CN103664876B

CN103664876B - Quinoline derivatives and uses thereof

Info

Publication number: CN103664876B
Application number: CN201310535587.1A
Authority: CN
Inventors: 吉民; 张曙光; 李锐; 王义成
Original assignee: SUZHOU SOUTHEAST PHARMACEUTICALS CO Ltd
Current assignee: SUZHOU SOUTHEAST PHARMACEUTICALS CO Ltd
Priority date: 2013-11-01
Filing date: 2013-11-01
Publication date: 2016-04-20
Anticipated expiration: 2033-11-01
Also published as: CN103664876A

Abstract

The invention discloses class quinoline derivatives and uses thereof, as the formula (1) the compound of structure or its pharmacy acceptable salt.Compound of the present invention or its pharmacy acceptable salt can be applicable to preparation prevention or Therapeutic cancer pharmaceutical field.

Description

Quinoline derivatives and uses thereof

Technical field

The invention belongs to medicinal chemistry art, be specifically related to a kind of synthesis technology of preparing of Wnt signal path inhibitor, i.e. quinoline derivatives and uses thereof.

Background technology

Wnt signal path is a signal path conservative on evolving, and most important to fetal development, can the growth of regulating cell, migration and differentiation.Wnt part and cell surface receptor Fzd family or the LRPS/LRP6 receptors bind of secretion form mixture, and receptor complex causes β-catenin in intracellular accumulation.When Wnt signal path activates, Wnt is combined with acceptor Fzd, Dsh albumen in activating cells, signal reaches in cell by the Dsh albumen of phosphorylation, suppresses APC, GSK-3 β, the activity of the complex kinase that Axin, CK1 α forms, causes β-catenin in intracellular accumulation, and the transcription factor entering nucleus and the T cell factor (TCF)-lymphocyte enhancement factor family forms mixture, activate transcribing of downstream gene.β-catenin be Wnt signal to the signal of interest molecule in nucleus transmittance process, the key of Wnt signal transduction whether there is constitutionally stable, solubility β-catenin in endochylema, 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 signal transduction and carbohydrate metabolism process.Stretching, extension, the polarity of APC and cell are moved relevant.Therefore, Wnt signal path is not single path, but forms complicated network, plays important regulating and controlling effect to the growth stimulation of whole cell.Under the state not having Wnt signal, the mixture of APC albumen, GSK-3 β, Axin and CK1 α composition 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 cell-cell adhesion afunction, 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.In Wnt signal path inducible protein Wnt-1, downstream effect albumen WISP-1 and cell, survivin and cyclinD1 interacts, and may accelerate cell cycle, cell proliferation and apoptosis inhibit, this and colorectal carcinoma have substantial connection.Extensively there is APC and β-catenin in adenoma of colon and colorectal carcinoma to suddenly change, this significant sudden change is not only confined to the tumour of gastrointestinal tissue's origin, also finds that there is the exception of the Wnt signal components such as β-catenin, APC and Axin in the tumour of Endometrial Carcinomas, prostate cancer, thyroid carcinoma and some mesenchymal cells origin.

The activation of Wnt signal path, plays keying action for the stable propagation maintaining the multiple human stem cells such as intestinal stem cell, hemopoietic stem cell, skin progenitor cell.APC is first mankind Wnt signal path genes involved be found, and APC expression deletion in the colorectal carcinoma of 80%.Be similar to human diseases, induction APC, β-catenin sudden change, also can cause the generation of a large amount of polyp 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 rejection ability,

Another object of the present invention is to provide a kind of composition containing 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 be reached by following measures:

Quinoline derivatives of the present invention is compound or its pharmacy acceptable salt of formula (1) structure,

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 the heteroalicyclyl forming and replace arbitrarily, and its substituting group is alkyl or hydroxyalkyl;

Ar is selected from the phenyl replaced arbitrarily ,-the R '-Ph group replaced arbitrarily; 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 ~ 6}alkyl, halogen ,-NR ₁r ₂or-CH ₂nR ₃r ₄, R ₁or R ₂independently selected from hydrogen or C _{1 ~ 6}alkyl, R ₃or R ₄select C independently _{1 ~ 6}alkyl, or R ₃and R ₄be connected the heteroalicyclyl forming and replace arbitrarily, and its substituting group is C _{1 ~ 6}alkyl or C _{1 ~ 6}hydroxyalkyl.

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 C1-4 alkyl independently, or R ₃or R ₄form substituted or non-substituted heteroalicyclyl altogether, wherein substituting group methyl, ethyl, methylol or hydroxyethyl.

In a kind of preferred version, R is selected from hydrogen, C _{1 ~ 4}alkyl ,-NR ₁r ₂or-CH ₂nR ₃r ₄, R ₁or R ₂independently selected from hydrogen or C _{1 ~ 4}alkyl, R ₃or R ₄select C independently _{1 ~ 4}alkyl, or R ₃and R ₄be connected the hexa-atomic heteroalicyclyl forming and replace arbitrarily, and its substituting group is C _{1 ~ 4}alkyl.

In a kind of preferred version, R is selected from hydrogen, methyl ,-N (CH ₃) ₂,

In a kind of preferred version, Ar is selected from the phenyl replaced arbitrarily ,-the R '-Ph group replaced arbitrarily, and wherein R ' is pyrrole ring, and Ph is phenyl, and its substituting group is selected from halogen, nitre element, C _{1 ~ 6}alkyl, C _{1 ~ 6}alkoxyl group, cyano group, thin base, hydroxyl, amino, ester group, methyl sulphonyl or C _{1 ~ 6}haloalkyl.

In a kind of preferred version, Ar is selected from the phenyl replaced arbitrarily ,-the R '-Ph group replaced arbitrarily, and wherein R ' is pyrrole ring, and Ph is phenyl, and its substituting group is selected from halogen, C _{1 ~ 4}alkyl, C _{1 ~ 4}alkoxyl group, methyl sulphonyl or C _{1 ~ 4}haloalkyl.

In a kind of preferred version, Ar is selected from the phenyl replaced arbitrarily ,-the R '-Ph group replaced arbitrarily, and wherein R ' is pyrrole ring, and Ph is phenyl, and its substituting group is selected from halogen, methyl, methoxyl group, methylsulfonyl methoxycarbonyl or chloromethyl.

In a kind of preferred version, when R is hydrogen, Ar is selected from the phenyl replaced arbitrarily ,-the R '-Ph group replaced arbitrarily, and wherein R ' is pyrrole ring, and Ph is phenyl, and its substituting group is selected from halogen, C _{1 ~ 6}alkyl, C _{1 ~ 6}alkoxyl group or methyl sulphonyl;

When R is C ₁~ ₆during alkyl, Ar is selected from the phenyl replaced arbitrarily, and its substituting group is selected from halogen, C _{1 ~ 6}alkyl or methyl sulphonyl;

When R is-NR ₁r ₂and R ₁or R ₂independently selected from C _{1 ~ 6}during alkyl, Ar is selected from the phenyl replaced arbitrarily, and its substituting group is selected from halogen, C _{1 ~ 6}alkyl or C _{1 ~ 6}haloalkyl;

When R is-CH ₂nR ₃r ₄and R ₃or R ₄select C independently _{1 ~ 6}during alkyl, Ar is selected from the phenyl replaced arbitrarily, and its substituting group is selected from halogen, C _{1 ~ 6}alkyl, methyl sulphonyl or C _{1 ~ 6}haloalkyl;

When R is-CH ₂nR ₃r ₄and R ₃and R ₄be connected the hexa-atomic heteroalicyclyl forming and replace arbitrarily, and its substituting group is C _{1 ~ 4}during alkyl, Ar is selected from the phenyl replaced arbitrarily ,-the R '-Ph group replaced arbitrarily, and wherein R ' is pyrrole ring, and Ph is phenyl, and its substituting group is selected from halogen, C _{1 ~ 6}alkyl, C _{1 ~ 6}alkoxyl group, methyl sulphonyl or C _{1 ~ 6}haloalkyl.

