CN107573325A

CN107573325A - Triazole-N- tetrahydroisoquinolicompounds compounds and its preparation method and application

Info

Publication number: CN107573325A
Application number: CN201710821021.3A
Authority: CN
Inventors: 黄文龙; 钱海; 廖晨; 赫斯曼; 李慧兰
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2017-09-07
Filing date: 2017-09-07
Publication date: 2018-01-12

Abstract

The present invention relates to logical formula (I) compound and its salt, this kind of compound has stronger reverse multiple drug resistance of tumor (MDR) effect, part of compounds activity is far above Verapamil, and there is less cytotoxicity, the invention further relates to the preparation method of such compound and the pharmaceutical preparation containing them.The present invention has synthesized a series of logical formula (I) compounds and its pharmaceutically acceptable salt：

Description

Triazole-N- tetrahydroisoquinolicompounds compounds and its preparation method and application

Technical field

The invention belongs to medicinal chemistry art, and in particular to a kind of P- glycoprotein inhibitors, the invention also discloses its system The application of Preparation Method and such compound in multidrug-resistance reversal agent.

Technical background

It is resistance to that multidrug resistance (multidrug resistance, MDR) refers to that tumour cell produces to a kind of antineoplastic After medicine, the phenomenon of crossing drug resistant is also produced to the other structures antineoplastic different with mechanism of action.The generation of multidrug resistance It is a main cause of current tumor chemical therapy failure, while is also most common, stubborn problem in oncotherapy.Cause This, find reversion MDR medicine to suppress the generation of multidrug resistance turns into urgent problem to be solved in oncotherapy.

Mechanism caused by tumor multi-medicine drug-resistant phenomenon is various, and the molecular biology mechanism for being related to complexity is not yet complete at present Parsing, but wherein tumour cell transmembrane transporter --- the overexpression of (P-glycoprotein, P-gp) is considered as more Main reason caused by medicine resistance.The P- glycoprotein of overexpression will enter tumour cell using the energy of ATP hydrolysis releases Interior medicine pumps out extracellular, causes the concentration of intracellular antineoplastic to be less than valid density, makes tumour cell to a variety ofization Drug resistance is treated, so as to produce MDR.Since first multidrug-resistance reversal agent Verapamil is found, multi-medicine tolerant reversal The research of agent is after three generations.Wherein using Verapamil and Ciclosporin A as representative, such inhibitor has larger the first generation Cardiovascular side effects；Second generation inhibitor activity strengthens, such as Valspodar and Biricodard, but the obvious shadow of such inhibitor The plasma pharmacokinetics in conjunction using cancer therapy drug are rung, limit its application clinically；Third generation inhibitor is The compound designed and developed based on structure activity study, such compound inhibitor have preferable activity and selectivity, such as Elacridar, Tariquidar and WK-X-34 etc..However, due to the appearance of various side effects, do not have yet at present effective inverse Turn agent and be applied to clinical treatment.

The present invention relates to the novel triazole-N- tetrahydroisoquinolicompounds compounds of structure, and there is P- glycoprotein to suppress to live for it Property, which part compound activity is higher than Verapamil and almost no cytotoxicity.The logical formula (I) compound and its pharmaceutical salts Occur and treat tumorigenic effect with potential prevention and treatment tumor multi-medicine drug-resistant, have and preparing antineoplastic The value of middle application.

The content of the invention

It is an object of the invention to provide a kind of new novel tumor multidrug-resistance reversal agent with P-gp inhibitory action. Such compound has triazole-N- tetrahydroisoquinoline structures, has relatively low cytotoxicity and stronger MDR Reversal activities, has The effect of beneficial to antineoplastic is improved.

The purpose of the present invention is also in the system for providing tolyltriazole-N- tetrahydroisoquinolicompounds tumor multi-drug resistance reversal agents Preparation Method.

Detailed description content is as follows：

The present invention has synthesized a series of logical formula (I) compounds and its pharmaceutically acceptable salt：

Wherein X is selected from：- NHCO- or-CONH- groups；

Wherein L is selected from：-CH₂- or-Ph- groups；

Wherein R₁It is selected from：Substitution or unsubstituted C₁~C₅Alkyl, substitution or unsubstituted C₁~C₅Alkoxy, substitution or unsubstituted Aromatic radical, aromatic heterocyclic, cycloalkyl；

Wherein R₂And R₃It is identical or different, it is respectively selected from：H, halogen, substitution or unsubstituted C₁-C₅Alkyl, substitute or do not take For C₁-C₅Alkoxy, nitro work as R₄And R₅The carbon atom that when on adjacent carbon atom and they are connected is substituted in be formed together Phenyl ring or methylene dioxy substituent.

The preferred scheme of the present invention, a kind of compound of logical formula (I) or its pharmaceutically useful salt, it is shown in logical formula (II) Compound or its pharmaceutically useful salt：

Wherein X is selected from：- NHCO- ,-CONH- ,-SO₂NH- or-NHSO₂- group；

Wherein Y is selected from：- O- or-NH- groups；

Wherein L is selected from：-CH₂- or-Ph- groups；

Preferred compounds of the invention includes, but are not limited to：

2- (((1- (2- (6,7- dimethoxy -3,4- dihydro-isoquinoline -2- bases) ethyl) 1H-1,2,3- triazole -4- Base) amido) methyl)-N phenylbenzamaides (1)；

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- Base) methyl) amino)-N- (3,4,5- trimethoxyphenyl) benzamide (2)；

N- (4- (tert-butyl group) phenyl) -2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) - 1H-1,2,3- triazole -4- bases) methyl) amino) benzamide (3)；

N- (4- chlorphenyls) -2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2, 3- triazole -4- bases) methyl) amino) benzamide (4)；

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- Base) methyl) amino))-N- (4- fluorophenyls) benzamide (5)；

(2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- Base) methyl) amino) phenyl) (morpholine) ketone (6)；

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- Base) methyl) amino)-N- (3,4- Dimethoxyphenethyl) benzamide (7)；

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- Base) methyl) amino)-N- (4- (trifluoromethoxy) phenyl) benzamide (8)；

