z:251.1[M+H] +.
2-bromoquinoline (6f)
Specific experiment operation is synthetic with compound 6a's, adds compound 5f (7.25g, 0.05mol), and tribromo oxygen phosphorus (21.53g, 0.075mol), obtains faint yellow solid 8.3g, yield 80.2%, mp55-56 ℃.
1H-NMR(DMSO-d 6,300MHz)δ(ppm):7.81-7.86(m,1H,Ar-H),7.97-8.03(m,1H,Ar-H),8.10(d,J=9.42Hz,1H,Ar-H),8.25-8.30(m,1H,Ar-H),8.33(s,1H,Ar-H),8.65(d,J=8.34Hz,1H,Ar-H).
The bromo-6-toluquinoline of 2-(6g)
Specific experiment operation is synthetic with compound 6a's, adds compound 5g (7.95g, 0.05mol), and tribromo oxygen phosphorus (21.53g, 0.075mol), obtains white solid 8.8g, yield 79.8%, mp124-126 ℃.
IR(KBr,cm -1):3435.90,3065.94,2977.94,2926.46,1609.27,1569.95,1526.30,1456.87,1316.44,1278.07,1087.05,1042.09,993.99,887.78,819.83,697.77; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):2.50(s,3H,-CH 3),7.64-7.65(m,1H,Ar-H),7.67-7.68(m,1H,Ar-H),7.80(s,1H,Ar-H),7.87(d,J=8.61Hz,1H,Ar-H),8.23(d,J=8.55Hz,1H,Ar-H);TOF-MS?m/z:222.0[M+H] +.
2-(3-nitrophenyl)-6-[(2-methyl piperidine) methyl] quinoline (7a)
In 250mL there-necked flask, add successively DMF (50mL), water (50mL), stirs lower argon replaces 0.5h.Then add successively compound 6a (3.18g, 0.01mol), m-nitro boric acid (1.67g, 0.01mol), tetra-triphenylphosphine palladium (0.058g), under argon shield, is warming up to reaction solution after 100 ℃ stirring reaction 6h.After reaction finishes, reaction solution is poured in 1L frozen water, stirred 0.5h, suction filtration, washing filter cake is to neutral, and vacuum-drying, obtains faint yellow solid 1.9g, yield 52.6%, mp137-138 ℃.
IR(KBr,cm -1):3095.19,2932.25,2845.42,1592.29,1522.37,1502.72,1444.99,1344.52,1323.34,1276.34,1106.00,1081.13,889.94,844.36,804.80,740.48; 1H-NMR(DMSO-d 6,500MHz)δ(ppm):1.14-1.15(m,3H,-CH 3),1.27-1.33(m,2H,1×2-methylpiperidine-CH 2),1.40-1.42(m,1H,0.5×2-methylpiperidine-CH 2),1.47(s,1H,0.5×2-methylpiperidine-CH 2),1.62-1.64(m,2H,1×2-methylpiperidine-CH 2),1.99-2.05(m,1H,0.5×2-methylpiperidine-CH 2),2.40(s,1H,0.5×2-methylpiperidine-CH 2),2.67-2.70(m,1H,0.5×2-methylpiperidine-CH 2),3.30-3.36(m,2H,-CH 2-),7.79(d,J=8.6Hz,1H,Ar-H),7.84-7.87(m,1H,Ar-H),?7.90(s,1H,Ar-H),8.09(d,J=8.58Hz,1H,Ar-H),8.26(d,J=8.6Hz,1H,Ar-H),8.34(d,J=8.05Hz,1H,Ar-H),8.50(d,J=8.65Hz,1H,Ar-H),8.70(d,J=7.8Hz,1H,Ar-H),9.08(s,1H,Ar-H);TOF-MS?m/z:362.2[M+H] +.
2-(3-nitrophenyl)-6-(piperidine methyl) quinoline (7b)
Specific experiment operation is synthetic with compound 7a's, adds compound 6b (3.04g, 0.01mol), m-nitro boric acid (1.67g, 0.01mol), tetra-triphenylphosphine palladium (0.058g), obtain yellow solid 1.8g, yield 51.9%, mp103-105 ℃.
IR(KBr,cm -1):3437.96,2932.09,2852.22,2802.56,1596.33,1522.43,1498.44,1324.97,1274.91,1105.95,805.45,742.01; 1H-NMR(DMSO-d 6,500MHz)δ(ppm):1.40-1.41(m,2H,1×piperidine-CH 2),1.50-1.54(m,4H,2×piperidine-CH 2),2.38(s,4H,2×piperidine-CH 2),3.30(s,2H,-CH 2-),7.75-7.77(m,1H,Ar-H),7.82-7.86(m,1H,Ar-H),7.98(s,1H,Ar-H),8.07(d,J=8.6Hz,1H,Ar-H),8.23(d,J=8.6Hz,1H,Ar-H),8.31-8.34(m,1H,Ar-H),8.47(d,J=8.65Hz,1H,Ar-H),8.68(d,J=7.85Hz,1H,Ar-H),9.05(s,1H,Ar-H); 13C-NMR(DMSO-d 6,125MHz)δ(ppm):23.92,25.52,25.52,53.96,53.96,62.51,118.56,121.36,123.81,126.69,127.06,128.92,130.37,133.19,137.33,137.84,140.23,146.81,148.44,153.06;TOF-MS?m/z:348.2[M+H] +.
2-(3-nitrophenyl)-6-[(diethylamine) methyl] quinoline (7c)
Specific experiment operation is synthetic with compound 7a's, adds compound 6c (2.93g, 0.01mol), m-nitro boric acid (1.67g, 0.01mol), and tetra-triphenylphosphine palladium (0.058g), obtains yellow solid 1.7g, yield 51.1%, mp83-85 ℃.
IR(KBr,cm -1):2972.66,2930.51,2815.65,1598.95,1529.93,1500.06,1459.15,1347.40,1201.88,1094.98,1069.19,836.04,799.78,737.75; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):0.99-1.04(m,6H,2×2-diethylamine-CH 3),2.47-2.54(m,4H,2×2-diethylamine-CH 2),3.68(s,2H,-CH 2-),7.74-7.75(m,1H,Ar-H),7.77-7.78(m,1H,Ar-H),7.85-7.87(m,1H,Ar-H),8.06(d,J=8.64Hz,1H,Ar-H),8.22(d,J=8.67Hz,1H,Ar-H),8.30-8.33(m,1H,Ar-H),8.45(d,J=8.67Hz,1H,Ar-H),8.67(d,J=7.92Hz,1H,Ar-H),9.0-9.05(m,1H,Ar-H); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):11.63,11.63,46.28,48.28,56.70,118.48,121.31,123.77,126.24,127.06,128.88,130.31,131.18,133.15,137.23,139.23,140.19,146.77,148.36,152.88;TOF-MS?m/z:336.3[M+H] +.
2-(3-nitrophenyl)-6-(morpholine methyl) quinoline (7d)
Specific experiment operation is synthetic with compound 7a's, adds compound 6d (3.06g, 0.01mol), m-nitro boric acid (1.67g, 0.01mol), tetra-triphenylphosphine palladium (0.058g), obtain yellow solid 1.83g, yield 52.7%, mp120-122 ℃.
IR(KBr,cm -1):3440.99,3290.00,3155.07,2935.31,2849.87,1635.44,1595.58,1556.46,1494.04,1464.73,1341.48,1320.53,1095.38,845.48; 1H-NMR(DMSO-d 6,500MHz)δ(ppm):2.43(s,4H,2×morpholine-CH 2),3.63(s,4H,2×morpholine-CH 2),3.64(s,2H,-CH 2-),7.76(d,J=8.55Hz,1H,Ar-H),7.79-7.83(m,1H,Ar-H),7.87(s,1H,Ar-H),8.06(d,J=8.55Hz,1H,Ar-H),8.20(d,J=8.6Hz,1H,Ar-H),8.30(d,J=7.9Hz,1H,Ar-H),8.44(d,J=8.6Hz,1H,Ar-H),8.65(d,J=7.7Hz,1H,Ar-H),9.03(s,1H,Ar-H);TOF-MS?m/z:350.2[M+H] +.
2-(3-nitrophenyl)-6-(N, N-dimethyl) quinoline (7e)
Specific experiment operation is synthetic with compound 7a's, adds compound 6e (2.5g, 0.01mol), m-nitro boric acid (1.67g, 0.01mol), tetra-triphenylphosphine palladium (0.058g), obtain red solid 1.55g, yield 53.1%, mp175-177 ℃.
IR(KBr,cm -1):2923.61,2809.33,1618.73,1567.39,1511.55,1450.88,1366.90,1263.24,1151.14,1129.57,1085.18,934.56,844.78,813.40,633.51; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):3.08(s,6H,-N(CH 3) 2),6.97(d,J=2.7Hz,1H,Ar-H),7.49-7.66(m,2H,2×Ar-H),7.78-7.83(m,1H,Ar-H),7.96(d,J=9.33Hz,1H,Ar-H),8.12(d,J=8.7Hz,1H,Ar-H),8.22-8.29(m,1H,Ar-H),8.64(d,J=7.98Hz,1H,Ar-H),9.02-9.03(m,1H,Ar-H);? 13C-NMR(DMSO-d 6,75MHz)δ(ppm):40.33,40.33,118.59,120.74,123.05,128.64,128.80,129.83,130.33,131.38,132.01,132.59,135.14,140.71,148.49,148.71,148.75;TOF-MS?m/z:295.2[M+H] +.
2-(3-nitrophenyl) quinoline (7f)
Specific experiment operation is synthetic with compound 7a's, adds compound 6f (2.07g, 0.01mol), m-nitro boric acid (1.67g, 0.01mol), tetra-triphenylphosphine palladium (0.058g), obtain yellow solid 1.34g, yield 53.6%, mp117-119 ℃.
IR(KBr,cm -1):3075.46,2853.18,1596.53,1523.92,1508.31,1343.99,1289.65,844.25,801.52,766.85,738.15;? 1H-NMR(DMSO-d 6,300MHz)δ(ppm):7.64-7.69(m,1H,Ar-H),7.81-7.89(m,2H,2×Ar-H),8.06(d,?J=8.22Hz,1H,Ar-H),8.16(d,J=8.43Hz,1H,Ar-H),8.30-8.37(m,2H,2×Ar-H),8.56(d,J=8.61Hz,1H,Ar-H),8.73(d,J=7.86Hz,1H,Ar-H),9.09(s,1H,Ar-H);TOF-MS?m/z:251.2[M+H] +.
2-(3-nitrophenyl)-6-toluquinoline (7g)
Specific experiment operation is synthetic with compound 7a's, adds compound 6g (2.21g, 0.01mol), m-nitro boric acid (1.67g, 0.01mol), tetra-triphenylphosphine palladium (0.058g), obtain yellow solid 1.36g, yield 51.6%, mp122-124 ℃.
IR(KBr,cm -1):2920.72,2852.86,1595.15,1518.07,1499.84,1444.17,1349.09,1330.77,1286.79,1277.53,822.30,810.28,739.46; 1H-NMR(DMSO-d 6,500MHz)δ(ppm):2.52(s,3H,-CH 3),7.64-7.66(m,1H,Ar-H),7.78(s,1H,Ar-H),7.81-7.85(m,1H,Ar-H),8.02(d,J=8.55Hz,1H,Ar-H),8.21(d,J=8.6Hz,1H,Ar-H),8.31-8.33(m,1H,Ar-H),8.40(d,J=8.6Hz,1H,Ar-H),8.67(d,J=7.85Hz,1H,Ar-H),9.04(s,1H,Ar-H);? 13C-NMR(DMSO-d 6,125MHz)δ(ppm):21.05,118.53,121.27,123.72,126.39,127.26,128.86,130.32,132.32,133.11,136.60,136.85,140.21,145.96,148.40,152.60;TOF-MS?m/z:265.1[M+H] +.