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-of 4-[6-(pipecoline base)-2-quinolyl] phenyl } benzamide;

The chloro-N-{3-of 2-[6-(pipecoline base)-2-quinolyl] phenyl }-4-methanesulfonylbenzamide;

2,5-dimethyl-N-{3-[2-(6-toluquinoline base)] phenyl }-1-phenyl-1H-pyrrole-3-carboxamide;

The chloro-N-{3-of 3-[6-(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-of 4-[3-(2-quinolyl)-phenyl] benzamide;

The chloro-N-of 3-[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-of 2-[2-(6-toluquinoline base)] phenyl }-4-(methylsulfonyl) benzamide;

The chloro-N-{3-of 4-[2-(6-toluquinoline base)] phenyl } benzamide;

The chloro-N-{3-of 3-[2-(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-of 4-[6-(piperidines-1-methyl)] quinolyl } phenyl } benzamide;

The chloro-N-{3-{2-of 3-[6-(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-of 4-[6-(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-of 4-[6-(N, N-dimethyl)] quinolyl } phenyl } benzamide;

4-chloromethyl-N-{3-{2-[6-(N, N-dimethyl)] quinolyl } phenyl } benzamide;

The bromo-N-{3-{2-of 4-[6-(N, N-dimethyl)] quinolyl } phenyl } benzamide;

The fluoro-N-{3-{2-of 3-[6-(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-of 4-[6-(diethylin)] quinolyl } phenyl } benzamide;

The chloro-N-{3-{2-of 3-[6-(diethylin)] quinolyl } phenyl } benzamide;

4-chloromethyl-N-{3-{2-[6-(diethylin)] quinolyl } phenyl } benzamide;

The bromo-N-{3-{2-of 4-[6-(diethylin)] quinolyl } phenyl } benzamide;

The chloro-4-of 2-(methylsulfonyl)-N-{3-{2-[6-(morpholinyl)] quinolyl } phenyl } benzamide;

The chloro-N-{3-{2-of 4-[6-(morpholinyl)] quinolyl } phenyl } benzamide;

4-chloromethyl-N-{3-{2-[6-(morpholinyl)] quinolyl } phenyl } benzamide;

The chloro-N-{3-{2-of 3-[6-(morpholinyl)] quinolyl } phenyl } benzamide;

Or the bromo-N-{3-{2-of 4-[6-(morpholinyl)] quinolyl phenyl benzamide.

The invention also discloses a kind of pharmaceutical composition, it for activeconstituents or main active ingredient, is aided with pharmaceutically acceptable auxiliary material with compound of the present invention or its pharmacy acceptable salt.

Compound of the present invention or its pharmacy acceptable salt can be applicable to, in preparation prevention or Therapeutic cancer medicine, 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 as raw material, can also be prepared into the spendable medicine being used for the treatment of the tumour such as liver cancer, colorectal carcinoma clinically.

By compound of the present invention with the form administration of prodrug.Prodrug refers to the compound of the pharmacological action just had after transforming in organism.Prodrug can be used to change physicochemical property or the pharmacokinetics aspect character of the compounds of this invention.When compound of the present invention contains the suitable group or substituted radical that can connect and change character group, form prodrug.

1. chemistry

Unless otherwise indicated, the following term used in the specification and in the claims 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 mentioned in the application's book, such as " 1-20 " refers to this group, it is now alkyl, can 1 carbon atom, 2 carbon atoms, 3 carbon atoms etc. be contained, 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.It is further preferred that alkyl is the medium sized alkyl having 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 having 1-4 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be replacement or unsubstituted.When for substituted alkyl, this substituting group is preferably one or more, and more preferably 1-3, most preferably 1 or 2 substituting group, they are preferred from following group independently: halogen, hydroxyl, lower alkoxy, aryl, aryloxy, hetero-aromatic ring, heteroalicyclyl and ester group.

" cycloalkyl " represents to be all the monocycle of carbon or ring (" condensing " ring means that each ring in system and other ring in system the share a pair carbon atom adjoined) group that condenses, containing 3-10 carbon atom, preferably 5,6 or 7 carbon atoms, most preferably 5 or 6 carbon atoms.The example (being not limited to) of cycloalkyl is hexanaphthene, pentamethylene, hexanaphthene, cyclohexadiene etc.Cycloalkyl can for replace with unsubstituted.When substituted, substituting group is preferably one or more is selected from following group separately, comprising: alkyl, aryl, heteroaryl, heteroalicyclyl, hydroxyl, alkoxyl group, aryloxy, cyano group, halogen, carbonyl etc.

" heteroalicyclyl " represents monocycle or fused ring group, has 5-18 annular atoms in ring, a preferred 5-12 annular atoms, more preferably 5-9 annular atoms, and 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 double bond, but these rings do not have the π-electron system of total conjugated.The limiting examples of unsubstituted heteroalicyclyl has piperidino-(1-position only), morpholine subbase, Piperazino, pyrrolidino etc.Heteroalicyclyl can be replacement or unsubstituted.When substituted, substituting group preferably one or more, be more preferably one, two or three, and then be 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 heteroalicyclyl in the present invention is selected from piperidyl or morpholinyl.

" hydroxyl " represents-OH group.

" hydroxyalkyl " represents to have the substituent alkyl of-OH, and wherein the concept of alkyl is described above.

" alkoxyl group " represents the unsubstituted alkyl of-O-() and the unsubstituted cycloalkyl of-O-(), wherein alkyl and cycloalkyl definition are as above.Representative example includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group etc.

" sulfydryl " represents-SH group.

" ester group " represents-C (O) O-R ' group, and wherein R ' defines the same, but R ' can not be hydrogen.

" halogen " represents fluorine, chlorine, bromine or iodine, preferred fluorine, chlorine, bromine or iodine.

" trihalogenmethyl " expression-CX ₃group, wherein X is halogen as defined above.

" cyano group " represents-CN group.

" amino " expression-NH ₂group.

" nitro " expression-NO ₂group.

" haloalkyl " represents that alkyl is replaced by one or more identical or different halogen atom, and preferably low alkyl group is replaced by one or more identical or different halogen atom as defined above, and wherein alkyl definition as above, such as-CH ₂cl ,-CH ₂br ,-CF ₃deng." halogenated alkoxy " represents that alkoxyl group is replaced by one or more identical or different halogen atom, and wherein alkoxyl group definition as above, such as-OCH ₂cl ,-OCH ₂br ,-OCF ₃deng.

" optionally " or " optionally " mean subsequently described event or environment can but need not occur, this explanation comprises the occasion that this event or environment occur and do not occur.Such as, " heteroaryl is optionally replaced by one or two substituting group " mean heteroaryl substituting group can but need not to be one, this explanation comprises situation that heteroaryl replaced by a substituting group and the situation that heterocyclic radical is replaced by two substituting groups.The statement " replaced arbitrarily " represents " replacement " or " replacement " 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 the reservation biological effectiveness of parent compound and those salt of character.This kind of salt comprises:

(1) with sour salify, react by the free alkali of parent compound and mineral acid or organic acid and obtain, 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, or (L) oxysuccinic acid (D), 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) acid proton be present in parent compound replaced by metal ion or with organic bases ligand compound the salt that generates, metal ion is alkalimetal ion, alkaline-earth metal ions or aluminum ion such as, and organic bases is as thanomin, diethanolamine, trolamine, Trometamol, N-METHYL-ALPHA-L-GLUCOSAMINE etc.