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- Base) methyl) amino)-N- (4- methoxyphenyls) benzamide (9)；

N- (benzo [1,3] 5- dioxa cyclopentenyls) -2- (((1- (2- (6,7- dimethoxy -3,4- dihydro-isoquinolines - 2 bases) ethyl) -1H-1,2,3- triazole -4- bases) methyl) amino) benzamide (10)；

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- Base) methyl) amino) isobutyl-benzene formamide (11)；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) thiophene-2-carboxamide derivatives (12)；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) thiophene -3- formamides (13)

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) -3 methyl thiophene -2- formamides (14)；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) -5- thiophene-2-carboxamide derivatives (15)；

The chloro- N- of 5- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- tri- Nitrogen azoles -4- bases) methyl) amino) phenyl) -2- thenoyl amines (16)；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) picolinamide (17)；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) Pyrazinamide (18)；

The chloro- N- of 2- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- tri- Nitrogen azoles -4- bases) methyl) amino) phenyl) niacinamide (19)；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) -1H- indole 2-carboxamides (20)；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) quinoline -3- formamides (21)；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) quinoline-2-formamide (22)；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) furans -2- formamides (23)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) thiophene-2-carboxamide derivatives (24)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) thiophene -3- formamides (25)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -2- methylthiophene -3- formamides (26)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -5- methylthiophene -2- formamides (27)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) thiophene-2-carboxamide derivatives (28)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) picolinamide (29)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) Pyrazinamide (30)；

The chloro- N- of 2- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H- 1,2,3- triazole -4- bases) methyl) amino) phenyl) niacinamide (31)；

The chloro- N- of 2- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H- 1,2,3- triazole -4- bases) methyl) amino) phenyl) -1H- indole 2-carboxamides (32)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) quinoline -3- formamides (33)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) quinoline-2-formamide (34)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) furans -2- formamides (35)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) benzamide (36)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -2- methyl benzamides (37)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -3- methyl benzamides (38)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -4- methyl benzamides (39)；

4- (tert-butyl group)-N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) benzene Base) -1H-1,2,3- triazole -4- bases) methyl) amino) phenyl) benzamide (40)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -2- methoxy benzamides (41)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -3- methoxy benzamides (42)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -4- methoxy benzamides (43)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -3,4- dimethoxybenzarnides (44)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -3,5- dimethoxybenzarnides (45)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -3,4,5- trimethoxy-benzamides (46)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -2- (3,4- Dimethoxyphenyl) acetamide (47)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -2- (3,4- Dimethoxyphenyl) benzamide (48)；

The chloro- N- of 2- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H- 1,2,3- triazole -4- bases) methyl) amino) phenyl) benzamide (49)；

The chloro- N- of 3- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H- 1,2,3- triazole -4- bases) methyl) amino) phenyl) benzamide (50)；

The chloro- N- of 4- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H- 1,2,3- triazole -4- bases) methyl) amino) phenyl) benzamide (51)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -4- chlorobenzamides (52)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -3- nitrobenzamides (53)；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -4- nitrobenzamides (54)；

4- cyano group-N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) - 1H-1,2,3- triazole -4- bases) methyl) amino) phenyl) benzamide (55)；

N- (2- (((1- (4- (2- ((the 1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H- 1,2,3- triazole -4- bases) methyl) acid amides) phenyl) -4- oxo -4H- chromene -2- formamides (56).

The structure of part of compounds is：

According to the present invention, pharmaceutically acceptable salt includes the addition salts formed with following acid：Hydrochloric acid, sulfuric acid, phosphoric acid, hydrogen Bromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzene sulfonic acid, butanedioic acid and with it is similar Salt formed by known acceptable acid.

The preparation method of quinazoline-N- phenethyl tetrahydroisoquinolicompounds compounds of the present invention is as follows：

It is the pharmacological experiment data of part of compounds of the present invention below：

1st, reverse effect of the compound to adriamycin-resistant human leukemia cell (K562/A02)

Verapamil (Verapamil, VRP) is positive control.K562/A02 adriamycin-resistants human leukemia cell line is with containing 10% calf serum and the final concentration of 1mg/L adriamycins (ADM) of addition the culture mediums of RPMI 1640 are in 37 DEG C, 5%CO₂It is full Cultivated with conditions of humidity, and drug-resistant cell strain is cultivated 14 days under conditions of without adriamycin before experiment.Take the logarithm growth The cell of phase, with 1 × 10⁴Individual/ml density is inoculated in 96 well culture plates, in 37 DEG C of 5%CO₂Under the conditions of cultivate 24h after, respectively Final concentration of 5 μm of ol/L test-compound and a series of adriamycin of concentration gradients are added, continues after being incubated 48h, adds per hole Enter MTT (5mg/ml), be further cultured for 4 hours, centrifuge, board-washing machine sucks nutrient solution, and 150 μ L DMSO dissolvings are added per hole, and shaking table shakes 20min is shaken, is then measured on ELIASA with wavelength 570nm, calculates suppress cell growth up to concentration when 50% respectively, With IC₅₀Value represents that reversal index is with IC₅₀(ADM)/IC₅₀(ADM+ reversal agents) represents.

56 compounds of this measuring are drug-fast inverse to the leukaemia of adriamycin-resistant under 5 μm of ol/L concentration Turning a work property, as shown in table 1, result of the test show that 56 compounds are respectively provided with reversion MDR activity, and the reverse of part of compounds Activity exceedes positive reference substance Wella pa.