2-(3-aminophenyl)-6-[(2-methyl piperidine) methyl] quinoline (8a)
In 100mL there-necked flask, add successively compound 7a (1.8g, 5mmol), methyl alcohol (50mL), stirring is dissolved it, adds iron oxide hydroxide (0.18g), and reaction solution is warming up to after reflux temperature, drip 80% hydrazine hydrate (5mL), after dropwising, stirring reaction 5h.After reaction finishes, suction filtration while hot, methanol wash filter cake, vacuum-drying solvent, obtains yellow solid 1.6g, yield 96.8%.
2-(3-aminophenyl)-6-(piperidine methyl) quinoline (8b)
Specific experiment operation is synthetic with compound 8a's, adds compound 7b (1.74g, 5mmol), and 80% hydrazine hydrate (5mL), obtains faint yellow solid 1.54g, yield 97.1%.
1H-NMR(DMSO-d 6,300MHz)δ(ppm):1.15-1.22(m,2H,piperidine-CH 2),1.39-1.51(m,4H,2×piperidine-CH 2),2.37(s,4H,2×piperidine-CH 2),3.60(s,2H,-CH 2-),5.26(s,2H,-NH 2),6.68-6.71(m,1H,Ar-H),7.16-7.21(m,1H,Ar-H),7.34(d,J=7.8Hz,1H,Ar-H),7.52(s,1H,Ar-H),7.71(d,J=8.67Hz,1H,Ar-H),7.82(s,1H,Ar-H),7.95-8.0(m,2H,2×Ar-H),8.36(d,J=8.67Hz,1H,Ar-H); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):23.95,23.95,23.95,53.95,53.95,62.57,112.37,114.84,115.13,118.67,126.57,126.72,128.67,129.17,130.91,136.50,136.77,139.35,146.88,149.05,156.39;TOF-MS?m/z:318.2[M+H] +.
2-(3-aminophenyl)-6-[(diethylamine) methyl] quinoline (8c)
Specific experiment operation is synthetic with compound 8a's, adds compound 7c (1.68g, 5mmol), and 80% hydrazine hydrate (5mL), obtains faint yellow solid 1.48g, yield 97.3%.
2-(3-aminophenyl)-6-(morpholine methyl) quinoline (8d)
Specific experiment operation is synthetic with compound 8a's, adds compound 7d (1.75g, 5mmol), and 80% hydrazine hydrate (5mL), obtains yellow solid 1.56g, yield 97.5%.
1H-NMR(DMSO-d 6,300MHz)δ(ppm):2.41-2.51(m,4H,2×morpholine-CH 2),3.34(s,4H,2×morpholine-CH 2),3.59-3.65(m,2H,-CH 2-),5.27(s,2H,-NH 2),6.70(d,J=7.83Hz,1H,Ar-H),7.16-7.21(m,1H,Ar-H),7.34(d,J=7.68Hz,1H,Ar-H),7.53(s,1H,Ar-H),7.73(d,J=8.73Hz,1H,Ar-H),7.85(s,1H,Ar-H),7.96-8.01(m,2H,2×Ar-H),8.36(d,J=8.67Hz,1H,Ar-H); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):53.22,53.22,62.17,62.17,66.17,112.39,114.87,115.18,118.75,126.59,127.05,128.81,129.21,130.97,135.91,136.55,139.33,146.96,149.08,156.52;TOF-MS?m/z:320.2[M+H] +.
2-(3-aminophenyl)-6-(N, N-dimethyl) quinoline (8e)
Specific experiment operation is synthetic with compound 8a's, adds compound 7e (1.47g, 5mmol), and 80% hydrazine hydrate (5mL), obtains yellow solid 1.27g, yield 96.5%.
1H-NMR(DMSO-d 6,300MHz)δ(ppm):3.05(s,6H,-N(CH 3) 2),6.63(d,J=7.77Hz,1H,Ar-H),6.93-6.94(m,1H,Ar-H),7.12-7.17(m,1H,Ar-H),7.28(d,J=7.74Hz,1H,Ar-H),7.43-7.47(m,2H,2×Ar-H),7.80-7.87(m,2H,2×Ar-H),8.12(d,J=8.7Hz,1H,Ar-H); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):40.33,40.33,104.68,111.97,114.44,118.63,119.70,128.33,129.06,129.50,134.52,134.84,139.76,141.37,148.18,148.93,152.37.
2-(3-aminophenyl) quinoline (8f)
Specific experiment operation is synthetic with compound 8a's, adds compound 7f (1.25g, 5mmol), and 80% hydrazine hydrate (5mL), obtains yellow solid 1.06g, yield 96.7%.
2-(3-aminophenyl)-6-toluquinoline (8g)
Specific experiment operation is synthetic with compound 8a's, adds compound 7g (1.32g, 5mmol), and 80% hydrazine hydrate (5mL), obtains yellow solid 1.12g, yield 96.9%.
Embodiment 2
Martonite (9)
In 500mL there-necked flask, add successively acetone (50mL, 0.687mol), Glacial acetic acid (38mL) and water (180mL), stir.Reaction solution is heated to 65 ℃, then slowly drips bromine (35.4mL, 0.687mol), control rate of addition and make system temperature be no more than 65 ℃.After dropwising, continuing stirring reaction 2h at this temperature, is colourless to reaction solution color.Reaction solution is cooled to 0 ℃ with ice bath, slowly adds frozen water (100mL), control reacting liquid temperature lower than 0 ℃.Then add anhydrous sodium carbonate to regulate reaction system to neutral, stratification, separates lower floor's liquid, and dry with Calcium Chloride Powder Anhydrous, suction filtration, and residuum underpressure distillation at 70-75 ℃, obtains colourless liquid 33.7g, yield 35.82%.
Embodiment 3
3-ethoxycarbonyl-2,5-hexanedione (10)
In 500mL there-necked flask, add sodium (6.9g, 0.3mol), cryosel is bathed and is cooled to-5 ℃, slowly drips dehydrated alcohol (300mL), maintains temperature of reaction and is no more than 10 ℃.After dropwising, under room temperature, be stirred to solution clarification.Cryosel is bathed and is cooled to-10 ℃, adds methyl aceto acetate (36.1mL, 0.238mol), stirs after 0.5h, slowly drips martonite (32.59g, 0.238mol).After dropwising, under room temperature, stirring reaction spends the night.Hydrochloric acid regulates reaction system pH to neutral, underpressure distillation concentration of reaction solution, residuum acetic acid ethyl dissolution, washing organic layer, anhydrous magnesium sulfate drying, suction filtration, solvent evaporated in vacuo, residuum be take sherwood oil: the mixed solvent of ethyl acetate (V:V)=5:1 is eluent, and silica gel column chromatography separating-purifying obtains weak yellow liquid 21.3g, yield 48.12%.
1H-NMR(DMSO-d 6,300MHz)δ(ppm):1.15-1.20(m,3H,-OCH 2 CH 3 ),2.11(s,3H,-CH 3),2.23(s,3H,-CH 3),2.89-3.06(m,2H,- CH 2 COCH 3),3.30-3.32(m,1H,-CH-),4.06-4.13(m,2H,-O CH 2 CH 3);TOF-MS?m/z:185.1[M-H] -.
Embodiment 4
2,5-dimethyl-1-phenylpyrrole-3-ethyl formate (11)
In 500mL single port bottle, add successively compound 10 (18.6g, 0.1mol), tosic acid (1.6g, 0.0093mol), aniline (9mL, 0.1mol) and toluene (200mL), stir and make its dissolving.Reaction solution is heated to reflux temperature reaction 12h.After reaction finishes, reaction solution is cooled to room temperature, by saturated sodium carbonate solution washing, ethyl acetate aqueous layer extracted, merge organic layer, anhydrous magnesium sulfate drying, suction filtration, solvent evaporated in vacuo, residuum be take sherwood oil: the mixed solvent of ethyl acetate (V:V)=10:1 is eluent, silica gel column chromatography separating-purifying obtains faint yellow solid 17.9g, yield 73.96%, mp145-146 ℃.
1H-NMR(DMSO-d 6,500MHz)δ(ppm):1.24-1.27(m,3H,-OCH 2 CH 3 ),1.92(s,3H,-CH 3),2.20(s,3H,-CH 3),4.15-4.20(m,2H,-O CH 2 CH 3),6.27(s,1H,Ar-H),7.29-7.31(m,2H,2×Ar-H),7.50-7.53(m,1H,Ar-H),7.54-7.58(m,2H,2×Ar-H);TOF-MS?m/z:266.1[M+Na] +.
Embodiment 5
2,5-dimethyl-1-phenylpyrrole-3-formic acid (12)
In the there-necked flask of 250mL, add successively compound 19 (24.3g, 0.1mol), potassium hydroxide (16.88g, 0.3mol), methyl alcohol (150mL) and water (15mL), stir and make its dissolving.Reaction solution is heated to reflux temperature reaction to spend the night.After reaction finishes, reaction solution slowly to frozen water, and with hydrochloric acid regulation system pH to 2, is separated out to solid, suction filtration, vacuum-drying obtains yellow solid 19.87g, yield 92.4%, mp220-222 ℃.
IR(KBr,cm -1):2921.35,2598.49,1656.81,1596.58,1580.96,1533.55,1495.25,1402.35,1332.16,1265.22,1085.92,1008.45,955.25,773.39,728.57; 1H-NMR(DMSO-d 6,500MHz)δ(ppm):2.19-2.51(m,6H,2×-CH 3),6.22-6.23(m,1H,Ar-H),7.29-7.31(m,2H,2×Ar-H),7.49-7.52(m,1H,Ar-H),7.54-7.57(m,2H,2×Ar-H),11.58(s,1H,-COOH);TOF-MS?m/z:214.0[M-H] -.
Embodiment 6
4-methoxyl group-N-{3-[6-(pipecoline base)-2-quinolyl] phenyl } benzamide (KLB-001)
Figure BDA0000407223010000141
In 100mL eggplant-shape bottle, add successively anisic acid (0.23g, 1.5mmol), anhydrous tetrahydro furan (20mL), sulfur oxychloride (2mL), after stirring, is heated to reflux temperature reaction 2h.After reaction finishes, concentrating under reduced pressure, anhydrous tetrahydro furan for residuum (20mL) dissolves, cryosel is bathed and is cooled to-10 ℃, slowly drips the solution that compound 8a (0.33g, 1mmol) is dissolved in anhydrous tetrahydro furan (20mL), after dropwising, drip again TEA (2mL), after dropwising, under room temperature, stir and spend the night.After reaction finishes, reaction solution is poured in frozen water, stirred 0.5h.Ethyl acetate extraction (3 * 50mL), anhydrous magnesium sulfate drying, suction filtration, solvent evaporated in vacuo, residuum be take sherwood oil: the mixed solvent of ethyl acetate (V:V)=1:2 is eluent, and silica gel column chromatography separating-purifying obtains brown solid 0.27g, yield 58.7%, mp271-273 ℃.
IR(KBr,cm -1):3432.02,1652.23,1604.94,1545.90,1508.74,1431.29,1305.96,1250.13,1174.60,1079.58,1027.92,961.63,842.76,784.47; 1H-NMR(DMSO-d 6,500MHz)δ(ppm):1.21-1.28(m,3H,-CH 3),1.40(s,2H,1×2-methylpiperidine-CH 2),1.51-1.61(m,2H,1×2-methylpiperidine-CH 2),1.68-1.70(m,2H,1×2-methylpiperidine-CH 2),1.79-1.87(m,2H,1×2-methylpiperidine-CH 2),2.81(s,1H,0.5×2-methylpiperidine-CH 2),3.62(s,2H,-CH 2-),3.86(s,3H,-OCH 3),7.08(d,J=8.75Hz,2H,2×Ar-H),7.53-7.56(m,1H,Ar-H),7.98(d,J=7.85Hz,1H,Ar-H),8.04(d,J=8.05Hz,1H,Ar-H),8.10-8.17(m,5H,5×Ar-H),8.28(s,1H,Ar-H),8.49(d,J=8.5Hz,1H,Ar-H),8.74(s,1H,Ar-H),10.47(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,125MHz)δ(ppm):21.72,22.12,30.74,45.28,50.54,55.15,55.43,59.88,113.57,113.57,119.33,119.43,121.88,122.44,126.52,126.71,128.28,129.05,129.05,129.25,129.75,131.41,132.57,137.47,138.79,140.01,147.41,157.00,161.96,165.03;HR-TOF?MS?m/z:calcd?forC 30H 32N 3O 2[M+H] +:466.2495,found:466.2501.