2. general synthetic method

The total preparation of the compound mentioned in the present invention is:

With to nitro bromobenzyl for starting raw material, product 2 is obtained with secondary amine generation substitution reaction, then be catalyzer with iron oxide hydroxide, hydrazine hydrate is that reductive agent obtains reduzate 3, compound 3 and ethoxy propylene acyl chloride reaction obtain amide product 4, compound 4 obtains product 5 at sulfuric acid catalysis ShiShimonoseki ring, compound 5 and tribromo oxygen phosphorus reaction obtain bromination product 6, linked reaction is there is and obtains product 7 in compound 6 and m-nitro boric acid under tetra-triphenylphosphine palladium catalysis, then be catalyzer with iron oxide hydroxide, hydrazine hydrate is that reductive agent obtains reduzate 8, last and corresponding acyl chloride reaction obtains target compound.

3. biological assessment method

Screening method at present for inhibition tumor cell proliferation mechanism is a lot, and mtt assay is one of them.MTT chemistry 3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt by name, being commonly called as tetrazolium bromide, is a kind of dyestuff of yellow color.In viable cell plastosome succinodehydrogenase can metabolism reduction exogenous colourless MTT, simultaneously under the effect of cytochrome C, generate blue (or bluish voilet) water-fast formazan (Formazan), and be deposited in cell, not containing succinodehydrogenase in dead cell, MTT is not reduced.Its absorbance value can be measured by microplate reader at 490nm wavelength place with after DMSO Rong Xie formazan.Under normal conditions, formazan growing amount is directly proportional to viable count, therefore can infer according to optical density(OD) OD value the number viable cell.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 Culture Cells on 96 orifice plates, testing drug inhibition tumor cell proliferation activity, the cell quantity of needs is few, and the quantity adding test medicine is many, be easy to carry out dose-effect relationship investigation, also can point out the restraining effect of drug on tumor cell proliferation to a certain extent.

Beneficial effect of the present invention: the invention provides a class and show the quinoline derivatives propagation of tumour cell to rejection ability, provides a kind of composition containing above-mentioned quinoline derivatives.There is provided above-mentioned quinoline derivatives in purposes pharmaceutically.To the propagation of human hepatoma cell strain (SMMC7721), human colon cancer cell strain (HCT116), there is significant restraining effect.These compounds above-mentioned can be applicable to the preparation of antitumor drug.

Embodiment

Provide following preparation and embodiment, enable those skilled in the art 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

The synthesis of intermediate 8

2-methyl isophthalic acid-(4-nitrobenzyl) piperidines (2a)

In 500mL there-necked flask, add nitro bromobenzyl (21.5g successively, 0.1mol), methylene dichloride (200mL), stirs and makes it dissolve, reaction solution ice-water bath is cooled to 0 DEG C, then pipecoline (9.9g is dripped, 0.1mol), triethylamine (17.5g), the mixing solutions of methylene dichloride (50mL).After dropwising, after reaction solution is warming up to room temperature, stirring reaction 5h.After reaction terminates, poured into by reaction solution in 400mL saturated sodium carbonate solution, stir 0.5h, separate organic layer, water layer methylene dichloride 3 × 100mL extracts, and merges organic layer, successively with water and saturated nacl aqueous solution washing, and 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-MSm/z:235.2[M+H] ⁺.

1-(4-nitrobenzyl) piperidines (2b)

Specific experiment operation is with the synthesis of compound 2a, and add nitro bromobenzyl (21.5g, 0.1mol), 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 with the synthesis of compound 2a, and add nitro bromobenzyl (21.5g, 0.1mol), 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-MSm/z:209.0[M+H] ⁺.

4-(4-nitrobenzyl) morpholine (2d)

Specific experiment operation, with the synthesis of compound 2a, adds nitro bromobenzyl (21.5g, 0.1mol), morpholine (8.7g, 0.1mol), obtains yellow solid 19.4g, yield 87.4%, mp76-78 DEG C.

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-[(pipecoline-1-base) methyl] aniline (3a)

In 500mL there-necked flask, add compound 2a (18g successively, 0.077mol), methyl alcohol (200mL), stirs and makes it dissolve, add iron oxide hydroxide (1.8g), after reaction solution is warming up to reflux temperature, drip 80% hydrazine hydrate (15mL), after dropwising, stirring reaction 5h.After reaction terminates, suction filtration while hot, methanol wash filter cake, vacuum-drying solvent, obtains yellow solid 15.1g, yield 96.2%, mp50-51 DEG C.

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-MSm/z:205.2[M+H] ⁺.

4-(piperidines-1-methyl) aniline (3b)

Specific experiment operation is with the synthesis of compound 3a, and add compound 7b (18g, 0.078mol), 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 with the synthesis of compound 3a, and add compound 7c (18g, 0.086mol), 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-MSm/z:179.1[M+H] ⁺.

4-(morpholine methyl) aniline (3d)

Specific experiment operation is with the synthesis of compound 3a, and add compound 7d (18g, 0.081mol), 80% hydrazine hydrate (18mL), obtains white solid 15.2g, yield 97.4%, mp101-102 DEG C.

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-[(pipecoline-1-base) methyl] phenyl } acrylamide (4a)

In 500mL there-necked flask, add compound 3a (15.3g successively, 0.075mol), pyridine (8.9g, 0.1125mol), anhydrous tetrahydro furan (200mL), stirring makes it dissolve, the bath of reaction solution cryosel is cooled to-10 DEG C, then drips the mixing solutions of 3-ethoxy propylene acyl chlorides (15.1g, 0.1125mol) and anhydrous tetrahydro furan (50mL).After dropwising, continue stirring reaction 2h at this temperature.After reaction solution is warming up to room temperature, stirring is spent the night.After reaction terminates, poured into by reaction solution in 1L saturated sodium carbonate solution, stir 0.5h, the solid that suction filtration is separated out, vacuum-drying, obtains brown solid 18.6g, yield 82.1%, mp110-112 DEG C.

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 ₂CH 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-MSm/z:303.1[M+H] ⁺.

(E)-3-oxyethyl group-N-[4-(piperidin-1-yl-methyl) phenyl] acrylamide (4b)

Specific experiment operation, with the synthesis of compound 4a, adds compound 3b (14.25g, 0.075mol), 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-ethanol acrylamides (4c)

Specific experiment operation, with the synthesis of compound 4a, adds compound 3c (13.35g, 0.075mol), 3-ethoxy propylene acyl chlorides (15.1g, 0.1125mol), obtains yellow-brown solid 18.5g, yield 89.8%, mp114-116 DEG C.

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 ₂CH 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-MSm/z:277.1[M+H] ⁺.

(E)-3-oxyethyl group-N-[4-(piperidin-1-yl-methyl) phenyl] acrylamide (4d)

Specific experiment operation, with the synthesis of compound 4a, adds compound 3d (14.4g, 0.075mol), 3-ethoxy propylene acyl chlorides (15.1g, 0.1125mol), obtains faint yellow solid 19.8g, yield 91.0%, mp134-135 DEG C.

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-ethanol acrylamides (4e)

Specific experiment operation, with the synthesis of compound 4a, adds 4-(N, N-dimethyl) aniline (10.2g, 0.075mol), 3-ethoxy propylene acyl chlorides (15.1g, 0.1125mol), obtain brown solid 15.5g, yield 88.6%, mp143-144 DEG C.

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, with the synthesis of compound 4a, adds aniline (6.98g, 0.075mol), 3-ethoxy propylene acyl chlorides (15.1g, 0.1125mol), obtains brown solid 13.2g, yield 92.3%, mp137-138 DEG C.

¹H-NMR(CDCl ₃,500MHz)δ(ppm):1.33-1.36(m,3H,-CH ₂ CH ₃),3.92-3.96(m,2H,- CH ₂CH 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-MSm/z:192.0[M+H] ⁺.