The compound of table 1 (5 μM) is to the reverse effect of adriamycin-resistant human leukemia cell's drug resistance

2nd, the CDCC of compound

This experimental test CDCCs of 56 compounds to K562/A02 and K562 cells.The people of adriamycin-resistant is white Containing the 10% calf serum and final concentration of culture mediums of 1mg/L adriamycins RPMI 1640 of addition of blood disease cell line K562/A02 In 37 DEG C, 5%CO₂Cultivated under conditions of saturated humidity, and drug-resistant cell strain is cultivated under conditions of without adriamycin before experiment 14 days.Take the logarithm the cell in growth period, be inoculated in 6 × 104/ml density in 96 well culture plates, per the μ L of hole 180, at 37 DEG C 5%CO₂Under the conditions of cultivate.It is grouped after overnight, respectively blank control group, test-compound group.In test-compound group respectively Add a series of testing compound of final concentration of concentration gradients；Positive controls give adriamycin；Blank control group is given The 0.1%DMSO of volume.Administered volume is 20 μ L.It is incubated 48 hours, 20 μ l MTT (5mg/ml) is then added per hole, then train Support 4 hours, centrifugation, board-washing machine sucks nutrient solution, and 150 μ l DMSO dissolvings, shaking table shaking 20min, then in enzyme mark are added per hole Optical density (OD) is read on instrument at wavelength 490nm, calculates the inhibiting rate of compound on intracellular, and with GraphPad Prism Amount effect curve in 5.0 softwares calculates the IC of compound₅₀Value.

Result of the test is as shown in table 2, from test result as can be seen that in addition to compound 36 (IC₅₀=25.76 ± 0.92), Remaining compound does not show obvious cytotoxicity (IC to K562₅₀30 μM of ＞)；All compounds are to K562/A02 cells Without obvious cytotoxicity (IC₅₀30 μM of ＞).

CDCC of the compound of table 2 to K562/A02 cells

3rd, the reverse effect of 3,50 pairs of K562/A02 cell adriamycin-resistants of various concentrations compound

Verapamil (Verapamil, VRP) is positive control.K562/A02 adriamycin-resistants human leukemia cell line is with containing 10% calf serum and the final concentration of 1mg/L adriamycins (ADM) of addition the culture mediums of RPMI 1640 are in 37 DEG C, 5%CO₂It is full Cultivated with conditions of humidity, and drug-resistant cell strain is cultivated 14 days under conditions of without adriamycin before experiment.Take the logarithm growth The cell of phase, with 1 × 10⁴Individual/ml density is inoculated in 96 well culture plates, after cultivating 24h under the conditions of 37 DEG C, 5%CO2, point Final concentration of 1.0 μm of ol/L, 0.5 μm of ol/L, 0.25 μm of ol/L, 0.10 μm of ol/L, 0.050 μm of ol/L, 0.025 μ are not added Mol/L test-compound 3 and a series of adriamycin of concentration gradients, and concentration are 0.5 μm of ol/L, 0.25 μm of ol/L, 0.125 μm ol/L, 0.064 μm of ol/L, 0.032 μm of ol/L, 0.016 μm of ol/L test-compound 50 and a series of concentration gradients Ah Mycin, continue after being incubated 48h, MTT (5mg/ml) is added per hole, is further cultured for 4 hours, centrifuge, board-washing machine sucks nutrient solution, per hole 150 μ L DMSO dissolvings are added, shaking table shaking 20min, is then measured on ELIASA with wavelength 570nm, calculates suppression respectively Cell growth processed is up to concentration when 50%, with IC₅₀Value represents that reversal index is with IC₅₀(ADM)/IC₅₀(ADM+ reversal agents) represents. Compound 3,50 shows stronger Reversal activity, reverses the EC of K562/A02 cell Adriamycin resistants₅₀Value is in nanomolar range point Wei (132.6 ± 1.72nM) and (78.1 ± 5.4nM).

Above pharmacology data shows, the logical formula (I) compound of the present invention with positive control drug Verapamil compared with compared with The effect of strong reverse multiple drug resistance of tumor, and preferred compound almost no cytotoxicity.

The formulation of the present composition can be tablet, capsule, pill, suppository, soft capsule, oral liquid, supensoid agent, injection The formulation commonly used in the pharmacies such as liquid.Medicine and capsule for oral use contain traditional excipient such as filler, diluent, lubrication Agent, dispersant and adhesive.It can be prepared according to method known in the art.

The dosage of above activating agent will be because of formula and different.

Usually, it has therefore proved that favourable amount, to reach required result, per formula (I) chemical combination of kg body weight administration in 24 hours The total amount of thing is about 0.01-80mg, preferably total amount about 0.1-40mg/kg.If necessary, it is administered in the form of single dose several times.

However, if necessary, above-mentioned dosage can be deviateed, i.e., this depends on the type of subject to be treated and body weight, individual Behavior of the body to medicine, the property and seriousness of disease, the type of preparation and administration and administration time or interval.

The invention will be further described by the following examples.

Embodiment

With reference to embodiment, the invention will be further described.It should be noted that following embodiments are merely to illustrate, And it is not intended to limit the present invention.The various change that those skilled in the art are made according to the teachings of the present invention all should be in this Shen Within protection domain that please be required by claim.

Embodiment 1

6,7- dimethoxys -1,2, the preparation of 3,4- four hydrogen isoquinoline hydrochloric acid salts (ii)

Add 3,4- dimethoxy-phenylethylamines (18.1g, 100mmol) in the mono- neck bottles of 250ml, paraformaldehyde (3.6g, 120mmol), absolute ethyl alcohol (30ml).After 3h is stirred at room temperature, PH=2 is adjusted with concentrated hydrochloric acid, 4h is heated to reflux, cold filtration, obtains To white crystals HCl, solid 14.2g, yield 61.8%

Embodiment 2

2- (((1- (2- (6,7- dimethoxy -3,4- dihydro-isoquinoline -2- bases) ethyl) 1H-1,2,3- triazole -4- Base) amido) methyl) and-N phenylbenzamaides (4) preparation

(a) 2- (2- azidoethyls) -6,7- dimethoxys -1,2, the preparation of 3,4- tetrahydroisoquinolines (iii)

2- nitrine -4- toluene sulfonic acides esters (3.1g, 13mmol) and compound (ii) (2.5g, 11mmol) are dissolved in drying Acetonitrile (50ml), into mixed liquor instill triethylamine (2.8mL, 21mmol).It is heated to 60 DEG C to stir, after 24h, removes under reduced pressure Solvent, column chromatography.Obtain yellow solid compound 2.0g, yield 70%；