Embodiment 7
The chloro-N-{3-[6-of 4-(pipecoline base)-2-quinolyl] phenyl } benzamide (KLB-002)
Figure BDA0000407223010000142
Specific experiment operation is synthetic with compound KLB-001's, adds compound 8a (0.33g, 1mmol), and Chlorodracylic acid (0.23g, 1.5mmol), obtains brown solid 0.28g, yield 59.3%, mp88-90 ℃.
IR(KBr,cm -1):3473.61,3067.53,2929.50,2855.21,1653.45,1594.36,1548.86,1486.74,1432.85,1384.25,1328.96,1298.22,1114.19,1093.36,1013.78,841.14,793.15,754.90; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):1.16-1.18(m,3H,-CH 3),1.30-1.47(m,4H,2×2-methylpiperidine-CH 2),1.64(s,2H,1×2-methylpiperidine-CH 2),2.06(s,1H,0.5×2-methylpiperidine-CH 2),2.45-2.52(m,1H,0.5×2-methylpiperidine-CH 2),2.69-2.72(m,1H,0.5×2-methylpiperidine-CH 2),3.37-3.41(m,5H,-CH 2-and-CH 3),7.52-7.57(m,1H,Ar-H),7.62-7.65(m,2H,2×Ar-H),7.78(d,J=8.34Hz,1H,Ar-H),7.89(s,1H,Ar-H),7.97-8.15(m,6H,6×Ar-H),8.44(d,J=8.64Hz,1H,Ar-H),8.73(s,1H,Ar-H),10.70(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):18.58,23.06,25.25,33.77,51.35,56.10,57.36,118.67,119.30,121.56,122.60,126.72,126.88,128.38,128.38,128.76,129.03,129.76,129.76,131.18,133.41,136.44,136.91,136.91,139.15,139.60,146.91,155.49,164.47;HR-TOF?MS?m/z:calcd?forC 29H 29N 3OCl[M+H] +:470.1999,found:470.2003.
Embodiment 8
The chloro-N-{3-[6-of 2-(pipecoline base)-2-quinolyl] phenyl }-4-methylsulfonyl benzamide (KLB-003)
Figure BDA0000407223010000151
Specific experiment operation is synthetic with compound KLB-001's, adds compound 8a (0.33g, 1mmol), and 2-chlorin-4-mesyl benzoic acid (0.35g, 1.5mmol), obtains yellow solid 0.33g, yield 60.5%, mp153-155 ℃.
IR(KBr,cm -1):3256.92,3066.29,2926.32,2853.34,1661.68,1593.36,1546.80,1470.15,1435.68,1374.22,1317.22,1153.43,1099.15,1049.73,965.69,888.30,838.45,797.02; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):1.14-1.16(m,3H,-CH 3),1.22-1.46(m,4H,2×2-methylpiperidine-CH 2),1.62(s,2H,1×2-methylpiperidine-CH 2),1.98-2.04(m,1H,0.5×2-methylpiperidine-CH 2),2.38(s,1H,0.5×2-methylpiperidine-CH 2),2.66-2.70(m,1H,0.5×2-methylpiperidine-CH 2),3.30-3.38(m,5H,-CH 2-and-SO 2CH 3),7.54-7.59(m,1H,Ar-H),7.75(d,J=8.61Hz,2H,2×Ar-H),7.87-7.90(m,2H,2×Ar-H),7.94-8.09(m,4H,4×Ar-H),8.17(s,1H,Ar-H),8.44(d,J=8.64Hz,1H,Ar-H),8.65(s,1H,Ar-H),10.91(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):18.80,23.26,25.58,34.12,43.10,51.52,55.89,57.63,118.30,118.60,120.65,122.97,125.86,126.51,126.78,128.04,128.74,129.37,129.94,130.98,131.13,136.93,138.43,139.12,139.49,141.18,142.99,146.86,155.17,163.81;HR-TOF?MS?m/z:calcd?forC 30H 31N 3O 3SCl[M+H]+:548.1775,found:548.1779.
Embodiment 9
2,5-dimethyl-N-{3-[2-(6-toluquinoline base)] phenyl }-1-phenyl-1H-pyrrole-3-carboxamide (KLB-004)
Figure BDA0000407223010000152
Specific experiment operation is synthetic with compound KLB-001's, adds compound 8a (0.33g1mmol), and 25-dimethyl-1-phenylpyrrole-3-formic acid (0.32g, 1.5mmol), obtains yellow solid 0.29g, yield 55.7%, mp82-84 ℃.
IR(KBr,cm -1):3328.19,3058.86,2924.48,2852.87,1645.52,1598.03,1534.90,1498.19,1408.11,1375.58,1321.59,1300.93,1242.50,1225.86,1157.93,1074.61,1008.90,886.98,838.23,777.92,698.81;? 1H-NMR(DMSO-d 6,500MHz)δ(ppm):1.14-1.19(m,3H,-CH 3),1.22-1.29(m,3H,1.5×2-methylpiperidine-CH 2),1.30-1.39(m,1H,0.5×2-methylpiperidine-CH 2),1.46(s,1H,0.5×2-methylpiperidine-CH 2),1.61-1.64(m,2H,1×2-methylpiperidine-CH 2),2.00(s,3H,-CH 3),2.29(s,3H,-CH 3),2.39(s,1H,0.5×2-methylpiperidine-CH 2),2.67-2.70(m,1H,0.5×2-methylpiperidine-CH 2),3.31-3.35(m,2H,-CH 2-),6.72(s,1H,Ar-H),7.33-7.34(m,2H,2×Ar-H),7.46-7.54(m,2H,2×Ar-H),7.57-7.60(m,2H,2×Ar-H),7.75(d,J=8.65Hz,1H,Ar-H),7.86-7.89(m,2H,2×Ar-H),7.97(d,J=7.95Hz,1H,Ar-H),8.03-8.05(m,2H,2×Ar-H),8.42(d,J=8.65Hz,1H,Ar-H),8.63(s,1H,Ar-H),9.58(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,125MHz)δ(ppm):12.09,12.48,18.72,23.20,25.55,34.09,51.47,55.84,57.61,105.79,114.30,118.62,120.95,121.45,126.45,126.66,127.36,127.95,128.05,128.44,128.67,128.78,129.01,129.43,129.65,130.98,133.79,136.73,137.10,138.24,139.04,140.39,146.85,155.67,163.83;HR-TOF?MS?m/z:calcd?forC 35H 37N 4O[M+H] +:529.2967,found:529.2971.
Embodiment 10
The chloro-N-{3-[6-of 3-(pipecoline base)-2-quinolyl] phenyl } benzamide (KLB-005)
Figure BDA0000407223010000161
Specific experiment operation is synthetic with compound KLB-001's, adds compound 8a (0.33g, 1mmol), and m-chlorobenzoic acid (0.23g, 1.5mmol), obtains yellow solid 0.19g, yield 41.3%, mp95-97 ℃.
IR(KBr,cm -1):3479.64,3245.24,2925.00,2853.75,1650.84,1596.37,1544.27,1468.79,1434.05,1323.10,1289.52,1255.36,1075.58,891.01,801.21,737.75; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):1.12-1.16(m,3H,-CH 3),1.18-1.44(m,4H,2×2-methylpiperidine-CH 2),1.61(s,2H,1×2-methylpiperidine-CH 2),1.94-2.02(m,1H,0.5×2-methylpiperidine-CH 2),2.36(s,1H,0.5×2-methylpiperidine-CH 2),2.65-2.69(m,1H,0.5×2-methylpiperidine-CH 2),3.28-3.58(m,2H,-CH 2-),7.53-7.63(m,2H,2×Ar-H),7.68-7.77(m,2H,2×Ar-H),7.84(s,1H,Ar-H),7.97-8.13(m,6H,6×Ar-H),8.42(d,J=8.64Hz,1H,Ar-H),8.69(s,1H,Ar-H),10.58(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):18.77,23.24,25.56,34.10,51.49,55.89,57.61,118.57,119.17,121.43,122.70,126.50,126.74,127.44,128.59,128.70,129.08,130.33,131.05,131.40,133.21,136.72,136.83,138.30,139.25,139.45,146.88,155.31,164.06;TOF-MS?m/z:470.1[M+H] +.
Embodiment 11
2,5-dimethyl-1-phenyl-N-[3-(2-quinolyl) phenyl]-1H-pyrrole-3-carboxamide (KLB-006)
Figure BDA0000407223010000162
Specific experiment operation is synthetic with compound KLB-001's, adds compound 8f (0.23g, 1mmol), and 2,5-dimethyl-1-phenylpyrrole-3-formic acid (0.32g, 1.5mmol), obtains brown solid 0.24g, yield 58.1%, mp115-117 ℃.
IR(KBr,cm -1):3428.33,3189.93,2917.45,1633.18,1595.24,1533.20,1498.22,1437.80,1412.68,1375.11,1274.73,1255.01,1213.54,1073.03,1006.49,876.35,832.77,779.37,698.21; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):2.00(s,3H,-CH 3),2.29(s,3H,-CH 3),6.71(s,1H,Ar-H),7.33(d,J=6.99Hz,1H,Ar-H),7.46-7.64(m,5H,5×Ar-H),7.77-7.82(m,1H,Ar-H),7.90(d,J=7.83Hz,1H,Ar-H),7.96-8.03(m,2H,2×Ar-H),8.09(d,J=8.61Hz,2H,2×Ar-H),8.48(d,J=8.67Hz,1H,Ar-H),8.64(s,1H,Ar-H),8.73(d,J=7.86Hz,1H,Ar-H),9.59(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):12.13,12.52,105.80,114.28,118.75,121.10,121.58,126.37,126.95,127.40,127.79,128.08,128.48,128.48,128.48,128.86,128.95,128.95,128.95,129.47,129.90,133.84,137.13,138.96,140.42,147.50,156.24,163.86;HR-TOF?MS?m/z:calcd?forC 28H 24N 3O[M+H] +:418.1919,found:418.1923.
Embodiment 12
The chloro-4-of 2-(methylsulfonyl)-N-[3-(2-quinolyl)-phenyl] benzamide (KLB-007)
Specific experiment operation is synthetic with compound KLB-001's, adds compound 8f (0.23g, 1mmol), and 2-chlorin-4-mesyl benzoic acid (0.35g, 1.5mmol), obtains off-white color solid 0.27g, yield 62.7%, mp231-233 ℃.
IR(KBr,cm -1):3251.48,3075.25,2922.45,2853.54,1664.07,1596.86,1560.01,1545.98,1466.15,1422.21,1334.40,1315.12,1300.60,1150.75,1103.05,1047.24,968.55,832.00,798.60,783.79; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):3.37(s,3H,-SO 2CH 3),7.56-7.65(m,2H,2×Ar-H),7.79-7.84(m,1H,Ar-H),7.89-7.92(m,1H,Ar-H),7.95-7.98(m,1H,Ar-H),8.01-8.04(m,3H,3×Ar-H),8.06-8.13(m,2H,2×Ar-H),8.17-8.18(m,1H,?Ar-H),8.50(d,J=8.7Hz,1H,Ar-H),8.67(s,1H,Ar-H),10.92(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):43.11,118.40,118.70,120.80,123.11,125.90,126.56,127.06,127.84,128.64,129.01,129.45,130.03,131.00,131.48,137.33,139.16,139.41,141.19,143.00,147.49,155.74,163.86;TOF-MS?m/z:437.2[M+H] +.
Embodiment 13
4-methoxyl group-N-[3-(2-quinolyl)-phenyl] benzamide (KLB-008)
Figure BDA0000407223010000171
Specific experiment operation is synthetic with compound KLB-001's, adds compound 8f (0.23g, 1mmol), and anisic acid (0.23g, 1.5mmol), obtains off-white color solid 0.21g, yield 61.3%, mp184-186 ℃.