(E)-3-oxyethyl group N-(p-methylphenyl)-acrylamide (4g)

Specific experiment operation is with the synthesis of compound 4a, and add open-chain crown ether (8.02g, 0.075mol), 3-ethoxy propylene acyl chlorides (15.1g, 0.1125mol), obtains gray solid 13.9g, yield 90.3%, mp165-167 DEG C.

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-[(pipecoline) methyl] quinoline (5a)

In 500mL there-necked flask, add the vitriol oil (30mL), be cooled to-10 DEG C with cryosel bath, then add compound 4a (12.08g, 0.04mol) in batches.After adding, after reaction solution is warming up to room temperature, stirring reaction 5h.After reaction terminates, poured into by reaction solution in 1L saturated sodium carbonate solution, stir 0.5h, the solid that suction filtration is separated out, vacuum-drying, obtains yellow solid 7.6g, yield 74.2%, mp179-181 DEG C.

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-MSm/z:257.1[M+H] ⁺.

2-hydroxyl-6-(piperidine methyl) quinoline (5b)

Specific experiment operation, with the synthesis of compound 5a, adds compound 4b (11.52g, 0.04mol), sulfuric acid (30mL), obtains off-white color solid 7.54g, yield 77.9%, mp197-199 DEG C.

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-MSm/z:243.2[M+H] ⁺,265.2[M+Na] ⁺.

2-hydroxyl-6-(diethylamine methyl) quinoline (5c)

Specific experiment operation is with the synthesis of compound 5a, and add compound 4c (11.04g, 0.04mol), sulfuric acid (30mL), obtains yellow solid 6.77g, yield 73.6%, mp154-155 DEG C.

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-MSm/z:231.1[M+H] ⁺,253.1[M+Na] ⁺.

2-hydroxyl-6-(morpholine methyl) quinoline (5d)

Specific experiment operation, with the synthesis of compound 5a, adds compound 4d (11.6g, 0.04mol), sulfuric acid (30mL), obtains off-white color solid 7.2g, yield 73.8%, mp229-231 DEG C.

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-MSm/z:245.2[M+H] ⁺,267.2[M+Na] ⁺.

2-hydroxyl-6-(N, N-dimethyl) quinoline (5e)

Specific experiment operation, with the synthesis of compound 5a, adds compound 4e (9.36g, 0.04mol), sulfuric acid (30mL), obtains brown solid 5.42g, yield 72.1%, mp243-244 DEG C.

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-MSm/z:189.1[M+H] ⁺,211.1[M+Na] ⁺.

2-hydroxyquinoline (5f)

Specific experiment operation is with the synthesis of compound 5a, and add compound 4f (7.64g, 0.04mol), sulfuric acid (30mL), obtains yellow solid 4.21g, yield 72.7%, mp200-201 DEG C.

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-MSm/z:146.0[M+H] ⁺,168.0[M+Na] ⁺.

2-hydroxyl-6-toluquinoline (5g)

Specific experiment operation is with the synthesis of compound 5a, and add compound 4g (8.2g, 0.04mol), sulfuric acid (30mL), obtains white solid 4.66g, yield 73.4%, mp244-245 DEG C.

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-MSm/z:160.1[M+H] ⁺.

The bromo-6-of 2-[(pipecoline) methyl] quinoline (6a)

In 500mL there-necked flask, compound 5a (12.8g, 0.05mol) successively, chloroform (200mL), stirs and makes it dissolve.Then tribromo oxygen phosphorus (21.53g, 0.075mol) is added.After adding, after reaction solution is warming up to reflux temperature, stirring reaction 8h.After reaction terminates, reaction solution is poured in 1L saturated sodium carbonate solution, stir 0.5h, separate organic layer, water layer methylene dichloride 3 × 150mL extracts, and merges organic layer, anhydrous magnesium sulfate drying, suction filtration, solvent evaporated in vacuo, obtains white solid 12.9g, yield 81.6%, mp62-63 DEG C.

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-MSm/z:319.1[M+H] ⁺.

The bromo-6-of 2-(piperidine methyl) quinoline (6b)

Specific experiment operation, with the synthesis of compound 6a, adds compound 5b (12.1g, 0.05mol), tribromo oxygen phosphorus (21.53g, 0.075mol), obtains off-white color solid 12.4g, yield 81.9%, mp83-85 DEG C.

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-MSm/z:305.1[M+H] ⁺.

The bromo-6-of 2-(diethylamine methyl) quinoline (6c)

Specific experiment operation is with the synthesis of compound 6a, and add compound 5c (11.5g, 0.05mol), 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-MSm/z:293.1[M+H] ⁺.

The bromo-6-of 2-(morpholine methyl) quinoline (6d)

Specific experiment operation, with the synthesis of compound 6a, adds compound 5d (12.2g, 0.05mol), tribromo oxygen phosphorus (21.53g, 0.075mol), obtains white solid 12.7g, yield 83.2%, mp69-72 DEG C.

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-MSm/z:307.1[M+H] ⁺.

The bromo-6-of 2-(N, N-dimethyl) quinoline (6e)

Specific experiment operation, with the synthesis of compound 6a, adds compound 5e (9.4g, 0.05mol), tribromo oxygen phosphorus (21.53g, 0.075mol), obtains yellow solid 9.15g, yield 73.2%, mp80-81 DEG C.

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-MSm/z:251.1[M+H] ⁺.

2-bromoquinoline (6f)

Specific experiment operation, with the synthesis of compound 6a, adds compound 5f (7.25g, 0.05mol), tribromo oxygen phosphorus (21.53g, 0.075mol), obtains faint yellow solid 8.3g, yield 80.2%, mp55-56 DEG C.

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 (6g) of 2-

Specific experiment operation, with the synthesis of compound 6a, adds compound 5g (7.95g, 0.05mol), tribromo oxygen phosphorus (21.53g, 0.075mol), obtains white solid 8.8g, yield 79.8%, mp124-126 DEG C.

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-MSm/z:222.0[M+H] ⁺.

2-(3-nitrophenyl)-6-[(pipecoline) methyl] quinoline (7a)

In 250mL there-necked flask, add DMF (50mL) successively, water (50mL), stir lower argon replaces 0.5h.Then compound 6a (3.18g, 0.01mol) is added successively, m-nitro boric acid (1.67g, 0.01mol), tetra-triphenylphosphine palladium (0.058g), under argon shield, after reaction solution being warming up to 100 DEG C, stirring reaction 6h.After reaction terminates, poured into by reaction solution in 1L frozen water, stir 0.5h, suction filtration, washing filter cake is to neutral, and vacuum-drying, obtains faint yellow solid 1.9g, yield 52.6%, mp137-138 DEG C.

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-MSm/z:362.2[M+H] ⁺.

2-(3-nitrophenyl)-6-(piperidine methyl) quinoline (7b)

Specific experiment operation, with the synthesis of compound 7a, 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 DEG C.

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-MSm/z:348.2[M+H] ⁺.

2-(3-nitrophenyl)-6-[(diethylamine) methyl] quinoline (7c)

Specific experiment operation, with the synthesis of compound 7a, adds compound 6c (2.93g, 0.01mol), m-nitro boric acid (1.67g, 0.01mol), tetra-triphenylphosphine palladium (0.058g), obtain yellow solid 1.7g, yield 51.1%, mp83-85 DEG C.

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-MSm/z:336.3[M+H] ⁺.

2-(3-nitrophenyl)-6-(morpholine methyl) quinoline (7d)

Specific experiment operation, with the synthesis of compound 7a, 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 DEG C.

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-MSm/z:350.2[M+H] ⁺.

2-(3-nitrophenyl)-6-(N, N-dimethyl) quinoline (7e)

Specific experiment operation, with the synthesis of compound 7a, 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 DEG C.

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-MSm/z:295.2[M+H] ⁺.

2-(3-nitrophenyl) quinoline (7f)

Specific experiment operation, with the synthesis of compound 7a, 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 DEG C.