(b) 2- ((1- (2- (6,7- dimethoxy -3,4- dihydro-isoquinoline -2- bases) ethyl) 1H-1,2,3- triazole -4- Base) methoxyl group)-N- benzanilides preparation 100ml round-bottomed flasks in add (iv) (1mmol), compound (iii) (1mmol) and the aqueous solution (30ml) containing 75% methanol, it is stirred at room temperature so that solid dissolving, adds sodium ascorbate (30mg), CuSO4 (8mg), 24h is stirred at room temperature, solution is in light green color clarified solution, removes the methanol in solvent under reduced pressure, adds dichloromethane (30ml) and water (30ml), liquid separation, organic layer is with saturated common salt water washing (20ml × 3), anhydrous sodium sulfate drying, filtering, subtracts Solvent is evaporated off in pressure, obtains grease, column chromatography, proportion of mobile phase is ethyl acetate: methanol=19: 1, obtain sterling white solid 0.3g, yield 60.2%；mp：111-113℃；

¹H NMR (300MHz, DMSO-d₆)δppm：10.08 (s, 1H), 8.01 (s, 1H), 7.77-7.61 (m, 5H), 7.29 (dd, J=15.6,7.6Hz, 4H), 7.04 (s, 1H), 6.64 (t, J=11.2Hz, 1H), 6.57 (d, J=11.1Hz, 2H), 4.52 (t, J=6.0Hz, 2H), 4.38 (d, J=5.3Hz, 2H), 3.65 (s, 6H), 3.50 (s, 2H), 2.85 (s, 2H), 2.62 (s, 4H)；¹³C NMR (75MHz, DMSO-d₆)δppm：148.16,146.32,145.99,143.95,143.69,131.78, 127.62,122.24,119.75,113.88,108.99,54.57,46.15,37.63,37.57,37.29；ESI-MS m/z： 513.6([M+H]⁺)。

Embodiment 3

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- Base) methyl) amino) and-N- (3,4,5- trimethoxyphenyl) benzamides (5) preparation

With reference in embodiment 21 preparation method, compound 5 is made, obtains faint yellow solid, yield 60.6%, m.p.123-124℃；

¹H NMR (300MHz, CDCl₃-d₆)δppm：10.08 (s, 1H), 8.12 (s, 1H), 7.87 (t, J=5.0Hz, 1H), 7.78 (d, J=7.5Hz, 1H), 7.40 (t, J=7.5Hz, 1H), 6.94 (d, J=8.4Hz, 1H), 6.80-6.73 (m, 1H), 6.70 (d, J=11.2Hz, 2H), 4.64 (t, J=5.6Hz, 2H), 4.52 (d, J=5.1Hz, 2H), 3.86 (s, 6H), 3.79 (s, 5H), 3.75 (s, 3H), 3.63 (s, 2H), 3.43 (s, 4H), 2.99 (t, J=5.6Hz, 2H), 2.75 (s, 4H), 2.61 (s, 2H)；13C NMR (75MHz, DMSO-d₆)δppm：167.79,152.51,148.66,147.14,144.67, 135.21,132.60,128.85,126.23,125.73,123.12,115.95,114.66,111.61,109.83,98.23, 60.08,56.72,55.70,55.10,50.09,47.01,40.30,38.92,28.02；ESI-MS m/z：603.7([M+H ]⁺)。

Embodiment 4

N- (4- (tert-butyl group) phenyl) -2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) - 1H-1,2,3- triazole -4- bases) methyl) amino) and benzamide (6) preparation

With reference in embodiment 21 preparation method, compound 6 is made, obtains white solid, yield 56.3%, m.p.126- 128℃；

¹H NMR (300MHz, DMSO-d₆)δppm：10.03 (s, 1H), 8.02 (s, 1H), 7.78 (t, J=5.1Hz, 1H), 7.68 (d, J=7.5Hz, 1H), 7.61 (d, J=8.6Hz, 2H), 7.34 (d, J=8.7Hz, 2H), 7.28 (d, J=7.4Hz, 1H), 6.82 (d, J=8.3Hz, 1H), 6.70-6.53 (m, 3H), 4.54 (t, J=5.9Hz, 2H), 4.40 (d, J=5.2Hz, 2H), 3.67 (s, 6H), 3.52 (s, 2H), 2.88 (t, J=5.9Hz, 2H), 2.65 (s, 4H), 1.27 (s, 9H)；¹³C NMR (75MHz, DMSO-d₆)δppm：167.82,148.70,147.15,146.87,145.87,136.44,132.54,128.88, 126.25,125.76,125.05,123.06,120.39,116.01,114.71,111.75,111.44,109.86,56.72, 55.41,54.82,50.09,47.01,38.16,33.98,31.16,28.05；ESI-MS m/z：569.2([M+H]⁺)。

Embodiment 5

N- (4- chlorphenyls) -2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2, 3- triazole -4- bases) methyl) amino) and benzamide (7) preparation

With reference in embodiment 21 preparation method, compound 7 is made, obtains yellow solid, yield 64.4%, m.p.111- 113℃；

¹H NMR (300MHz, DMSO-d₆)δppm：10.16 (s, 1H), 8.03 (s, 1H), 7.82-7.62 (m, 4H), 7.31 (t, J=7.6Hz, 1H), 7.18 (t, J=8.8Hz, 2H), 6.84 (d, J=8.2Hz, 1H), 6.67 (t, J=7.3Hz, 1H), 6.60 (d, J=11.7Hz, 2H), 3.68 (s, 6H), 3.52 (s, 2H), 2.87 (d, J=4.8Hz, 2H), 2.65 (s, 4H)；¹³C NMR (75MHz, DMSO-d₆)δppm：167.87,148.74,147.19,146.92,144.56,135.37,132.66, 128.89,126.29,125.80,123.04,122.46,115.76,115.16,114.80,111.84,111.50,109.96, 56.71,55.46,54.82,50.10,47.04,41.36,40.82,40.36,39.27,39.11,38.17,28.04；ESI- MS m/z：548.2([M+H]⁺)。

Embodiment 6

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- Base) methyl) amino)) preparations of-N- (4- fluorophenyls) benzamides (8)

With reference in embodiment 21 preparation method, compound 8 is made, obtains yellow solid, yield 67.4%, m.p.109- 110℃；