IR(KBr,cm -1):3327.41,2952.02,2835.20,1644.58,1601.10,1530.43,1500.79,1463.94,1428.39,1325.64,1250.77,1173.13,1028.86,843.13,823.79,798.30,781.98; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):3.86(s,3H,-OCH 3),7.08-7.11(m,2H,2×Ar-H),7.51-7.56(m,1H,Ar-H),7.59-7.64(m,1H,Ar-H),7.78-7.84(m,1H,Ar-H),7.98-8.01(m,2H,2×Ar-H),8.04-8.07(m,2H,2×Ar-H),8.08-8.09(m,2H,2×Ar-H),8.11-8.12(m,1H,Ar-H),8.49(d,J=8.67Hz,1H,Ar-H),8.68(s,1H,Ar-H),10.31(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):55.39,113.57,113.57,118.70,119.20,121.52,122.34,126.42,126.79,126.98,127.80,127.80,128.95,129.02,129.61,129.94,137.19,139.08,139.90,147.49,156.01,161.93,164.96;TOF-MS?m/z:355.2[M+H] +.
Embodiment 14
The chloro-N-[3-of 4-(2-quinolyl)-phenyl] benzamide (KLB-009)
Figure BDA0000407223010000172
Specific experiment operation is synthetic with compound KLB-001's, adds compound 8f (0.23g, 1mmol), and Chlorodracylic acid (0.23g, 1.5mmol), obtains off-white color solid 0.23g, yield 62.5%, mp217-218 ℃.
IR(KBr,cm -1):3301.29,1648.19,1599.09,1538.19,1488.30,1410.82,1327.93,1305.39,1258.46,1091.22,1014.80,845.04,819.15,777.69; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):7.52-7.58(m,1H,Ar-H),7.61-7.65(m,3H,3×Ar-H),7.77-7.82(m,1H,Ar-H),7.97-8.02(m,3H,3×Ar-H),8.05-8.12(m,4H,4×Ar-H),8.47(d,J=8.67Hz,1H,Ar-H),8.67(s,1H,Ar-H),10.52(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):118.67,119.27,121.59,122.73,126.45,127.00,127.49,128.42,128.94,128.94,129.11,129.63,129.95,129.95,133.46,136.45,137.22,139.15,139.53,147.48,155.89,164.48;TOF-MS?m/z:359.1[M+H] +.
Embodiment 15
The chloro-N-[3-of 3-(2-quinolyl)-phenyl] benzamide (KLB-010)
Figure BDA0000407223010000173
Specific experiment operation is synthetic with compound KLB-001's, adds compound 8f (0.23g, 1mmol), and m-chlorobenzoic acid (0.23g, 1.5mmol), obtains brown solid 0.22g, yield 60.7%, mp164-166 ℃.
IR(KBr,cm -1):3207.79,1645.16,1597.69,1556.78,1522.39,1505.98,1467.54,1430.41,1419.10,1327.03,1296.75,1261.67,1213.42,1127.20,1083.71,901.29,832.04,800.92,759.83; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):7.55-7.65(m,3H,3×Ar-H),7.71(d,J=8.7Hz,1H,Ar-H),7.79-7.85(m,1H,Ar-H),8.01-8.05(m,4H,4×Ar-H),8.10-8.14(m,3H,3×Ar-H),8.50(d,J=8.67Hz,1H,Ar-H),8.71(s,1H,Ar-H),10.59(s,1H,?-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):118.67,119.27,121.57,122.81,126.45,126.50,127.00,127.42,127.79,128.94,129.13,129.95,130.34,131.40,133.19,136.71,137.22,139.16,139.45,147.48,155.86,164.09;TOF-MS?m/z:359.1[M+H] +.
Embodiment 16
4-chloromethyl-N-[3-(2-quinolyl)-phenyl] benzamide (KLB-011)
Figure BDA0000407223010000181
Specific experiment operation is synthetic with compound KLB-001's, adds compound 8f (0.23g, 1mmol), and p-chloromethyl benzoic acid (0.26g, 1.5mmol), obtains brown solid 0.23g, yield 61.8%, mp192-194 ℃.
IR(KBr,cm -1):3277.68,3056.76,1652.73,1599.20,1540.22,1483.10,1431.95,1330.54,1301.59,1265.25,1089.22,875.15,831.76,798.46,697.50,699.88; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):4.90(s,2H,-CH 2Cl),7.56-7.67(m,4H,4×Ar-H),7.81-7.86(m,1H,Ar-H),8.01-8.07(m,4H,4×Ar-H),8.09-8.16(m,3H,3×Ar-H),8.52(d,J=8.64Hz,1H,Ar-H),8.72(s,1H,Ar-H),10.53(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):45.39,118.70,119.24,121.55,122.66,126.46,127.01,127.81,127.81,128.07,128.74,128.74,128.96,129.11,129.97,134.62,137.23,139.15,139.66,141.09,147.50,155.94,165.15;TOF-MS?m/z:373.2[M+H] +.
Embodiment 17
2,5-dimethyl-1-phenyl-N-{3-[2-(6-toluquinoline base)] phenyl }-1H-pyrrole-3-carboxamide (KLB-012)
Figure BDA0000407223010000182
Specific experiment operation is synthetic with compound KLB-001's, adds compound 8g (0.23g, 1mmol), and 2,5-dimethyl-1-phenylpyrrole-3-formic acid (0.32g, 1.5mmol), obtains brown solid 0.25g, yield 59.7%, mp157-159 ℃.
IR(KBr,cm -1):3432.91,3194.73,2923.78,2853.88,1668.84,1633.36,1586.11,1533.60,1497.66,1465.45,1430.17,1412.07,1375.42,1275.13,1254.55,1073.80,776.19; 1H-NMR(DMSO-d 6,500MHz)δ(ppm):2.00(s,3H,-CH 3),2.30(s,3H,-CH 3),3.32(s,3H,-CH 3),6.72(s,1H,Ar-H),7.32-7.34(m,2H,2×Ar-H),7.46-7.64(m,5H,5×Ar-H),7.76(s,1H,Ar-H),7.88(d,J=7.4Hz,1H,Ar-H),7.96-8.04(m,3H,3×Ar-H),8.36(d,J=8.5Hz,1H,Ar-H),8.63(s,1H,Ar-H),9.58(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,125MHz)δ(ppm):12.15,12.55,21.09,105.81,114.30,118.65,118.73,120.93,121.47,126.49,126.95,127.41,128.10,128.10,128.50,128.74,128.83,129.50,132.05,133.84,135.88,136.42,137.13,139.08,140.40,146.11,148.30,155.40,163.86;HR-TOF?MS?m/z:calcd?forC 29H 26N 3O[M+H] +:432.2076,found:432.2081.
Embodiment 18
The chloro-N-{3-[2-of 2-(6-toluquinoline base)] phenyl }-4-(methylsulfonyl) benzamide (KLB-013)
Figure BDA0000407223010000183
Specific experiment operation is synthetic with compound KLB-001's, adds compound 8g (0.23g, 1mmol), and 2-chlorin-4-mesyl benzoic acid (0.35g, 1.5mmol), obtains brown solid 0.27g, yield 60.8%, mp258-260 ℃.
IR(KBr,cm -1):3248.37,3009.88,2923.69,1662.85,1598.35,1560.28,1473.61,1431.77,1372.85,1310.22,1150.77,1102.37,968.51,889.12,833.15,798.39; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):2.52(s,3H,-CH 3),3.34(s,3H,-SO 2CH 3),7.52-7.58(m,1H,Ar-H),7.64(d,J=8.7Hz,1H,Ar-H),7.77(s,1H,Ar-H),7.86(d,J=7.7Hz,1H,Ar-H),7.92-8.07(m,5H,5×Ar-H),8.14-8.15(m,1H,Ar-H),8.37(d,J=8.64Hz,1H,Ar-H),8.62?(s,1H,Ar-H),10.91-10.89(m,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):21.09,43.09,118.32,118.64,120.66,122.87,125.83,126.48,127.01,128.01,128.75,129.34,129.93,130.95,132.13,136.04,136.55,139.27,139.47,141.27,142.92,146.07,154.87,163.84;TOF-MS?m/z:451.1[M+H]+.
Embodiment 19
The chloro-N-{3-[2-of 4-(6-toluquinoline base)] phenyl } benzamide (KLB-014)
Specific experiment operation is synthetic with compound KLB-001's, adds compound 8g (0.23g, 1mmol), and Chlorodracylic acid (0.23g, 1.5mmol), obtains brown solid 0.23g, yield 61.4%, mp192-194 ℃.
IR(KBr,cm -1):3309.35,1644.55,1596.93,1534.44,1483.34,1412.94,1335.81,1297.21,1260.74,1096.36,1016.22,835.86,798.13; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):2.50-2.52(m,3H,-CH 3),7.51-7.57(m,1H,Ar-H),7.63-7.65(m,3H,3×Ar-H),7.77(s,1H,Ar-H),7.97-8.00(m,3H,3×Ar-H),8.05-8.08(m,3H,3×Ar-H),8.37(d,J=8.64Hz,1H,Ar-H),8.65(s,1H,Ar-H),10.52(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):21.07,118.64,119.15,121.40,122.60,126.47,126.98,128.43,128.43,128.71,129.07,129.63,129.63,132.10,133.47,135.97,136.48,136.48,139.25,139.50,146.08,155.02,164.46;TOF-MS?m/z:373.1[M+H] +.
Embodiment 20
The chloro-N-{3-[2-of 3-(6-toluquinoline base)] phenyl } benzamide (KLB-015)
Figure BDA0000407223010000192
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8g (0.23g, 1mmol), and m-chlorobenzoic acid (0.23g, 1.5mmol), obtains brown solid 0.22g, yield 60.7%, mp158-160 ℃.
IR(KBr,cm -1):3212.21,1644.66,1599.33,1525.12,1469.43,1427.87,1378.20,1324.42,1297.67,1262.00,1213.06,1131.48,1083.33,886.59,831.43,796.37,758.17; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):2.52(s,3H,-CH 3),7.53-7.76(m,5H,5×Ar-H),7.97-8.12(m,6H,6×Ar-H),8.36(d,J=8.61Hz,1H,Ar-H),8.67(s,1H,Ar-H),10.57(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):21.05,118.61,119.15,121.38,122.67,126.45,126.49,126.97,127.42,128.71,129.07,130.33,131.39,132.07,133.20,135.95,136.46,136.72,139.27,139.42,146.09,154.99,164.07;TOF-MS?m/z:373.1[M+H] +.
Embodiment 20
4-chloromethyl-N-{3-[2-(6-toluquinoline base)] phenyl } benzamide (KLB-016)
Figure BDA0000407223010000193
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8g (0.23g, 1mmol), and p-chloromethyl benzoic acid (0.26g, 1.5mmol), obtains yellow solid 0.24g, yield 61.2%, mp196-198 ℃.
IR(KBr,cm -1):3276.61,3057.43,2967.01,1651.52,1603.80,1542.82,1483.43,1419.21,1329.92,1303.30,1265.16,1216.47,1087.81,886.43,874.32,832.39,797.86,777.47,684.33; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):2.52(s,3H,-CH 3),4.87(s,2H,-CH 2Cl),7.53-7.76(m,5H,5×Ar-H),7.97-8.12(m,6H,6×Ar-H),8.36(d,J=8.61Hz,1H,Ar-H),8.67(s,1H,Ar-H),10.49(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):21.07,45.38,118.65,119.11,121.35,122.51,126.47,126.98,128.05,128.05,128.72,128.72,129.06,132.09,134.62,135.95,136.47,139.24,139.24,139.62,141.07,146.09,155.06,165.12;TOF-MS?m/z:387.2[M+H] +.
Embodiment 21
The chloro-4-of 2-(methylsulfonyl)-N-{3-{2-[6-(piperidines-1-methyl)] quinolyl } phenyl } benzamide (KLB-017)
Figure BDA0000407223010000201
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8b (0.32g, 1mmol), and 2-chlorin-4-mesyl benzoic acid (0.35g, 1.5mmol), obtains off-white color solid 0.32g, yield 60.1%, mp242-244 ℃.