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-MSm/z:251.2[M+H] ⁺.

2-(3-nitrophenyl)-6-toluquinoline (7g)

Specific experiment operation, with the synthesis of compound 7a, 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 DEG C.

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-MSm/z:265.1[M+H] ⁺.

2-(3-aminophenyl)-6-[(pipecoline) methyl] quinoline (8a)

In 100mL there-necked flask, add compound 7a (1.8g successively, 5mmol), methyl alcohol (50mL), stirs and makes it dissolve, add iron oxide hydroxide (0.18g), after reaction solution is warming up to reflux temperature, drip 80% hydrazine hydrate (5mL), after dropwising, stirring reaction 5h.After reaction terminates, 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 with the synthesis of compound 8a, and add compound 7b (1.74g, 5mmol), 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-MSm/z:318.2[M+H] ⁺.

2-(3-aminophenyl)-6-[(diethylamine) methyl] quinoline (8c)

Specific experiment operation is with the synthesis of compound 8a, and add compound 7c (1.68g, 5mmol), 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 with the synthesis of compound 8a, and add compound 7d (1.75g, 5mmol), 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-MSm/z:320.2[M+H] ⁺.

2-(3-aminophenyl)-6-(N, N-dimethyl) quinoline (8e)

Specific experiment operation is with the synthesis of compound 8a, and add compound 7e (1.47g, 5mmol), 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 with the synthesis of compound 8a, and add compound 7f (1.25g, 5mmol), 80% hydrazine hydrate (5mL), obtains yellow solid 1.06g, yield 96.7%.

2-(3-aminophenyl)-6-toluquinoline (8g)

Specific experiment operation is with the synthesis of compound 8a, and add compound 7g (1.32g, 5mmol), 80% hydrazine hydrate (5mL), obtains yellow solid 1.12g, yield 96.9%.

Embodiment 2

Martonite (9)

In 500mL there-necked flask, add acetone (50mL, 0.687mol) successively, Glacial acetic acid (38mL) and water (180mL), stir.Reaction solution is heated to 65 DEG C, then slowly drips bromine (35.4mL, 0.687mol), control rate of addition and make system temperature be no more than 65 DEG C.After dropwising, continuing stirring reaction 2h at this temperature, is colourless to reaction solution color.Reaction solution ice bath is cooled to 0 DEG C, slowly adds frozen water (100mL), control reacting liquid temperature lower than 0 DEG C.Then adding anhydrous sodium carbonate regulates reaction system to neutral, and stratification, separates lower floor's liquid, and dry with Calcium Chloride Powder Anhydrous, and suction filtration, residuum underpressure distillation at 70-75 DEG C, obtains colourless liquid 33.7g, yield 35.82%.

Embodiment 3

3-ethoxycarbonyl-2,5-hexanedione (10)

Add sodium (6.9g, 0.3mol) in 500mL there-necked flask, cryosel bath is cooled to-5 DEG C, slowly drips dehydrated alcohol (300mL), maintains temperature of reaction and is no more than 10 DEG C.After dropwising, stirred at ambient temperature is clarified to solution.Cryosel bath is cooled to-10 DEG C, adds methyl aceto acetate (36.1mL, 0.238mol), after stirring 0.5h, slowly drips martonite (32.59g, 0.238mol).After dropwising, stirred at ambient temperature reaction is spent 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 is with 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 ₂COCH ₃),3.30-3.32(m,1H,-CH-),4.06-4.13(m,2H,-O CH ₂CH ₃);TOF-MSm/z:185.1[M-H] ^-.

Embodiment 4

2,5-dimethyl-1-phenylpyrrole-3-ethyl formate (11)

Add compound 10 (18.6g, 0.1mol) successively in 500mL single port bottle, tosic acid (1.6g, 0.0093mol), aniline (9mL, 0.1mol) and toluene (200mL), stir and make it dissolve.Reaction solution is heated to reflux temperature reaction 12h.After reaction terminates, reaction solution is cooled to room temperature, with saturated sodium carbonate solution washing, extraction into ethyl acetate water layer, merge organic layer, anhydrous magnesium sulfate drying, suction filtration, solvent evaporated in vacuo, residuum is with 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 DEG C.

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 ₂CH 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-MSm/z:266.1[M+Na] ⁺.

Embodiment 5

2,5-dimethyl-1-phenylpyrrole-3-formic acid (12)

In the there-necked flask of 250mL, add compound 19 (24.3g, 0.1mol) successively, potassium hydroxide (16.88g, 0.3mol), methyl alcohol (150mL) and water (15mL), stir and make it dissolve.Reaction solution is heated to reflux temperature reaction spend the night.After reaction terminates, by reaction solution slowly down in frozen water, and with hydrochloric acid regulation system pH to 2, precipitation solid, suction filtration, vacuum-drying obtains yellow solid 19.87g, yield 92.4%, mp220-222 DEG C.

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-MSm/z:214.0[M-H] ^-.

Embodiment 6

4-methoxyl group-N-{3-[6-(pipecoline base)-2-quinolyl] phenyl } benzamide (KLB-001)

In 100mL eggplant-shape bottle, add anisic acid (0.23g, 1.5mmol) successively, anhydrous tetrahydro furan (20mL), sulfur oxychloride (2mL), after stirring, be heated to reflux temperature reaction 2h.After reaction terminates, concentrating under reduced pressure, residuum anhydrous tetrahydro furan (20mL) dissolves, cryosel bath is cooled to-10 DEG C, slowly drips the solution that compound 8a (0.33g, 1mmol) is dissolved in anhydrous tetrahydro furan (20mL), after dropwising, drip TEA (2mL) again, after dropwising, room temperature for overnight.After reaction terminates, reaction solution is poured in frozen water, stir 0.5h.Extraction into ethyl acetate (3 × 50mL), anhydrous magnesium sulfate drying, suction filtration, solvent evaporated in vacuo, residuum is with sherwood oil: the mixed solvent of ethyl acetate (V:V)=1:2 is eluent, silica gel column chromatography separating-purifying obtains brown solid 0.27g, yield 58.7%, mp271-273 DEG C.

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-TOFMSm/z:calcdforC ₃₀H ₃₂N ₃O ₂[M+H] ⁺:466.2495,found:466.2501.

Embodiment 7

The chloro-N-{3-of 4-[6-(pipecoline base)-2-quinolyl] phenyl } benzamide (KLB-002)

Specific experiment operation, with the synthesis of compound KLB-001, adds compound 8a (0.33g, 1mmol), Chlorodracylic acid (0.23g, 1.5mmol), obtains brown solid 0.28g, yield 59.3%, mp88-90 DEG C.

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-TOFMSm/z:calcdforC ₂₉H ₂₉N ₃OCl[M+H] ⁺:470.1999,found:470.2003.

Embodiment 8

The chloro-N-{3-of 2-[6-(pipecoline base)-2-quinolyl] phenyl }-4-methanesulfonylbenzamide (KLB-003)

Specific experiment operation, with the synthesis of compound KLB-001, adds compound 8a (0.33g, 1mmol), 2-chlorin-4-mesyl benzoic acid (0.35g, 1.5mmol), obtains yellow solid 0.33g, yield 60.5%, mp153-155 DEG C.

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-TOFMSm/z:calcdforC 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)

Specific experiment operation, with the synthesis of compound KLB-001, adds compound 8a (0.33g1mmol), 25-dimethyl-1-phenylpyrrole-3-formic acid (0.32g, 1.5mmol), obtains yellow solid 0.29g, yield 55.7%, mp82-84 DEG C.

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-TOFMSm/z:calcdforC ₃₅H ₃₇N ₄O[M+H] ⁺:529.2967,found:529.2971.