¹H NMR (300MHz, DMSO-d₆)δppm：10.13 (s, 1H), 8.01 (s, 1H), 7.70 (s, 4H), 7.28 (d, J =6.8Hz, 1H), 7.23-7.05 (m, 2H), 6.83 (d, J=7.3Hz, 1H), 6.74-6.45 (m, 3H), 4.52 (s, 2H), 4.40 (d, J=2.1Hz, 2H), 3.67 (s, 6H), 3.51 (s, 2H), 2.87 (s, 2H), 2.64 (s, 4H)；¹³C NMR (75MHz, DMSO-d₆)δppm：167.87,148.74,147.19,146.92,144.56,135.37,132.66,128.89,126.29, 125.80,123.04,122.46,115.76,115.16,114.80,111.84,111.50,109.96,56.71,55.46, 54.82,50.10,47.04,38.17,28.04；ESI-MS m/z：531.3([M+H]⁺)。

Embodiment 7

(2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- Base) methyl) amino) phenyl) (morpholine) ketone (9) preparation

With reference in embodiment 21 preparation method, compound 9 is made, obtains yellow solid, yield 56.1%, m.p.103- 105℃；

¹H NMR (300MHz, DMSO-d6) δ ppm：7.79 (s, 1H), 7.02 (t, J=7.5Hz, 1H), 6.91 (d, J= 7.3Hz, 1H), 6.60 (d, J=8.1Hz, 1H), 6.47 (d, J=16.1Hz, 3H), 5.68 (s, 1H), 4.40 (s, 2H), 4.23 (d, J=4.4Hz, 2H), 3.56 (d, J=2.0Hz, 6H), 3.44 (s, 4H), 3.38 (s, 3H), 2.73 (s, 2H)；¹³C NMR (75MHz, DMSO-d6) δ ppm：168.48,147.17,146.89,145.06,130.30,127.69,126.24,125.76, 122.89,119.92,115.72,111.78,111.21,109.87,66.06,56.75,55.44,54.81,50.07, 46.98,40.00,39.72,39.44,39.02,38.41,28.05；ESI-MS m/z：522.3([M+H]+).

Embodiment 8

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- Base) methyl) amino) and-N- (3,4- Dimethoxyphenethyl) benzamides (10) preparation

With reference in embodiment 21 preparation method, compound 10 is made, obtains faint yellow solid, yield 77.4%, m.p.109-110℃；

¹H NMR (300MHz, DMSO-d₆)δppm：8.36 (s, 1H, NHCO), 8.12 (s, 1H), 8.01 (s, 1H), 7.52 (d, J=7.4Hz, 1H), 7.29-7.17 (m, 1H), 7.00-6.81 (m, 3H), 6.81-6.71 (m, 2H), 6.64 (s, 1H), 6.59 (s, 2H), 4.55 (s, 2H), 4.37 (d, J=4.6Hz, 2H), 3.72 (s, 6H), 3.70 (s, 6H), 3.54 (s, 2H), 3.41 (d, J=5.1Hz, 2H), 2.90 (s, 2H), 2.76 (s, 2H), 2.67 (s, 4H)；¹³C NMR (75MHz, DMSO-d₆)δ ppm：168.89,157.87,148.71,147.13,146.86,132.05,128.15,126.24,125.76,123.03, 120.42,112.49,111.83,111.30,109.89,56.73,55.37,47.00,38.13,34.55,28.03；ESI-MS m/z：601.2([M+H]⁺)。

Embodiment 9

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- Base) methyl) amino) and-N- (4- (trifluoromethoxy) phenyl) benzamide (11) preparation

With reference in embodiment 21 preparation method, compound 11 is made, obtains white solid, yield 62.5%, m.p.115-117℃；

¹H NMR (300MHz, DMSO-d₆)δppm：10.25 (s, 1H), 8.02 (s, 1H), 7.82 (d, J=7.4Hz, 2H), 7.78-7.65 (m, 2H), 7.33 (d, J=7.8Hz, 3H), 6.84 (d, J=7.9Hz, 1H), 6.67 (t, J=6.9Hz, 1H), 6.59 (d, J=11.1Hz, 2H), 4.53 (s, 2H), 4.40 (s, 2H), 3.68 (s, 6H), 3.52 (s, 2H), 2.88 (s, 2H), 2.65 (s, 4H)；¹³C NMR (75MHz, DMSO-d₆)δppm：168.05,148.74,147.09,146.80,144.49, 138.30,132.86,129.02,126.19,125.70,123.10,121.86,121.36,115.48,114.73,111.59, 109.75,56.74,55.36,54.81,50.08,46.97,38.10,28.04；ESI-MS m/z：597.3([M+H]⁺)。

Embodiment 10

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- Base) methyl) amino) and-N- (4- methoxyphenyls) benzamides (12) preparation

With reference in embodiment 21 preparation method, compound 12 is made, obtains white solid, yield 79.1%, m.p.111-113℃；

¹H NMR (300MHz, DMSO-d₆)δppm：10.05 (s, 1H), 8.02 (s, 1H), 7.77-7.61 (m, 2H), 7.45-7.19 (m, 4H), 6.81 (t, J=10.4Hz, 1H), 6.76-6.48 (m, 4H), 4.54 (s, 2H), 4.41 (d, J= 2.7Hz, 2H), 3.74 (s, 3H), 3.68 (s, 6H), 3.53 (s, 2H), 2.88 (s, 2H), 2.65 (s, 4H)；¹³C NMR (75MHz, DMSO-d₆)δppm：167.97,148.67,144.59,140.26,132.64,129.09,126.23,125.76, 123.09,115.99,114.71,112.75,111.60,109.86,108.99,106.23,56.73,55.42,54.89, 50.09,47.00,40.04,38.93,38.13,28.04；ESI-MS m/z：542.2([M+H]⁺)。

Embodiment 11

N- (benzo [1,3] 5- dioxa cyclopentenyls) -2- (((1- (2- (6,7- dimethoxy -3,4- dihydro-isoquinolines - 2 bases) ethyl) -1H-1,2,3- triazole -4- bases) methyl) amino) and benzamide (13) preparation

With reference in embodiment 21 preparation method, compound 13 is made, obtains faint yellow solid, yield 71.1%, m.p.115-117℃；