IR(KBr,cm -1):3260.05,3066.95,2933.31,2850.06,1663.10,1596.24,1544.23,1473.44,1432.35,1315.42,1299.69,1151.74,1102.37,1047.46,838.28,798.45,788.96,690.79; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):1.38-1.40(m,2H,1×piperidine-CH 2),1.49-1.51(m,4H,2×piperidine-CH 2),2.36-2.52(m,4H,2×piperidine-CH 2),3.39(s,3H,-SO 2CH 3),3.59(s,2H,-CH 2-),7.55-7.60(m,1H,Ar-H),7.73(d,J=8.76Hz,1H,Ar-H),7.84(s,1H,Ar-H),7.91(d,J=8.19Hz,1H,Ar-H),7.95-8.09(m,5H,5×Ar-H),8.18(s,1H,Ar-H),8.43(d,J=8.67Hz,1H,Ar-H),8.67(s,1H,Ar-H),10.93(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):23.93,25.53,25.53,43.10,53.94,53.94,62.54,118.31,118.59,120.66,122.97,125.85,126.74,128.04,128.77,129.35,129.93,130.99,131.15,136.95,137.26,139.12,139.12,139.46,141.17,142.97,146.90,155.25,163.80;TOF-MS?m/z:534.2[M+H] +.
Embodiment 22
The chloro-N-{3-{2-[6-of 4-(piperidines-1-methyl)] quinolyl } phenyl } benzamide (KLB-018)
Figure BDA0000407223010000202
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8b (0.32g, 1mmol), and Chlorodracylic acid (0.23g, 1.5mmol), obtains off-white color solid 0.24g, yield 52.7%, mp188-190 ℃.
IR(KBr,cm -1):3309.76,2929.23,2843.57,1644.95,1600.36,1532.48,1482.48,1415.43,1334.40,1305.64,1262.36,1095.18,1014.77,899.88,841.26,786.37,756.90,685.11; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):1.40-1.42(m,2H,1×piperidine-CH 2),1.50-1.52(m,4H,2×piperidine-CH 2),2.38-2.51(m,4H,2×piperidine-CH 2),3.62(s,2H,-CH 2-),7.52-7.57(m,1H,Ar-H),7.63-7.65(m,2H,2×Ar-H),7.73-7.76(m,1H,Ar-H),7.86(s,1H,Ar-H),7.97-8.02(m,3H,3×Ar-H),8.05-8.09(m,3H,3×Ar-H),8.44(d,J=8.7Hz,1H,Ar-H),8.66(s,1H,Ar-H),10.53(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):23.95,25.54,25.54,53.97,53.97,62.55,118.65,119.18,121.48,122.66,126.78,128.43,128.74,128.74,129.09,129.35,129.64,129.64,131.17,133.47,136.44,136.94,137.20,139.21,139.51,146.91,155.44,164.47;TOF-MS?m/z:456.2[M+H] +.
Embodiment 23
The chloro-N-{3-{2-[6-of 3-(piperidines-1-methyl)] quinolyl } phenyl } benzamide (KLB-019)
Figure BDA0000407223010000203
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8b (0.32g, 1mmol), and m-chlorobenzoic acid (0.23g, 1.5mmol), obtains off-white color solid 0.27g, yield 59.3%, mp137-139 ℃.
IR(KBr,cm -1):3280.31,2930.44,2850.65,2810.50,1644.59,1601.76,1530.97,1481.06,1420.76,1335.11,1305.07,1294.28,1093.54,980.17,841.61,787.49,680.88; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):1.20(s,2H,1×piperidine-CH 2),1.39-1.52(m,4H,2×piperidine-CH 2),2.38-2.53(m,4H,2×piperidine-CH 2),3.61(s,2H,-CH 2-),7.53-7.63(m,2H,2×Ar-H),7.67-7.76(m,2H,2×Ar-H),7.85(s,1H,Ar-H),7.97-8.02(m,3H,3×Ar-H),?8.05-8.09(m,1H,Ar-H),8.11-8.12(m,2H,2×Ar-H),8.44(d,J=8.73Hz,1H,Ar-H),8.67(s,1H,Ar-H),10.57(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):23.94,25.54,25.54,53.96,53.96,62.55,118.63,119.18,121.46,122.73,126.50,126.76,127.43,128.74,129.10,130.35,131.15,131.41,133.19,136.72,136.92,137.20,139.23,139.44,139.51,146.91,155.41,164.07;TOF-MS?m/z:454.3[M-H] -.
Embodiment 24
4-chloromethyl-N-{3-{2-[6-(piperidines-1-methyl)] quinolyl } phenyl } benzamide (KLB-020)
Figure BDA0000407223010000211
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8b (0.32g, 1mmol), and p-chloromethyl benzoic acid (0.26g, 1.5mmol), obtains yellow solid 0.28g, yield 60.8%, mp152-154 ℃.
IR(KBr,cm -1):3308.42,2926.98,2799.90,1645.77,1600.88,1529.96,1473.95,1430.90,1325.72,1264.33,1102.85,1020.33,993.87,902.29,846.34,793.35,688.82; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):1.40-1.42(m,2H,1×piperidine-CH 2),1.53(s,4H,2×piperidine-CH 2),2.39-2.51(m,4H,2×piperidine-CH 2),3.63(s,2H,-CH 2-),4.87(s,1H,-CH 2Cl),7.52-7.57(m,1H,Ar-H),7.61-7.64(m,2H,2×Ar-H),7.76(d,J=8.67Hz,1H,Ar-H),7.87(s,1H,Ar-H),7.96-8.10(m,6H,6×Ar-H),8.45(d,J=8.64Hz,1H,Ar-H),8.68(s,1H,Ar-H),10.50(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):23.90,25.49,25.49,45.38,53.93,53.93,62.51,118.67,119.15,121.44,122.56,126.73,128.06,128.44,128.44,128.72,128.72,129.08,129.38,131.19,134.61,136.95,139.19,139.19,139.64,141.07,146.93,155.51,165.11;TOF-MS?m/z:470.3[M+H] +.
Embodiment 25
4-methoxyl group-N-{3-{2-[6-(piperidines-1-methyl)] quinolyl } phenyl } benzamide (KLB-021)
Figure BDA0000407223010000212
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8b (0.32g, 1mmol), and anisic acid (0.23g, 1.5mmol), obtains brown solid 0.27g, yield 59.6%, mp166-168 ℃.
IR(KBr,cm -1):3318.10,2932.93,2916.71,2833.20,1640.74,1606.98,1532.25,1509.29,1482.77,1410.62,1306.41,1251.77,1174.63,1029.19,905.27,837.80,783.63; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):1.38-1.39(m,2H,1×piperidine-CH 2),1.49-1.51(m,4H,2×piperidine-CH 2),2.36-2.52(m,4H,2×piperidine-CH 2),3.59(s,2H,-CH 2-),3.87(s,1H,-OCH 3),7.09-7.12(m,2H,2×Ar-H),7.51-7.56(m,1H,Ar-H),7.72-7.75(m,1H,Ar-H),7.83(s,1H,Ar-H),7.94-7.97(m,2H,2×Ar-H),8.00-8.08(m,4H,4×Ar-H),8.43(d,J=8.67Hz,1H,Ar-H),8.69(s,1H,Ar-H),10.33(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):23.94,25.54,25.54,53.95,53.95,55.37,62.56,113.56,118.63,119.12,121.42,122.26,126.75,126.82,126.82,128.75,128.75,128.99,129.62,131.11,136.87,137.15,139.16,139.92,139.92,146.93,155.56,161.93,164.95;TOF-MS?m/z:452.3[M+H] +.
Embodiment 26
The bromo-N-{3-{2-[6-of 4-(piperidines-1-methyl)] quinolyl } phenyl } benzamide (KLB-022)
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8b (0.32g, 1mmol), and parabromobenzoic acid (0.30g, 1.5mmol), obtains brown solid 0.30g, yield 60.6%, mp196-198 ℃.
IR(KBr,cm -1):3356.05,2927.74,2804.19,1645.32,1598.13,1537.53,1482.48,1432.07,1327.00,1259.21,?1115.30,1051.01,1010.65,832.80,785.57,751.81; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):1.40-1.42(m,2H,1×piperidine-CH 2),1.50-1.52(m,4H,2×piperidine-CH 2),2.38-2.52(m,4H,2×piperidine-CH 2),3.62(s,2H,-CH 2-),7.52-7.57(m,1H,Ar-H),7.73-7.79(m,3H,3×Ar-H),7.86(s,1H,Ar-H),7.97-8.02(m,5H,5×Ar-H),8.05-8.09(m,1H,Ar-H),8.45(d,J=8.64Hz,1H,Ar-H),8.66(s,1H,Ar-H),10.53(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):23.95,25.54,25.54,53.97,53.97,62.55,118.65,119.18,121.48,122.66,125.39,126.78,128.74,129.10,129.81,131.17,131.17,131.37,133.83,133.83,136.94,137.20,139.21,139.21,139.50,146.91,155.43,164.59;TOF-MS?m/z:500.2[M+H] +.
Embodiment 27
The chloro-4-of 2-(methylsulfonyl)-N-{3-{2-[6-(N, N-dimethyl)] quinolyl } phenyl } benzamide (KLB-023)
Figure BDA0000407223010000221
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8e (0.26g, 1mmol), and 2-chlorin-4-mesyl benzoic acid (0.35g, 1.5mmol), obtains brown solid 0.30g, yield 62.1%, mp257-259 ℃.
IR(KBr,cm -1):3253.77,3072.64,2999.43,2921.00,1664.26,1619.26,1557.85,1546.01,1505.26,1432.14,1376.03,1315.69,1301.04,1151.80,1102.05,1049.73,966.07,855.38,812.02,793.83,735.16,682.99;1H-NMR(DMSO-d 6,300MHz)δ(ppm):3.05(s,6H,-N(CH 3) 2),3.39(s,3H,-CH 3),6.95(s,1H,Ar-H),7.45-7.55(m,2H,2×Ar-H),7.82-7.84(m,1H,Ar-H),7.88-7.96(m,4H,4×Ar-H),8.03-8.06(m,1H,Ar-H),8.17-8.20(m,2H,2×Ar-H),8.59(s,1H,Ar-H),10.87(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):40.33,40.33,43.10,104.52,117.80,118.55,119.70,119.92,122.39,125.84,128.02,128.58,129.23,129.60,129.93,130.98,134.86,139.02,139.88,141.22,141.37,142.95,148.38,151.10,163.76;TOF-MS?m/z:480.2[M+H] +.
Embodiment 28
The chloro-N-{3-{2-[6-of 4-(N, N-dimethyl)] quinolyl } phenyl } benzamide (KLB-024)
Figure BDA0000407223010000222
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8e (0.26g, 1mmol), and Chlorodracylic acid (0.23g, 1.5mmol), obtains yellow solid 0.24g, yield 59.7%, mp218-220 ℃.
IR(KBr,cm -1):3279.52,2923.18,1646.22,1607.60,1552.66,1486.19,1378.69,1332.12,1308.32,1262.26,1193.58,1140.32,1090.55,1054.42,1014.45,836.68,805.60,724.11,679.68; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):3.05(s,6H,-N(CH 3) 2),6.95-6.96(m,1H,Ar-H),7.46-7.53(m,2H,2×Ar-H),7.62-7.65(m,2H,2×Ar-H),7.89-7.95(m,4H,4×Ar-H),8.06-8.09(m,2H,2×Ar-H),8.17-8.20(m,1H,Ar-H),8.61(s,1H,Ar-H),10.50(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):40.33,40.33,104.56,118.58,118.69,119.68,120.73,122.07,128.42,128.55,128.55,128.95,129.58,129.58,129.63,133.52,134.83,136.42,139.43,139.65,141.39,148.35,151.31,164.43;TOF-MS?m/z:402.2[M+H] +.