Embodiment 10

The chloro-N-{3-of 3-[6-(pipecoline base)-2-quinolyl] phenyl } benzamide (KLB-005)

Specific experiment operation, with the synthesis of compound KLB-001, adds compound 8a (0.33g, 1mmol), m-chlorobenzoic acid (0.23g, 1.5mmol), obtains yellow solid 0.19g, yield 41.3%, mp95-97 DEG C.

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-MSm/z:470.1[M+H] ⁺.

Embodiment 11

2,5-dimethyl-1-phenyl-N-[3-(2-quinolyl) phenyl]-1H-pyrrole-3-carboxamide (KLB-006)

Specific experiment operation, with the synthesis of compound KLB-001, adds compound 8f (0.23g, 1mmol), 2,5-dimethyl-1-phenylpyrrole-3-formic acid (0.32g, 1.5mmol), obtain brown solid 0.24g, yield 58.1%, mp115-117 DEG C.

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-TOFMSm/z:calcdforC 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, with the synthesis of compound KLB-001, adds compound 8f (0.23g, 1mmol), 2-chlorin-4-mesyl benzoic acid (0.35g, 1.5mmol), obtains off-white color solid 0.27g, yield 62.7%, mp231-233 DEG C.

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-MSm/z:437.2[M+H] ⁺.

Embodiment 13

4-methoxyl group-N-[3-(2-quinolyl)-phenyl] benzamide (KLB-008)

Specific experiment operation, with the synthesis of compound KLB-001, adds compound 8f (0.23g, 1mmol), anisic acid (0.23g, 1.5mmol), obtains off-white color solid 0.21g, yield 61.3%, mp184-186 DEG C.

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-MSm/z:355.2[M+H] ⁺.

Embodiment 14

The chloro-N-of 4-[3-(2-quinolyl)-phenyl] benzamide (KLB-009)

Specific experiment operation, with the synthesis of compound KLB-001, adds compound 8f (0.23g, 1mmol), Chlorodracylic acid (0.23g, 1.5mmol), obtains off-white color solid 0.23g, yield 62.5%, mp217-218 DEG C.

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-MSm/z:359.1[M+H] ⁺.

Embodiment 15

The chloro-N-of 3-[3-(2-quinolyl)-phenyl] benzamide (KLB-010)

Specific experiment operation, with the synthesis of compound KLB-001, adds compound 8f (0.23g, 1mmol), m-chlorobenzoic acid (0.23g, 1.5mmol), obtains brown solid 0.22g, yield 60.7%, mp164-166 DEG C.

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-MSm/z:359.1[M+H] ⁺.

Embodiment 16

4-chloromethyl-N-[3-(2-quinolyl)-phenyl] benzamide (KLB-011)

Specific experiment operation, with the synthesis of compound KLB-001, adds compound 8f (0.23g, 1mmol), p-chloromethyl benzoic acid (0.26g, 1.5mmol), obtains brown solid 0.23g, yield 61.8%, mp192-194 DEG C.

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-MSm/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)

Specific experiment operation, with the synthesis of compound KLB-001, adds compound 8g (0.23g, 1mmol), 2,5-dimethyl-1-phenylpyrrole-3-formic acid (0.32g, 1.5mmol), obtain brown solid 0.25g, yield 59.7%, mp157-159 DEG C.

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-TOFMSm/z:calcdforC ₂₉H ₂₆N ₃O[M+H] ⁺:432.2076,found:432.2081.

Embodiment 18

The chloro-N-{3-of 2-[2-(6-toluquinoline base)] phenyl }-4-(methylsulfonyl) benzamide (KLB-013)

Specific experiment operation, with the synthesis of compound KLB-001, adds compound 8g (0.23g, 1mmol), 2-chlorin-4-mesyl benzoic acid (0.35g, 1.5mmol), obtains brown solid 0.27g, yield 60.8%, mp258-260 DEG C.

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-MSm/z:451.1[M+H]+.

Embodiment 19

The chloro-N-{3-of 4-[2-(6-toluquinoline base)] phenyl } benzamide (KLB-014)

Specific experiment operation, with the synthesis of compound KLB-001, adds compound 8g (0.23g, 1mmol), Chlorodracylic acid (0.23g, 1.5mmol), obtains brown solid 0.23g, yield 61.4%, mp192-194 DEG C.

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-MSm/z:373.1[M+H] ⁺.

Embodiment 20

The chloro-N-{3-of 3-[2-(6-toluquinoline base)] phenyl } benzamide (KLB-015)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8g (0.23g, 1mmol), m-chlorobenzoic acid (0.23g, 1.5mmol), obtains brown solid 0.22g, yield 60.7%, mp158-160 DEG C.

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-MSm/z:373.1[M+H] ⁺.

Embodiment 20

4-chloromethyl-N-{3-[2-(6-toluquinoline base)] phenyl } benzamide (KLB-016)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8g (0.23g, 1mmol), p-chloromethyl benzoic acid (0.26g, 1.5mmol), obtains yellow solid 0.24g, yield 61.2%, mp196-198 DEG C.

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-MSm/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)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8b (0.32g, 1mmol), 2-chlorin-4-mesyl benzoic acid (0.35g, 1.5mmol), obtains off-white color solid 0.32g, yield 60.1%, mp242-244 DEG C.

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-MSm/z:534.2[M+H] ⁺.

Embodiment 22

The chloro-N-{3-{2-of 4-[6-(piperidines-1-methyl)] quinolyl } phenyl } benzamide (KLB-018)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8b (0.32g, 1mmol), Chlorodracylic acid (0.23g, 1.5mmol), obtains off-white color solid 0.24g, yield 52.7%, mp188-190 DEG C.

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-MSm/z:456.2[M+H] ⁺.

Embodiment 23

The chloro-N-{3-{2-of 3-[6-(piperidines-1-methyl)] quinolyl } phenyl } benzamide (KLB-019)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8b (0.32g, 1mmol), m-chlorobenzoic acid (0.23g, 1.5mmol), obtains off-white color solid 0.27g, yield 59.3%, mp137-139 DEG C.

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-MSm/z:454.3[M-H] ^-.

Embodiment 24

4-chloromethyl-N-{3-{2-[6-(piperidines-1-methyl)] quinolyl } phenyl } benzamide (KLB-020)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8b (0.32g, 1mmol), p-chloromethyl benzoic acid (0.26g, 1.5mmol), obtains yellow solid 0.28g, yield 60.8%, mp152-154 DEG C.

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-MSm/z:470.3[M+H] ⁺.

Embodiment 25

4-methoxyl group-N-{3-{2-[6-(piperidines-1-methyl)] quinolyl } phenyl } benzamide (KLB-021)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8b (0.32g, 1mmol), anisic acid (0.23g, 1.5mmol), obtains brown solid 0.27g, yield 59.6%, mp166-168 DEG C.

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-MSm/z:452.3[M+H] ⁺.

Embodiment 26

The bromo-N-{3-{2-of 4-[6-(piperidines-1-methyl)] quinolyl } phenyl } benzamide (KLB-022)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8b (0.32g, 1mmol), parabromobenzoic acid (0.30g, 1.5mmol), obtains brown solid 0.30g, yield 60.6%, mp196-198 DEG C.

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-MSm/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)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8e (0.26g, 1mmol), 2-chlorin-4-mesyl benzoic acid (0.35g, 1.5mmol), obtains brown solid 0.30g, yield 62.1%, mp257-259 DEG C.

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-MSm/z:480.2[M+H] ⁺.

Embodiment 28

The chloro-N-{3-{2-of 4-[6-(N, N-dimethyl)] quinolyl } phenyl } benzamide (KLB-024)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8e (0.26g, 1mmol), Chlorodracylic acid (0.23g, 1.5mmol), obtains yellow solid 0.24g, yield 59.7%, mp218-220 DEG C.