¹H NMR (300MHz, DMSO-d₆)δppm：10.02 (s, 1H, NHCO), 8.03 (s, 1H), 7.78 (s, 1H), 7.68 (d, J=5.5Hz, 1H), 7.39 (s, 1H), 7.30 (s, 1H), 7.15 (d, J=6.4Hz, 1H), 6.86 (dd, J=12.7, 8.0Hz, 2H), 6.66 (s, 1H), 6.61 (d, J=12.7Hz, 2H), 6.01 (s, 2H), 4.54 (s, 2H), 4.42 (s, 2H), 3.69 (s, 6H), 3.53 (s, 2H), 2.89 (s, 2H), 2.66 (s, 4H)；ESI-MS m/z：557.2([M+H]⁺)。

Embodiment 12

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- Base) methyl) amino) and isobutyl-benzene formamide (14) preparation

With reference in embodiment 21 preparation method, compound 14 is made, obtains faint yellow solid, yield 82.5%, m.p.101-103℃；

¹H NMR (300MHz, CDCl₃)δppm：7.83 (s, 1H), 7.56 (s, 1H), 7.31 (d, J=7.4Hz, 1H), 7.16 (t, J=7.7Hz, 1H), 6.66 (d, J=8.3Hz, 1H), 6.53 (t, J=7.4Hz, 2H), 6.45 (s, 1H), 6.35 (s, 1H), 4.44 (s, 4H), 3.79 (d, J=4.4Hz, 6H), 3.55 (s, 2H), 3.16 (d, J=12.7Hz, 2H), 2.91 (t, J=6.2Hz, 2H), 2.69 (s, 3H), 1.83 (dt, J=13.3,6.6Hz, 1H), 0.93 (s, 3H), 0.91 (s, 3H)；¹³C NMR (75MHz, CDCl₃)δppm：169.30,148.35,147.09,132.07,126.77,125.42,121.93,115.66, 114.89,111.49,110.92,108.96,56.60,55.42,54.93,50.34,47.53,46.47,38.68,29.15, 27.99 19.71；ESI-MS m/z：493.3([M+H]⁺)。

Embodiment 13

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) thiophene-2-carboxamide derivatives (15) preparation

With reference in embodiment 21 preparation method, compound 15 is made, obtains faint yellow solid, yield 35.4%, M.p.94~96 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.68 (s, 1H), 7.94 (d, J=7.5Hz, 2H), 7.82 (s, 1H), 7.17 (m, 2H), 7.04 (d, J=7.5Hz, 1H), 6.78 (s, 1H), 6.63 (s, 3H), 5.55 (t, J=5.7Hz, 1H), 4.52 (t, J=6.0Hz, 2H), 4.36 (d, J=5.7Hz, 2H), 3.69 (s, 6H), 3.52 (s, 2H), 2.87 (t, J=6.0Hz, 2H), 2.64 (s, 4H)；¹³C NMR (75MHz, DMSO-d₆)δppm：160.38,147.22,147.06,145.38,143.33, 139.72,131.23,129.13,127.92,127.64,127.10,126.29,125.83,122.99,116.05,111.88, 111.42,109.97,56.72,55.50,54.85,50.07,47.02,40.10,38.98,38.67,28.01；ESI-MS m/ z：519.4([M+H]⁺)。

Embodiment 14

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) thiophene -3- formamides (16) preparation

With reference in embodiment 21 preparation method, compound 16 is made, obtains faint yellow solid, yield 33.5%, M.p.95~97 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.52 (s, 1H), 8.29 (s, 1H), 7.93 (s, 1H), 7.62 (s, 2H), 7.13 (d, J=6.4Hz, 1H), 7.03 (t, J=7.5Hz, 1H), 6.76 (d, J=7.5Hz, 1H), 6.63 (s, 2H), 6.57 (s, 1H), 5.52 (t, J=5.7Hz, 1H), 4.51 (t, J=6.0Hz, 2H), 4.35 (d, J=5.7Hz, 2H), 3.75- 3.62 (s, 6H), 3.51 (s, 2H), 2.86 (t, J=6.0Hz, 2H), 2.64 (s, 4H)；¹³C NMR (75MHz, DMSO-d₆)δ ppm：161.51,147.42,146.90,145.41,143.22,139.23,129.52,127.28,126.94,126.55, 125.82,123.41,123.00,116.07,111.85,111.40,109.97,56.72,55.50,54.85,50.06, 47.01,42.50,40.33,38.96,38.67,28.00；ESI-MS m/z：519.4([M+H]⁺)。

Embodiment 15

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) -3 methyl thiophene -2- formamides (17) preparation

With reference in embodiment 21 preparation method, compound 17 is made, obtains faint yellow solid, yield 47.5%, M.p.84~86 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.18 (s, 1H), 7.95 (s, 1H), 7.64 (d, J=4.5Hz, 1H), 7.20 (d, J=6.8Hz, 1H), 7.00 (d, J=4.5Hz, 2H), 6.77 (d, J=6.8Hz, 1H), 6.63 (s, 2H), 6.58 (s, 1H), 5.43 (t, J=4.5Hz, 1H), 4.53 (t, J=4.8Hz, 2H), 4.34 (d, J=4.5Hz, 2H), 3.69 (s, 6H), 3.52 (s, 2H), 2.87 (t, J=4.8Hz, 2H), 2.64 (s, 4H), 2.45 (s, 3H)；¹³C NMR (75MHz, CDCl₃)δ ppm：161.61,145.98,132.29,127.26,125.90,125.58,122.53,119.06,114.32,111.33, 109.33,57.11,55.91,55.48,50.82,47.99,40.38,28.47,15.99；ESI-MS m/z：555.6([M+H ]⁺)。

Embodiment 16

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) -5- thiophene-2-carboxamide derivatives (18) preparation