Embodiment 29
4-chloromethyl-N-{3-{2-[6-(N, N-dimethyl)] quinolyl } phenyl } benzamide (KLB-025)
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8e (0.26g, 1mmol), and p-chloromethyl benzoic acid (0.26g, 1.5mmol), obtains yellow solid 0.21g, yield 50.6%, mp180-182 ℃.
IR(KBr,cm -1):3275.11,2923.97,2853.53,1644.33,1619.00,1591.82,1538.10,1506.25,1434.26,1378.33,1289.05,1257.50,1192.73,1107.71,1067.56,1017.96,963.64,829.52,787.71,687.82; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):3.06(s,6H,-N(CH 3) 2),4.87(s,2H,-CH 2Cl),6.97-6.98(m,1H,Ar-H),7.47-7.53(m,2H,2×Ar-H),7.60-7.63(m,2H,2×Ar-H),7.89-7.95(m,4H,4×Ar-H),8.03-8.06(m,2H,2×Ar-H),8.20(d,J=8.7Hz,1H,Ar-H),8.61(s,1H,Ar-H),10.46(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):40.32,40.32,45.38,104.56,118.66,119.77,120.73,122.02,127.69,128.04,128.56,128.56,128.71,128.71,128.94,129.40,134.65,134.99,139.46,139.46,139.54,141.04,148.38,151.28,165.07;TOF-MS?m/z:416.1[M+H] +.
Embodiment 30
The bromo-N-{3-{2-[6-of 4-(N, N-dimethyl)] quinolyl } phenyl } benzamide (KLB-026)
Figure BDA0000407223010000232
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8e (0.26g, 1mmol), and parabromobenzoic acid (0.30g, 1.5mmol), obtains yellow solid 0.27g, yield 61.5%, mp214-216 ℃.
IR(KBr,cm -1):3279.89,2923.36,1646.64,1607.52,1552.26,1497.33,1482.87,1399.61,1378.26,1331.79,1308.45,1262.42,1067.96,1010.70,845.89,805.01; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):3.05(s,6H,-N(CH 3) 2),6.96(s,1H,Ar-H),7.50-7.53(m,2H,2×Ar-H),7.76-7.79(m,2H,2×Ar-H),7.89-8.01(m,6H,6×Ar-H),8.18(d,J=8.61Hz,1H,Ar-H),8.60(s,1H,Ar-H),10.49(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):40.33,40.33,104.56,118.57,118.68,119.68,120.72,122.08,125.36,128.55,128.95,129.57,129.57,129.80,129.80,131.35,133.88,134.82,139.40,139.64,141.39,148.35,151.30,164.55;TOF-MS?m/z:446.2[M+H] +.
Embodiment 31
The fluoro-N-{3-{2-[6-of 3-(N, N-dimethyl)] quinolyl } phenyl } benzamide (KLB-027)
Figure BDA0000407223010000233
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8e (0.26g, 1mmol), and m-fluorobenzoic acid (0.21g, 1.5mmol), obtains yellow solid 0.22g, yield 56.2%, mp187-189 ℃.
IR(KBr,cm -1):3310.80,2924.02,2853.60,1651.00,1620.18,1603.26,1538.02,1482.02,1446.18,1400.00,1380.87,1330.08,1270.39,1198.18,787.06; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):3.06(s,6H,-N(CH 3) 2),6.96-6.97(m,1H,Ar-H),7.44-7.53(m,3H,3×Ar-H),7.58-7.66(m,1H,Ar-H),7.83-7.94(m,6H,6×Ar-H),8.19(d,J=8.67Hz,1H,Ar-H),8.60(s,1H,Ar-H),10.48(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):40.33,40.33,104.57,114.63,118.32,118.58,119.70,120.73,122.14,123.87,128.56,128.96,129.57,130.47,130.58,134.84,137.07,137.16,139.32,139.64,141.38,148.37,151.28,164.09;TOF-MS?m/z:386.2[M+H] +.
Embodiment 32
The chloro-4-of 2-(methylsulfonyl)-N-{3-{2-[6-(diethylin)] quinolyl } phenyl } benzamide (KLB-028)
Figure BDA0000407223010000241
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8c (0.30g, 1mmol), and 2-chlorin-4-mesyl benzoic acid (0.35g, 1.5mmol), obtains brown solid 0.32g, yield 61.6%, mp179-181 ℃.
IR(KBr,cm -1):3297.22,3023.77,2966.46,2922.22,1676.31,1591.67,1559.91,1496.93,1471.12,1433.83,1373.85,1307.36,1279.14,1152.03,1096.05,1048.39,961.22,896.65,838.03,800.43,751.82;? 1H-NMR(DMSO-d 6,300MHz)δ(ppm):0.99-1.04(m,6H,2×2-diethylamine-CH 3),2.48-2.55(m,4H,2×2-diethylamine-CH 2),3.38(s,3H,-SO 2CH 3),3.71(s,2H,-CH 2-),7.54-7.59(m,1H,Ar-H),7.77(d,J=8.7Hz,1H,Ar-H),7.88(s,2H,2×Ar-H),7.88-8.06(m,5H,5×Ar-H),8.16(s,1H,Ar-H),8.44(d,J=8.7Hz,1H,Ar-H),8.65(s,1H,Ar-H),10.91(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):11.67,11.67,46.28,46.28,56.72,118.29,118.59,120.64,122.97,125.85,126.35,126.79,128.03,128.73,129.37,129.93,130.97,131.06,136.94,138.70,139.11,139.47,141.17,142.98,146.89,155.16,163.80;TOF-MS?m/z:522.3[M+H] +.
Embodiment 33
The chloro-N-{3-{2-[6-of 4-(diethylin)] quinolyl } phenyl } benzamide (KLB-029)
Figure BDA0000407223010000242
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8c (0.30g, 1mmol), and Chlorodracylic acid (0.23g, 1.5mmol), obtains brown solid 0.27g, yield 60.4%, mp142-144 ℃.
IR(KBr,cm -1):3306.87,2967.71,2930.94,2822.30,1644.84,1599.51,1532.51,1482.11,1416.28,1306.32,1261.60,1093.30,1014.51,844.46,794.59,683.62; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):0.99-1.04(m,6H,2×2-diethylamine-CH 3),2.49-2.56(m,4H,2×2-diethylamine-CH 2),3.72(s,2H,-CH 2-),7.52-7.57(m,1H,Ar-H),7.62-7.66(m,2H,2×Ar-H),7.75-7.79(m,1H,Ar-H),7.88(s,1H,Ar-H),7.97-8.02(m,3H,3×Ar-H),8.05-8.06(m,2H,2×Ar-H),8.09(s,1H,Ar-H),8.44(d,J=8.64Hz,1H,Ar-H),8.66(s,1H,Ar-H),10.53(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):11.68,11.68,46.28,46.28,56.73,118.61,119.17,121.45,122.63,126.35,126.76,128.42,128.42,128.70,129.08,129.63,129.63,131.03,133.47,136.44,136.88,138.63,139.23,139.51,146.90,155.34,164.46;TOF-MS?m/z:444.2[M+H] +.
Embodiment 34
The chloro-N-{3-{2-[6-of 3-(diethylin)] quinolyl } phenyl } benzamide (KLB-030)
Figure BDA0000407223010000243
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8c (0.30g, 1mmol), and m-chlorobenzoic acid (0.23g, 1.5mmol), obtains brown solid 0.28g, yield 62.9%, mp84-86 ℃.
IR(KBr,cm -1):3463.27,3284.98,2962.54,2926.32,2854.13,1649.10,1596.18,1544.86,1497.92,1471.04,1434.65,1322.74,1290.69,1259.04,1122.16,1070.52,886.09,799.58,739.06,689.36; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):0.99-1.03(m,6H,2×2-diethylamine-CH 3),2.48-2.55(m,4H,2×2-diethylamine-CH 2),3.70(s,2H,-CH 2-),7.53-7.63(m,2H,2×Ar-H),7.68-7.71(m,H,Ar-H),7.75-7.78(m,1H,Ar-H),7.87(s,1H,Ar-H),7.98-8.09(m,5H,5×Ar-H),8.12(s,1H,Ar-H),8.43(d,J=8.67Hz,1H,Ar-H),8.69(s,1H,Ar-H),10.58(s,1H,?-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):11.66,11.66,46.28,46.28,56.72,114.09,118.59,119.18,121.44,122.71,126.35,126.51,127.44,128.71,129.09,130.34,131.02,131.40,133.21,136.73,136.86,138.60,139.26,139.45,146.92,155.32,164.08;TOF-MS?m/z:444.1[M+H] +.
Embodiment 35
4-chloromethyl-N-{3-{2-[6-(diethylin)] quinolyl } phenyl } benzamide (KLB-031)
Figure BDA0000407223010000251
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8c (0.30g, 1mmol), and p-chloromethyl benzoic acid (0.26g, 1.5mmol), obtains brown solid 0.27g, yield 59.4%, mp183-185 ℃.
IR(KBr,cm -1):3387.60,2924.26,2853.73,1654.82,1597.00,1544.44,1468.08,1431.21,1324.36,1302.36,1255.87,1170.23,1109.34,1018.43,893.34,838.56,797.17,783.63,750.89,693.44; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):1.15(s,6H,2×2-diethylamine-CH 3),2.51-2.76(m,4H,2×2-diethylamine-CH 2),3.37(s,2H,-CH 2-),7.55-7.64(m,3H,3×Ar-H),7.84-7.87(m,2H,2×Ar-H),8.02-8.14(m,5H,5×Ar-H),8.36(s,1H,Ar-H),8.59-8.62(m,1H,Ar-H),8.75-8.82(m,1H,Ar-H),10.76-10.83(m,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):20.67,20.67,45.40,45.40,52.87,64.84,119.00,119.49,119.63,121.79,122.81,126.04,126.69,127.93,128.74,129.19,129.55,131.47,131.52,133.56,136.04,137.21,138.80,139.06,139.60,147.73,157.45,164.83;TOF-MS?m/z:458.2[M+H] +.
Embodiment 36
The bromo-N-{3-{2-[6-of 4-(diethylin)] quinolyl } phenyl } benzamide (KLB-032)
Figure BDA0000407223010000252
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8c (0.30g, 1mmol), and parabromobenzoic acid (0.30g, 1.5mmol), obtains yellow solid 0.29g, yield 61.1%, mp142-144 ℃.
IR(KBr,cm -1):3308.67,2966.70,2934.85,2823.57,1645.21,1591.49,1530.29,1482.11,1421.17,1365.90,1331.93,1306.54,1167.60,1072.01,1010.92,848.20,794.50,784.22,754.59,683.39; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):0.99-1.03(m,6H,2×2-diethylamine-CH 3),2.48-2.55(m,4H,2×2-diethylamine-CH 2),3.70(s,2H,-CH 2-),7.52-7.57(m,1H,Ar-H),7.75-7.79(m,3H,3×Ar-H),7.87(s,1H,Ar-H),7.96-8.02(m,4H,4×Ar-H),8.05-8.08(m,2H,2×Ar-H),8.43(d,J=8.67Hz,1H,Ar-H),8.68(s,1H,Ar-H),10.54(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):11.67,11.67,46.28,46.28,56.73,118.59,119.17,121.44,122.62,125.38,126.33,126.75,128.70,129.07,129.81,131.01,131.01,131.35,131.35,133.84,136.86,138.62,139.23,139.52,146.90,155.33,164.57;TOF-MS?m/z:488.2[M+H] +.
Embodiment 37
The chloro-4-of 2-(methylsulfonyl)-N-{3-{2-[6-(morpholinyl)] quinolyl } phenyl } benzamide (KLB-033)
Figure BDA0000407223010000253
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8d (0.32g, 1mmol), and 2-chlorin-4-mesyl benzoic acid (0.35g, 1.5mmol), obtains brown solid 0.35g, yield 64.8%, mp238-240 ℃.