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-MSm/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 with the synthesis of compound KLB-001, and drop into compound 8e (0.26g, 1mmol), p-chloromethyl benzoic acid (0.26g, 1.5mmol), obtains yellow solid 0.21g, yield 50.6%, mp180-182 DEG C.

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-MSm/z:416.1[M+H] ⁺.

Embodiment 30

The bromo-N-{3-{2-of 4-[6-(N, N-dimethyl)] quinolyl } phenyl } benzamide (KLB-026)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8e (0.26g, 1mmol), parabromobenzoic acid (0.30g, 1.5mmol), obtains yellow solid 0.27g, yield 61.5%, mp214-216 DEG C.

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-MSm/z:446.2[M+H] ⁺.

Embodiment 31

The fluoro-N-{3-{2-of 3-[6-(N, N-dimethyl)] quinolyl } phenyl } benzamide (KLB-027)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8e (0.26g, 1mmol), m-fluorobenzoic acid (0.21g, 1.5mmol), obtains yellow solid 0.22g, yield 56.2%, mp187-189 DEG C.

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-MSm/z:386.2[M+H] ⁺.

Embodiment 32

The chloro-4-of 2-(methylsulfonyl)-N-{3-{2-[6-(diethylin)] quinolyl } phenyl } benzamide (KLB-028)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8c (0.30g, 1mmol), 2-chlorin-4-mesyl benzoic acid (0.35g, 1.5mmol), obtains brown solid 0.32g, yield 61.6%, mp179-181 DEG C.

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-MSm/z:522.3[M+H] ⁺.

Embodiment 33

The chloro-N-{3-{2-of 4-[6-(diethylin)] quinolyl } phenyl } benzamide (KLB-029)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8c (0.30g, 1mmol), Chlorodracylic acid (0.23g, 1.5mmol), obtains brown solid 0.27g, yield 60.4%, mp142-144 DEG C.

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-MSm/z:444.2[M+H] ⁺.

Embodiment 34

The chloro-N-{3-{2-of 3-[6-(diethylin)] quinolyl } phenyl } benzamide (KLB-030)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8c (0.30g, 1mmol), m-chlorobenzoic acid (0.23g, 1.5mmol), obtains brown solid 0.28g, yield 62.9%, mp84-86 DEG C.

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-MSm/z:444.1[M+H] ⁺.

Embodiment 35

4-chloromethyl-N-{3-{2-[6-(diethylin)] quinolyl } phenyl } benzamide (KLB-031)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8c (0.30g, 1mmol), p-chloromethyl benzoic acid (0.26g, 1.5mmol), obtains brown solid 0.27g, yield 59.4%, mp183-185 DEG C.

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-MSm/z:458.2[M+H] ⁺.

Embodiment 36

The bromo-N-{3-{2-of 4-[6-(diethylin)] quinolyl } phenyl } benzamide (KLB-032)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8c (0.30g, 1mmol), parabromobenzoic acid (0.30g, 1.5mmol), obtains yellow solid 0.29g, yield 61.1%, mp142-144 DEG C.

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-MSm/z:488.2[M+H] ⁺.

Embodiment 37

The chloro-4-of 2-(methylsulfonyl)-N-{3-{2-[6-(morpholinyl)] quinolyl } phenyl } benzamide (KLB-033)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8d (0.32g, 1mmol), 2-chlorin-4-mesyl benzoic acid (0.35g, 1.5mmol), obtains brown solid 0.35g, yield 64.8%, mp238-240 DEG C.

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-MSm/z:536.2[M+H] ⁺.

Embodiment 38

The chloro-N-{3-{2-of 4-[6-(morpholinyl)] quinolyl } phenyl } benzamide (KLB-034)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8d (0.32g, 1mmol), Chlorodracylic acid (0.23g, 1.5mmol), obtains brown solid 0.26g, yield 56.9%, mp248-250 DEG C.

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-MSm/z:456.2[M-H] ^-.

Embodiment 39

4-chloromethyl-N-{3-{2-[6-(morpholinyl)] quinolyl } phenyl } benzamide (KLB-035)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8d (0.32g, 1mmol), p-chloromethyl benzoic acid (0.26g, 1.5mmol), obtains gray solid 0.29g, yield 61.7%, mp180-182 DEG C.

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-MSm/z:472.2[M+H] ⁺.

Embodiment 40

The chloro-N-{3-{2-of 3-[6-(morpholinyl)] quinolyl } phenyl } benzamide (KLB-036)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8d (0.32g, 1mmol), m-chlorobenzoic acid (0.23g, 1.5mmol), obtains off-white color solid 0.27g, yield 59.1%, mp153-155 DEG C.

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-MSm/z:458.2[M+H] ⁺.

Embodiment 41

The bromo-N-{3-{2-of 4-[6-(morpholinyl)] quinolyl } phenyl } benzamide (KLB-037)

Specific experiment operation is with the synthesis of compound KLB-001, and drop into compound 8d (0.32g, 1mmol), parabromobenzoic acid (0.30g, 1.5mmol), obtains off-white color solid 0.30g, yield 59.9%, mp252-254 DEG C.

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-MSm/z:502.1[M+H] ⁺.

Biological examples

Following experiments is adopted to screen the compound with the required activity of optimum extent.

Inhibition tumor cell proliferation assays (mtt assay)

In viable cell plastosome succinodehydrogenase can metabolism reduction exogenous colourless MTT, simultaneously under the effect of cytochrome C, generate blue (or bluish voilet) water-fast formazan (Formazan), and be deposited in cell, not containing succinodehydrogenase in dead cell, MTT is not reduced.Its absorbance value can be measured by microplate reader at 490nm wavelength place with after DMSO Rong Xie formazan.Under normal conditions, formazan growing amount is directly proportional to viable count, therefore can infer according to optical density(OD) OD value the number viable cell.Thus, adopt mtt assay can measure the multiplication capacity of target compound inhibition tumor cell, utilize method well known in the art simultaneously, similar measuring method can be used to any cancer cells.

1. reagent and instrument

Incomplete 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 citotoxicity 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

Prepared by Pyrvinium, VU-WS113(laboratory oneself)

4. experimental technique

4.1 cell cultures

The RPMI-1640 substratum of human hepatoma cell strain (SMMC7721) containing 10% foetal calf serum, in 37 DEG C, 5%CO ₂cultivate in constant incubator.McCoy ' the 5A substratum of human colon cancer cell strain (HCT116) containing 10% foetal calf serum, in 37 DEG C, 5%CO ₂cultivate in constant incubator.

4.2 cell dissociation process

Because human hepatoma cell strain (SMMC7721) and human colon cancer cell strain (HCT116) all belong to attached cell, need before inoculation to carry out digestion process.Concrete digestive process is as follows:

Getting the logarithmic phase tumour cell cultivated, suck nutrient solution, is 7.2-7.4 phosphoric acid buffer washed cell 1 time with aseptic pH, to remove the serum remained in culturing bottle.Then adding trysinization liquid makes it slightly cover cell, and culturing bottle is put into 37 DEG C, 5%CO ₂in constant incubator place 1 point 30 seconds, cell can be observed under microscope 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 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 blows and beats adherent cell.The cell drawing 90 μ L resuspended adds in centrifuge tube, adds 10 μ L Trypan Blue liquid, piping and druming mixing.Draw the cell suspension that 10 μ L are dyed, be added on blood counting chamber and count.Add cell suspension 100 μ L/ hole (about 1 × 104, every hole tumour cell) to 96 orifice plates, then 96 orifice plates are put into 37 DEG C, 5%CO ₂24h is cultivated in constant incubator.

4.4 compound preparations

Analytical balance accurately takes each test-compound, dissolves the storage liquid being mixed with 10mmol with DMSO, then add the substratum dilute sample containing serum as required.