With reference in embodiment 21 preparation method, compound 18 is made, obtains brown solid, yield 35.9%, m.p.92 ~94 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.57 (s, 1H), 7.93 (s, 1H), 7.77 (s, 1H), 7.12 (d, J= 6.3Hz, 1H), 7.07-6.98 (m, 1H), 6.90 (s, 1H), 6.75 (d, J=6.3Hz, 1H), 6.63 (s, 2H), 6.58 (s, 1H), 5.51 (t, J=4.5Hz, 1H), 4.52 (t, J=4.8Hz, 2H), 4.35 (d, J=4.5Hz, 2H), 3.69 (s, 6H), 3.52 (s, 2H), 2.87 (t, J=4.8Hz, 2H), 2.64 (s, 4H), 2.46 (s, 3H)；¹³C NMR (75MHz, DMSO-d₆)δ ppm：160.32,147.15,146.86,145.35,143.24,129.40,127.30,126.98,126.41,126.23, 126.55,125.72,125.43,123.17,123.09,123.01,116.07,111.78,111.40,109.88,56.72, 55.45,54.83,50.05,46.97,38.64,27.99,15.23；ESI-MS m/z：555.6([M+H]⁺)。

Embodiment 17

The chloro- N- of 5- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- tri- Nitrogen azoles -4- bases) methyl) amino) phenyl) -2- thenoyl amines (19) preparation

With reference in embodiment 21 preparation method, compound 19 is made, obtains faint yellow solid, yield 32.3%, M.p.92~94 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.74 (s, 1H), 7.90 (s, 1H), 7.83 (s, 1H), 7.23 (d, J= 7.8Hz, 1H), 7.05 (d, J=6.6Hz, 2H), 6.74 (d, J=7.8Hz, 1H), 6.62 (s, 2H), 6.56 (s, 1H), 5.52 (t, J=4.5Hz, 1H), 4.49 (t, J=4.8Hz, 2H), 4.34 (d, J=4.5Hz, 2H), 3.67 (s, 6H), 3.50 (s, 2H), 2.84 (t, J=4.8Hz, 2H), 2.63 (s, 4H)；¹³C NMR (75MHz, DMSO-d₆)δppm：159.28 147.18, 146.88,145.38,143.40,138.24,136.82,133.16,129.03,128.02,127.38,126.03,125.43, 122.72,122.14,119.78,115.94,111.57,109.91,56.72,55.47,54.85,50.03,46.98, 38.57 28.00；ESI-MS m/z：553.4([M+H]⁺)。

Embodiment 18

N- (2- (((1- (2- (base of 6,7-=methoxyl group -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) picolinamide (20) preparation

With reference in embodiment 21 preparation method, compound 20 is made, obtains brown solid, yield 23.5%, m.p.133 ~135 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：10.09 (s, 1H), 8.72 (d, J=4.5Hz, 1H), 8.13 (d, J= 7.7Hz, 1H), 8.05 (t, J=7.6Hz, 1H), 7.96 (s, 1H), 7.69-7.63 (m, 1H), 7.45 (d, J=7.7Hz, 1H), 7.01 (t, J=7.6Hz, 1H), 6.78 (d, J=8.1Hz, 1H), 6.69 (t, J=7.6Hz, 1H), 6.62 (s, 1H), 6.57 (s, 1H), 5.65 (t, J=5.5Hz, 1H), 4.52 (t, J=5.8Hz, 2H), 4.34 (d, J=5.5Hz, 2H), 3.68 (s, 6H), 3.51 (s, 2H), 2.86 (t, J=5.8Hz, 2H), 2.62 (s, 4H)；¹³C NMR (75MHz, DMSO-d₆)δppm： 162.59,149.91,149.11,148.37,146.84,145.44,141.97,137.92,126.70,126.23,125.75, 125.21,124.26,123.10,122.19,116.84,112.31,111.74,109.85,56.76,55.43,54.84, 50.08,46.99,36.68,28.00；ESI-MS m/z：536.5([M+H]⁺)。

Embodiment 19

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) Pyrazinamide (21) preparation

With reference in embodiment 21 preparation method, compound 21 is made, obtains faint yellow solid, yield 28.9%, M.p.98~100 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.90 (s, 1H), 8.77 (d, J=3.6Hz, 2H), 7.93 (s, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.17 (d, J=7.5Hz, 1H), 7.05 (t, J=7.2Hz, 1H), 6.77 (d, J= 8.0Hz, 1H), 6.66-6.60 (m, 2H), 6.57 (s, 1H), 5.69 (t, J=5.7Hz, 1H), 4.52 (t, J=6.0Hz, 2H), 4.36 (d, J=5.7Hz, 2H), 3.69 (s, 6H), 3.51 (s, 2H), 2.86 (t, J=6.0Hz, 2H), 2.64 (s, 4H)；¹³C NMR (75MHz, DMSO-d₆)δppm：164.19,150.06,147.16,146.86,145.49,143.27,141.59, 127.35,126.24,125.79,123.02,122.77,121.79,115.87,111.76,111.28,109.86,56.76, 55.44,54.87,50.04,46.98,28.03；ESI-MS m/z：536.5([M+H]⁺)。

Embodiment 20

The chloro- N- of 2- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- tri- Nitrogen azoles -4- bases) methyl) amino) phenyl) niacinamide (22) preparation

With reference in embodiment 21 preparation method, compound 22 is made, obtains faint yellow solid, yield 33.5%, M.p.99~102 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.88 (s, 1H), 8.53 (s, 1H), 8.15 (s, 1H), 7.98 (d, J= 6.0Hz, 1H), 7.56 (d, J=7.2Hz, 1H), 7.33 (d, J=6.0Hz, 1H), 7.06 (s, 1H), 6.79 (d ,=7.2Hz, 1H), 6.73-6.61 (m, 2H), 6.58 (s, 1H), 5.42 (t, J=4.5Hz, 2H, 1H), 4.54 (t, J=6.0Hz, 2H), 4.38 (d, J=4.5Hz, 2H), 3.69 (s, 6H), 3.53 (s, 2H), 2.88 (t, J=6.0Hz, 2H), 2.65 (s, 4H)；¹³C NMR (75MHz, CDCl₃)δppm：150.99,147.23,145.60,141.86,139.57,131.60,127.93,125.86, 123.58,122.80,122.52,118.70,113.63,111.32,109.34,57.10,55.91,55.47,50.81, 47.96,40.09,28.48.Anal.Calcd for C₂₈H₃₀ClN₇O₃：C, 61.37；H, 5.52；N, 17.89.Found：C, 61.48；H, 5.58；N, 15.45；ESI-MS m/z：570.5([M+H]⁺)。