IR(KBr,cm -1):3430.92,3260.17,3072.15,3005.57,2924.67,2860.48,2860.48,2813.01,1663.32,1596.37,1559.91,1543.60,1473.69,1431.14,1370.73,1315.98,1299.76,1151.60,1114.38,1050.33,1012.84,982.63,?891.83,840.00,798.71,692.14; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):2.42-2.51(m,6H,3×morpholine-CH 2),3.34-3.38(m,2H,1×morpholine-CH 2),3.61-3.66(m,5H,-CH 2-and-SO 2CH 3),7.54-7.59(m,1H,Ar-H),7.77(d,J=8.58Hz,1H,Ar-H),7.89(s,2H,2×Ar-H),7.94-8.09(m,5H,5×Ar-H),8.16(s,1H,Ar-H),8.45(d,J=8.37Hz,1H,Ar-H),8.65(s,1H,Ar-H),10.91(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):43.09,53.22,53.22,62.14,66.17,66.17,118.32,118.69,120.70,123.00,125.85,126.77,127.09,128.03,128.90,129.38,129.94,130.97,131.23,136.39,137.03,139.12,139.42,141.16,142.99,146.95,155.39,163.81;TOF-MS?m/z:536.2[M+H] +.
Embodiment 38
The chloro-N-{3-{2-[6-of 4-(morpholinyl)] quinolyl } phenyl } benzamide (KLB-034)
Figure BDA0000407223010000261
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8d (0.32g, 1mmol), and Chlorodracylic acid (0.23g, 1.5mmol), obtains brown solid 0.26g, yield 56.9%, mp248-250 ℃.
IR(KBr,cm -1):3345.12,2923.81,2854.46,2816.89,1643.47,1606.24,1536.32,1484.01,1452.41,1417.06,1329.25,1301.39,1257.60,1115.89,1092.42,1013.60,847.43,792.01; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):2.43(s,4H,2×morpholine-CH 2),3.59-3.62(m,4H,2×morpholine-CH 2),3.67(s,2H,-CH 2-),7.52-7.57(m,1H,Ar-H),7.63-7.66(m,2H,2×Ar-H),7.75-7.78(m,1H,Ar-H),7.89(s,1H,Ar-H),7.97-7.99(m,2H,2×Ar-H),8.03-8.10(m,4H,4×Ar-H),8.45(d,J=8.61Hz,1H,Ar-H),8.66(s,1H,Ar-H),10.53(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):53.23,53.23,62.15,66.18,66.18,118.72,119.20,121.35,122.68,126.75,127.11,128.44,128.44,128.87,129.11,129.65,129.65,131.22,133.47,136.33,136.46,136.99,139.18,139.53,146.97,155.57,164.48;TOF-MS?m/z:456.2[M-H] -.
Embodiment 39
4-chloromethyl-N-{3-{2-[6-(morpholinyl)] quinolyl } phenyl } benzamide (KLB-035)
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8d (0.32g, 1mmol), and p-chloromethyl benzoic acid (0.26g, 1.5mmol), obtains gray solid 0.29g, yield 61.7%, mp180-182 ℃.
IR(KBr,cm -1):3430.23,3297.75,2957.19,2923.39,2852.72,2818.96,1640.94,1601.52,1526.72,1482.41,1421.20,1333.49,1303.68,1288.14,1149.05,1118.98,1008.91,902.34,869.34,792.25; 1H-NMR(DMSO-d 6,300MHz)δ(ppm):2.43(s,4H,2×morpholine-CH 2),3.61-3.67(m,6H,2×morpholine-CH 2and-CH 2-),4.87(s,2H,-CH 2Cl),7.52-7.57(m,1H,Ar-H),7.61-7.64(m,2H,2×Ar-H),7.77(d,J=8.76Hz,1H,Ar-H),7.90(s,1H,Ar-H),7.96-8.01(m,2H,2×Ar-H),8.04-8.06(m,2H,2×Ar-H),8.07-8.10(m,2H,2×Ar-H),8.45(d,J=8.64Hz,1H,Ar-H),8.68(s,1H,Ar-H),10.49(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):45.39,53.20,53.20,62.14,66.15,66.15,118.74,119.17,121.49,122.59,126.74,127.13,128.61,128.61,128.74,128.90,129.10,129.10,131.45,134.62,136.29,137.00,139.16,139.65,141.09,147.00,155.64,165.13;TOF-MS?m/z:472.2[M+H] +.
Embodiment 40
The chloro-N-{3-{2-[6-of 3-(morpholinyl)] quinolyl } phenyl } benzamide (KLB-036)
Figure BDA0000407223010000271
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8d (0.32g, 1mmol), and m-chlorobenzoic acid (0.23g, 1.5mmol), obtains off-white color solid 0.27g, yield 59.1%, mp153-155 ℃.
IR(KBr,cm -1):3313.58,2959.72,2921.20,2856.08,2819.37,1644.01,1601.34,1526.24,1484.17,1411.29,1333.95,1289.99,1257.31,1212.61,1117.16,1068.62,1009.19,902.14,867.69,793.46,684.42;? 1H-NMR(DMSO-d 6,300MHz)δ(ppm):2.42-2.51(m,4H,2×morpholine-CH 2),3.59-3.62(m,4H,2×morpholine-CH 2),3.66(s,2H,-CH 2-),7.53-7.63(m,2H,2×Ar-H),7.68-7.71(m,1H,Ar-H),7.75-7.78(m,1H,Ar-H),7.89(s,1H,Ar-H),7.98-8.04(m,4H,4×Ar-H),8.07-8.08(m,1H,Ar-H),8.10(m,1H,Ar-H),8.45(d,J=8.67Hz,1H,Ar-H),8.68(s,1H,Ar-H),10.58(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):53.23,53.23,62.15,66.18,66.18,118.70,119.21,121.51,122.76,126.52,126.75,127.09,127.44,128.87,129.12,130.36,131.20,131.42,133.20,136.33,136.73,136.98,139.20,139.45,146.98,155.54,164.09;TOF-MS?m/z:458.2[M+H] +.
Embodiment 41
The bromo-N-{3-{2-[6-of 4-(morpholinyl)] quinolyl } phenyl } benzamide (KLB-037)
Figure BDA0000407223010000272
Specific experiment operation is synthetic with compound KLB-001's, drops into compound 8d (0.32g, 1mmol), and parabromobenzoic acid (0.30g, 1.5mmol), obtains off-white color solid 0.30g, yield 59.9%, mp252-254 ℃.
IR(KBr,cm -1):3345.49,2954.39,2923.07,2855.00,2815.48,1644.08,1606.78,1599.09,1536.01,1483.57,1451.79,1416.11,1328.83,1290.05,1256.71,1115.50,1072.51,1009.80,895.65,845.40,792.66;? 1H-NMR(DMSO-d 6,300MHz)δ(ppm):2.42(s,4H,2×morpholine-CH 2),3.61(s,4H,2×morpholine-CH 2),3.66(s,2H,-CH 2-),7.52-7.60(m,1H,Ar-H),7.63-7.66(m,1H,Ar-H),7.75-7.79(m,3H,3×Ar-H),7.89(s,1H,Ar-H),7.98-8.03(m,4H,4×Ar-H),8.06-8.10(m,1H,Ar-H),8.45(d,J=8.67Hz,1H,Ar-H),8.67(s,1H,Ar-H),10.54(s,1H,-NHCO-); 13C-NMR(DMSO-d 6,75MHz)δ(ppm):53.22,53.22,62.14,66.17,66.17,118.70,119.20,121.52,122.67,126.74,127.09,128.60,128.60,128.76,128.86,129.09,129.09,131.36,131.49,133.86,136.31,136.97,139.18,139.51,146.97,155.56,164.59;TOF-MS?m/z:502.1[M+H] +.
Biology embodiment
Adopt following experiment to screen the compound of the required activity with optimum extent.
Inhibition tumor cell proliferation assay method (mtt assay)
In viable cell plastosome succinodehydrogenase can metabolism the exogenous colourless MTT of reduction, simultaneously under the effect of cytochrome C, generate blue (or bluish voilet) water-fast formazan (Formazan), and be deposited in cell, in dead cell, not containing succinodehydrogenase, MTT is not reduced.With measuring its absorbance value at 490nm wavelength place by microplate reader after DMSO Rong Xie formazan.Under normal conditions, formazan growing amount is directly proportional to viable count, therefore can infer the number that viable cell according to optical density(OD) OD value.Thereby, adopt mtt assay can measure the multiplication capacity of target compound inhibition tumor cell, utilize method well known in the art simultaneously, can use similar measuring method to any cancer cells.
1. reagent and instrument
Not exclusively PRMI-1640 substratum is (containing penicillin: 80U/mL, containing Streptomycin sulphate: 0.08mg/mL, containing L-glutaminate and sodium bicarbonate), incomplete McCoy ' 5A substratum (containing penicillin: 80U/mL, containing Streptomycin sulphate: 0.08mg/mL, containing L-glutaminate and sodium bicarbonate), foetal calf serum, trypsinase-EDTA Digestive system, MTT cell proliferation and cytotoxicity detection kit, Trypan Blue test kit.
CO 2constant incubator, Bechtop, high-pressure steam sterilizing pan, whizzer, microplate reader, liquid-transfering gun, centrifuge tube, Tissue Culture Flask, 96 orifice plates, electronic analytical balance etc.
2. cell strain
Human hepatoma cell strain (SMMC7721), human colon cancer cell strain (HCT116)
3. reference substance
Pyrvinium, VU-WS113(laboratory oneself preparation)
4. experimental technique
4.1 cell cultures
RPMI-1640 substratum containing 10% foetal calf serum for human hepatoma cell strain (SMMC7721), in 37 ℃, 5%CO 2in constant incubator, cultivate.McCoy ' 5A substratum containing 10% foetal calf serum for human colon cancer cell strain (HCT116), in 37 ℃, 5%CO 2in constant incubator, cultivate.
4.2 cell dissociations are processed
Because human hepatoma cell strain (SMMC7721) and human colon cancer cell strain (HCT116) all belong to attached cell, before inoculation, need to carry out digestion process.Concrete digestive process is as follows:
Getting the logarithmic phase tumour cell of cultivating, suck nutrient solution, is 7.2-7.4 phosphoric acid buffer washed cell 1 time with aseptic pH, to remove the serum remaining in culturing bottle.Then add trysinization liquid to make it slightly cover cell, and culturing bottle is put into 37 ℃, 5%CO 2in constant incubator, place 1 minute and 30 seconds, under microscope, can observe cell and obviously shrink.Add the substratum containing foetal calf serum, the lower cell of piping and druming.
4.3 cell inoculations
The cell suspension that the digestion process of learning from else's experience is crossed adds in centrifuge tube, and in 1000 revs/min, centrifugal 5 minutes, then abandoning supernatant, rejoined the substratum containing serum, and blew and beat adherent cell.Draw the resuspended cell of 90 μ L and add in centrifuge tube, add 10 μ L Trypan Blue liquid, piping and druming mixes.Draw the dyed cell suspension of 10 μ L, be added on blood counting chamber and count.To 96 orifice plates, add cell suspension 100 μ L/ holes (approximately 1 * 104, every hole tumour cell), then 96 orifice plates are put into 37 ℃, 5%CO 2in constant incubator, cultivate 24h.
4.4 compound preparations
On analytical balance, accurately take each test-compound, with DMSO, dissolve the storage liquid that is mixed with 10mmol, then add as required the substratum dilute sample containing serum.
4.5 add test-compound
By the nutrient solution sucking-off of having cultivated in 96 orifice plates of 24h, add the test-compound of proper concn, each concentration arranges 3 parallel holes, and 100 μ L/ holes, then put into 37 ℃ by 96 orifice plates, in 5%CO2 constant incubator, cultivate 24h.
4.6 measure
5 * MTT is diluted to 1 * MTT with Dilution Buffer.Every hole adds 50 μ L1 * MTT, and 96 orifice plates are put into 37 ℃, in 5%CO2 constant incubator, cultivates 4h, makes MTT be reduced to formazan.Sucking-off supernatant liquor, every hole adds 150 μ L DMSO Shi formazans to dissolve, and then uses dull and stereotyped shaking table yawing 5min.It is 492nm that microplate reader is set to wavelength, measures the 96 every hole of orifice plate light absorption values, records result and calculates cell survival rate, to judge the anti-tumor activity of tested medicine.