4.5 add test-compound

To cultivate the nutrient solution sucking-off in 96 orifice plates of 24h, and add the test-compound of proper concn, each concentration arranges 3 parallel holes, and then 96 orifice plates are put into 37 DEG C, cultivated 24h in 5%CO2 constant incubator by 100 μ L/ holes.

4.6 measure

5 × MTT DilutionBuffer is diluted to 1 × MTT.Every hole adds 50 μ L1 × MTT, and 96 orifice plates are put into 37 DEG C, cultivates 4h in 5%CO2 constant incubator, makes MTT be reduced to formazan.Sucking-off supernatant liquor, every hole adds 150 μ LDMSO Shi formazans and dissolves, and then uses plate shaker yawing 5min.Microplate reader being set wavelength is 492nm, measures 96 orifice plate every hole light absorption values, and record result also calculates cell survival rate, to judge the anti-tumor activity of test medicine.

4.7 interpretation of result

(1) cell survival rate: the OD value of each test hole is deducted background OD value (perfect medium adds MTT, acellular) or blank medicine hole OD value (the different extent of dilution that perfect medium adds test medicine add MTT, acellular).

Cell survival rate represents with T/C%, and T is the OD value of dosing cell, and C is the OD value of compared with control cells.

Cell inhibitory rate %=[1-(dosing cell OD/ compared with control cells OD)] × 100

(2) drug level (IC50) during T/C=50% is obtained.Inhibiting rate higher than 50% compound, by GraphpadPrism5.0 computed in software IC50 value.

5. experimental result

5.1 inhibitory rate of cell growth

Under different concns, KLB list of 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.

Show 1KLB list of target compound under different concns to human hepatoma cell strain (SMMC7721) growth inhibition ratio

Show 2KLB list of target compound under different concns to human colon cancer cell strain (HCT116) growth inhibition ratio

4.2 Growth of Cells half-inhibition concentration (IC ₅₀μm ol/L)

KLB list of target compound is to the half-inhibition concentration (IC of different growth of tumour cell ₅₀μm ol/L) in table 3

Table 3KLB list of target compound is to the half-inhibition concentration (IC of different growth of tumour cell ₅₀μm ol/L)

A-IC ₅₀>10.0μmol/L

B-5.0<IC ₅₀<10.0μmol/L

C-IC ₅₀<5.0μmol/L

5. experiment conclusion

The propagation of the compound with formula (1) structure prepared in the embodiment of the present invention to human hepatoma cell strain (SMMC7721), human colon cancer cell strain (HCT116) has significant restraining effect.These compounds above-mentioned can be applicable to the preparation of antitumor drug.

Claims

1. the compound of structure shown in formula (1) or its pharmacy acceptable salt,

Wherein:

R is selected from hydrogen, C _{1 ~ 6}wan Ji Huo ?CH ₂nR ₃r ₄, R ₃or R ₄select C independently _{1 ~ 6}alkyl, or R ₃and R ₄be connected to form and replace hexa-atomic heteroalicyclyl arbitrarily, its substituting group is C _{1 ~ 6}alkyl or C _{1 ~ 6}hydroxyalkyl;

Ar be selected from replace arbitrarily phenyl, arbitrarily replace ?R ’ ?Ph group, wherein R ' is pyrrole ring, and Ph is phenyl, and its substituting group is selected from halogen, nitro, C _{1 ~ 6}alkyl, C _{1 ~ 6}alkoxyl group, cyano group, sulfydryl, hydroxyl, amino, ester group, methyl sulphonyl or C _{1 ~ 6}haloalkyl;

Further, when R is hydrogen, Ar be selected from replace arbitrarily ?R ’ ?Ph group, wherein R ' is pyrrole ring, and Ph is phenyl, and its substituting group is selected from halogen, C _{1 ~ 6}alkyl, C _{1 ~ 6}alkoxyl group or methyl sulphonyl;

When R is C _{1 ~ 6}during alkyl, Ar be selected from the phenyl that replaces arbitrarily or replace arbitrarily ?R ’ ?Ph group, wherein R ' is pyrrole ring, and Ph is phenyl, and its substituting group is selected from C _{1 ~ 4}alkyl, C _{1 ~ 4}alkoxyl group, methyl sulphonyl or C _{1 ~ 4}haloalkyl.

2. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that described hexa-atomic heteroalicyclyl is selected from piperidyl or morpholinyl.

3. compound according to claim 2 or its pharmacy acceptable salt, is characterized in that

R is selected from hydrogen, methyl ,-N (CH ₃) ₂,

4. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that

When R is hydrogen, Ar be selected from replace arbitrarily ?R ’ ?Ph group, wherein R ' is pyrrole ring, and Ph is phenyl, and its substituting group is selected from halogen, C _{1 ~ 6}alkyl, C _{1 ~ 6}alkoxyl group or methyl sulphonyl;

When R is C _{1 ~ 6}during alkyl, Ar be selected from the phenyl that replaces arbitrarily or replace arbitrarily ?R ’ ?Ph group, wherein R ' is pyrrole ring, and Ph is phenyl, and its substituting group is selected from C _{1 ~ 4}alkyl, C _{1 ~ 4}alkoxyl group, methyl sulphonyl or C _{1 ~ 4}haloalkyl;

When R Wei ?CH ₂nR ₃r ₄and R ₃and R ₄be connected the hexa-atomic heteroalicyclyl forming and replace arbitrarily, and its substituting group is C _{1 ~ 4}during alkyl, Ar be selected from replace arbitrarily phenyl, arbitrarily replace ?R ’ ?Ph group, wherein R ' is pyrrole ring, and Ph is phenyl, and its substituting group is selected from halogen, C _{1 ~ 6}alkyl, C _{1 ~ 6}alkoxyl group, methyl sulphonyl or C _{1 ~ 6}haloalkyl.

5. the compound according to any one of Claims 1 to 4 or its pharmacy acceptable salt, 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-of 4-[6-(pipecoline base)-2-quinolyl] phenyl } benzamide;

The chloro-N-{3-of 3-[6-(pipecoline base)-2-quinolyl] phenyl } benzamide;

2,5-dimethyl-1-phenyl-N-[3-(2-quinolyl) phenyl]-1H-pyrrole-3-carboxamide;

4-chloromethyl-N-{3-[2-(6-toluquinoline base)] phenyl } benzamide;

The chloro-N-{3-{2-of 4-[6-(morpholinyl)] quinolyl } phenyl } benzamide;

4-chloromethyl-N-{3-{2-[6-(morpholinyl)] quinolyl } phenyl } benzamide;

The chloro-N-{3-{2-of 3-[6-(morpholinyl)] quinolyl } phenyl } benzamide;

The bromo-N-{3-{2-of 4-[6-(morpholinyl)] quinolyl } phenyl } benzamide.

6. compound or its pharmacy acceptable salt, is characterized in that described compound is selected from:

4-chloromethyl-N-{3-{2-[6-(N, N-dimethyl)] quinolyl } phenyl } benzamide;

The chloro-N-{3-{2-of 4-[6-(diethylin)] quinolyl } phenyl } benzamide;

The chloro-N-{3-{2-of 3-[6-(diethylin)] quinolyl } phenyl } benzamide;

4-chloromethyl-N-{3-{2-[6-(diethylin)] quinolyl } phenyl } benzamide;

The bromo-N-{3-{2-of 4-[6-(diethylin)] quinolyl } phenyl } benzamide.

7. a pharmaceutical composition, is characterized in that it with the compound according to any one of Claims 1 to 5 or its pharmacy acceptable salt for activeconstituents or main active ingredient, is aided with pharmaceutically acceptable auxiliary material.

8. the compound according to any one of Claims 1 to 5 or the application of its pharmacy acceptable salt in preparation prevention or Therapeutic cancer medicine.

9. application according to claim 8, is characterized in that described cancer is colorectal carcinoma, liver cancer, prostate cancer, cervical cancer or mammary cancer.