4.7 interpretation of result
(1) cell survival rate: the OD value of each test hole is deducted to background OD value (perfect medium adds MTT, acellular) or blank medicine hole OD value (the different extent of dilution that perfect medium adds tested medicine add MTT, acellular).
Cell survival rate represents with T/C%, and T is the OD value of dosing cell, the OD value that C is control cells.
Cell inhibitory rate %=[1-(dosing cell OD/ control cells OD)] * 100
(2) drug level while obtaining T/C=50% (IC50).Inhibiting rate is higher than 50% compound, by Graphpad Prism5.0 computed in software IC50 value.
5. experimental result
5.1 inhibitory rate of cell growth
Under different concns, KLB series target compound to the growth inhibition ratio of human hepatoma cell strain (SMMC7721) and human colon cancer cell strain (HCT116) in Table 1 and 2.
Table 1KLB series target compound under different concns to human hepatoma cell strain (SMMC7721) growth inhibition ratio
Figure BDA0000407223010000291
Figure 20131053558711000021
Figure BDA0000407223010000301
Figure BDA0000407223010000311
Table 2KLB series target compound under different concns to human colon cancer cell strain (HCT116) growth inhibition ratio
Figure BDA0000407223010000322
Figure BDA0000407223010000331
Figure BDA0000407223010000341
4.2 Growth of Cells half-inhibition concentration (IC 50μ mol/L)
Half-inhibition concentration (the IC of KLB series target compound to different growth of tumour cell 50μ mol/L) in Table 3
Half-inhibition concentration (the IC of table 3KLB series target compound to different growth of tumour cell 50μ mol/L)
Figure DEST_PATH_IMAGE001
Figure 2013105355871100002DEST_PATH_IMAGE002
A-IC 50>10.0μmol/L
B-5.0<IC 50<10.0μmol/L
C-IC 50<5.0μmol/L
5. experiment conclusion
The compound with formula (1) structure of preparing in the embodiment of the present invention has significant restraining effect to the propagation of human hepatoma cell strain (SMMC7721), human colon cancer cell strain (HCT116).Above-mentioned these compounds can be applicable to the preparation of antitumor drug.

Claims (10)

1. the compound of structure or its pharmacy acceptable salt shown in formula (1),
Figure FDA0000407223000000011
Wherein:
R is selected from hydrogen, alkyl, haloalkyl, halogen ,-NR 1r 2or-CH 2nR 3r 4, R 1or R 2independently selected from hydrogen, alkyl or cycloalkyl, R 3or R 4independently selected from hydrogen, alkyl or cycloalkyl, or R 3and R 4be connected and form the heterolipid cyclic group replacing arbitrarily, its substituting group is alkyl or hydroxyalkyl;
Ar is selected from the phenyl of any replacement, any replacement-R '-Ph group; wherein R ' is five yuan or hexa-member heterocycle; Ph is phenyl, and its substituting group is selected from halogen, nitro, alkyl, alkoxyl group, cyano group, sulfydryl, hydroxyl, amino, ester group, alkyl sulphonyl or haloalkyl.
2. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that
R is selected from hydrogen, C 1～6alkyl, halogen ,-NR 1r 2or-CH 2nR 3r 4, R 1or R 2independently selected from hydrogen or C 1～6alkyl, R 3or R 4select independently C 1～6alkyl, or R 3and R 4be connected and form the heterolipid cyclic group replacing arbitrarily, its substituting group is C 1～6alkyl or C 1～6hydroxyalkyl;
Ar is selected from the phenyl of any replacement, any replacement-R '-Ph group, and wherein R ' is pyrrole ring, and Ph is phenyl, and its substituting group is selected from halogen, nitro, C 1～6alkyl, C 1～6alkoxyl group, cyano group, sulfydryl, hydroxyl, amino, ester group, methyl sulphonyl or C 1～6haloalkyl.
3. compound according to claim 2 or its pharmacy acceptable salt, is characterized in that
R is selected from hydrogen, C 1～4alkyl ,-NR 1r 2or-CH 2nR 3r 4, R 1or R 2independently selected from hydrogen or C 1～4alkyl, R 3or R 4select independently C 1～4alkyl, or R 3and R 4be connected and form the hexa-atomic heterolipid cyclic group replacing arbitrarily, its substituting group is C 1～4alkyl;
Ar is selected from the phenyl of any replacement, any replacement-R '-Ph group, and wherein R ' is pyrrole ring, and Ph is phenyl, and its substituting group is selected from halogen, C 1～4alkyl, C 1～4alkoxyl group, methyl sulphonyl or C 1～4haloalkyl.
4. compound according to claim 3 or its pharmacy acceptable salt, is characterized in that described hexa-atomic heterolipid cyclic group is selected from piperidyl or morpholinyl.
5. compound according to claim 4 or its pharmacy acceptable salt, is characterized in that
R is selected from hydrogen, methyl ,-N (CH 3) 2,
Figure FDA0000407223000000021
Ar is selected from the phenyl of any replacement, any replacement-R '-Ph group, and wherein R ' is pyrrole ring, and Ph is phenyl, and its substituting group is selected from halogen, methyl, methoxyl group, methylsulfonyl methoxycarbonyl or chloro methyl.
6. compound according to claim 2 or its pharmacy acceptable salt, is characterized in that
When R is hydrogen, Ar be selected from the phenyl of any replacement, replace arbitrarily-R '-Ph group, wherein R ' is pyrrole ring, Ph is phenyl, its substituting group is selected from halogen, C 1～6alkyl, C 1～6alkoxyl group or methyl sulphonyl;
When R is C 1～6during alkyl, Ar is selected from the phenyl of any replacement, and its substituting group is selected from halogen, C 1～6alkyl or methyl sulphonyl;
When R is-NR 1r 2and R 1or R 2independently selected from C 1～6during alkyl, Ar is selected from the phenyl of any replacement, and its substituting group is selected from halogen, C 1～6alkyl or C 1～6haloalkyl;
When R is-CH 2nR 3r 4and R 3or R 4select independently C 1～6during alkyl, Ar is selected from the phenyl of any replacement, and its substituting group is selected from halogen, C 1～6alkyl, methyl sulphonyl or C 1～6haloalkyl;
When R is-CH 2nR 3r 4and R 3and R 4be connected and form the hexa-atomic heterolipid cyclic group replacing arbitrarily, its substituting group is C 1～4during alkyl, Ar be selected from the phenyl of any replacement, replace arbitrarily-R '-Ph group, wherein R ' is pyrrole ring, Ph is phenyl, its substituting group is selected from halogen, C 1～6alkyl, C 1～6alkoxyl group, methyl sulphonyl or C 1～6haloalkyl.
7. according to the compound described in any one in claim 1～6 or its pharmacy acceptable salt, it is characterized in that described compound is selected from:
4-methoxyl group-N-{3-[6-(pipecoline base)-2-quinolyl] phenyl } benzamide;
The chloro-N-{3-[6-of 4-(pipecoline base)-2-quinolyl] phenyl } benzamide;
The chloro-N-{3-[6-of 2-(pipecoline base)-2-quinolyl] phenyl }-4-methylsulfonyl benzamide;
2,5-dimethyl-N-{3-[2-(6-toluquinoline base)] phenyl }-1-phenyl-1H-pyrrole-3-carboxamide;
The chloro-N-{3-[6-of 3-(pipecoline base)-2-quinolyl] phenyl } benzamide;
2,5-dimethyl-1-phenyl-N-[3-(2-quinolyl) phenyl]-1H-pyrrole-3-carboxamide;
The chloro-4-of 2-(methylsulfonyl)-N-[3-(2-quinolyl)-phenyl] benzamide;
4-methoxyl group-N-[3-(2-quinolyl)-phenyl] benzamide;
The chloro-N-[3-of 4-(2-quinolyl)-phenyl] benzamide;
The chloro-N-[3-of 3-(2-quinolyl)-phenyl] benzamide;
4-chloromethyl-N-[3-(2-quinolyl)-phenyl] benzamide;
2,5-dimethyl-1-phenyl-N-{3-[2-(6-toluquinoline base)] phenyl }-1H-pyrrole-3-carboxamide;
The chloro-N-{3-[2-of 2-(6-toluquinoline base)] phenyl }-4-(methylsulfonyl) benzamide;
The chloro-N-{3-[2-of 4-(6-toluquinoline base)] phenyl } benzamide;
The chloro-N-{3-[2-of 3-(6-toluquinoline base)] phenyl } benzamide;
4-chloromethyl-N-{3-[2-(6-toluquinoline base)] phenyl } benzamide;
The chloro-4-of 2-(methylsulfonyl)-N-{3-{2-[6-(piperidines-1-methyl)] quinolyl } phenyl } benzamide;
The chloro-N-{3-{2-[6-of 4-(piperidines-1-methyl)] quinolyl } phenyl } benzamide;
The chloro-N-{3-{2-[6-of 3-(piperidines-1-methyl)] quinolyl } phenyl } benzamide;
4-chloromethyl-N-{3-{2-[6-(piperidines-1-methyl)] quinolyl } phenyl } benzamide;
4-methoxyl group-N-{3-{2-[6-(piperidines-1-methyl)] quinolyl } phenyl } benzamide;
The bromo-N-{3-{2-[6-of 4-(piperidines-1-methyl)] quinolyl } phenyl } benzamide;
The chloro-4-of 2-(methylsulfonyl)-N-{3-{2-[6-(N, N-dimethyl)] quinolyl } phenyl } benzamide;
The chloro-N-{3-{2-[6-of 4-(N, N-dimethyl)] quinolyl } phenyl } benzamide;
4-chloromethyl-N-{3-{2-[6-(N, N-dimethyl)] quinolyl } phenyl } benzamide;
The bromo-N-{3-{2-[6-of 4-(N, N-dimethyl)] quinolyl } phenyl } benzamide;
The fluoro-N-{3-{2-[6-of 3-(N, N-dimethyl)] quinolyl } phenyl } benzamide;
The chloro-4-of 2-(methylsulfonyl)-N-{3-{2-[6-(diethylin)] quinolyl } phenyl } benzamide;
The chloro-N-{3-{2-[6-of 4-(diethylin)] quinolyl } phenyl } benzamide;
The chloro-N-{3-{2-[6-of 3-(diethylin)] quinolyl } phenyl } benzamide;
4-chloromethyl-N-{3-{2-[6-(diethylin)] quinolyl } phenyl } benzamide;
The bromo-N-{3-{2-[6-of 4-(diethylin)] quinolyl } phenyl } benzamide;
The chloro-4-of 2-(methylsulfonyl)-N-{3-{2-[6-(morpholinyl)] quinolyl } phenyl } benzamide;
The chloro-N-{3-{2-[6-of 4-(morpholinyl)] quinolyl } phenyl } benzamide;
4-chloromethyl-N-{3-{2-[6-(morpholinyl)] quinolyl } phenyl } benzamide;
The chloro-N-{3-{2-[6-of 3-(morpholinyl)] quinolyl } phenyl } benzamide;
The bromo-N-{3-{2-[6-of 4-(morpholinyl)] quinolyl } phenyl } benzamide.
8. a pharmaceutical composition, is characterized in that it take compound or its pharmacy acceptable salt described in any one in claim 1～6 is activeconstituents or main active ingredient, is aided with pharmaceutically acceptable auxiliary material.
9. the compound described in any one or its pharmacy acceptable salt application in preparation prevention or treatment cancer drug in claim 1～6.
10. application according to claim 9, is characterized in that described cancer is colorectal carcinoma, liver cancer, prostate cancer, cervical cancer or mammary cancer.
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EP3423452A4 (en) * 2016-03-01 2019-10-30 University of Maryland, Baltimore Wnt signaling pathway inhibitors for treatments of disease
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EP3423452A4 (en) * 2016-03-01 2019-10-30 University of Maryland, Baltimore Wnt signaling pathway inhibitors for treatments of disease
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