Embodiment 21

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) -1H- indole 2-carboxamides (23) preparation

With reference in embodiment 21 preparation method, compound 23 is made, obtains light green solid, yield 38.9%, M.p.115~117 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：11.69 (s, 1H), 9.70 (s, 1H), 7.96 (s, 1H), 7.66 (d, J =8.0Hz, 1H), 7.48 (d, J=8.0Hz, 1H), 7.36 (s, 1H), 7.22 (t, J=7.3Hz, 2H), 7.07 (t, J= 7.5Hz, 2H), 6.82 (d, J=8.0Hz, 1H), 6.68 (t, J=7.5Hz, 1H), 6.59 (s, 1H), 6.56 (s, 1H), 5.57 (t, J=5.2Hz, 1H), 4.52 (t, J=5.4Hz, 2H), 4.37 (d, J=5.2Hz, 2H), 3.68 (s, 6H), 3.51 (s, 2H), 2.87 (t, J=5.4Hz, 2H), 2.62 (s, 4H)；¹³C NMR (75MHz, DMSO-d₆)δppm：160.27 147.16, 146.87,145.29,143.16,136.62,131.47,127.05,126.23,125.77,123.55,123.15,121.57, 119.83,116.24,112.34,111.66,109.86,103.81,56.74,55.44,54.82,50.08,47.01, 38.83,28.24,27.99；ESI-MS m/z：552.5([M+H]⁺)。

Embodiment 22

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) quinoline -3- formamides (24) preparation

With reference in embodiment 21 preparation method, compound 24 is made, obtains faint yellow solid, yield 37.5%, M.p.105~107 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.99 (s, 1H), 9.41 (s, 1H), 8.99 (s, 1H), 8.13 (s, 2H), 7.94 (s, 2H), 7.73 (s, 1H), 7.23 (s, 1H), 7.06 (s, 1H), 6.78 (s, 1H), 6.75-6.48 (m, 3H), 5.76 (t, J=5.4Hz, 1H), 4.51 (t, J=5.4Hz, 2H), 4.38 (d, J=5.2Hz, 2H), 3.67 (s, 6H), 3.50 (s, 2H), 2.86 (t, J=5.4Hz, 2H), 2.62 (s, 4H)；¹³C NMR (75MHz, DMSO-d₆)δppm：165.45 149.36,148.55,147.03,145.53,143.30,136.10,131.18,130.67,130.46,129.09,128.76, 127.29,126.82,126.48,126.03,123.08,115.93,111.80,111.31,109.91,56.73,55.46, 54.88,50.01,46.99,38.77,38.65,28.00；ESI-MS m/z：564.5([M+H]⁺)。

Embodiment 23

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) quinoline-2-formamide (25) preparation

With reference in embodiment 21 preparation method, compound 25 is made, obtains yellow solid, yield 45.3%, m.p.94 ~95 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：10.22 (s, 1H), 8.61 (d, J=7.8Hz, 1H), 8.28-8.16 (m, 2H), 8.11 (d, J=7.3Hz, 1H), 7.98 (s, 1H), 7.91 (d, J=6.4Hz, 1H), 7.76 (d, J=6.4Hz, 1H), 7.50 (d, J=6.7Hz, 1H), 7.06 (d, J=5.7Hz, 1H), 6.83 (d, J=7.3Hz, 1H), 6.73 (d, J= 6.4Hz, 1H), 6.59 (s, 1H), 6.54 (s, 1H), 5.71 (t, J=5.4Hz, 1H), 4.52 (t, J=5.4Hz, 2H), 4.38 (d, J=5.2Hz, 2H), 3.67 (s, 6H), 3.50 (s, 2H), 2.86 (t, J=5.4Hz, 2H), 2.61 (s, 4H)；¹³C NMR (75MHz, DMSO-d₆)δppm：162.87,150.13,147.18,146.89,145.87,145.52,142.18,137.93, 130.54,129.30,128.87,128.13,126.37,125.78,125.35,124.22,123.05,120.39,118.73, 116.90,112.42,111.81,109.92,56.74,55.47,54.83,50.07,47.05,36.68,27.99；ESI-MS m/z：586.7([M+H]⁺)。

Embodiment 24

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) furans -2- formamides (26) preparation

With reference in embodiment 21 preparation method, compound 26 is made, obtains faint yellow solid, yield 39.6%, M.p.96~98 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.55 (s, 1H), 7.92 (d, J=11.1Hz, 2H), 7.26 (s, 1H), 7.15 (d, J=7.3Hz, 1H), 7.03 (t, J=7.5Hz, 1H), 6.75 (d, J=8.1Hz, 1H), 6.63 (m, 4H), 5.55 (t, J=5.4Hz, 1H), 4.52 (t, J=5.4Hz, 2H), 4.34 (d, J=4.8Hz, 2H), 3.69 (s, 6H), 3.52 (s, 2H), 2.87 (t, J=5.4Hz, 2H), 2.64 (s, 4H)；¹³C NMR (75MHz, DMSO-d₆)δppm：156.80 147.74, 147.16,146.86,145.32,143.14,127.06,126.25,125.78,122.94,118.99,116.11,114.31, 111.86,111.48,109.88,56.74,55.45,54.84,50.08,46.99,38.65,27.99；ESI-MS m/z： 525.6([M+H]⁺)。

Embodiment 25

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) thiophene-2-carboxamide derivatives (24) preparation

(a) 6,7- dimethoxys -2- (4- nitrophenethyls) -1, the preparation of 2,3,4- tetrahydroquinolines

The addition p-nitrophenyl bromic ether (2.42g, 10mmol) in the mono- neck bottles of 250ml, compound (ii) (2.41g, 10.5mmol) and Anhydrous potassium carbonate (3.48g, 25.2mmol) is heated to reflux 10h in acetonitrile (50ml), and TLC is monitored to reaction Terminate, cool down, filtering, dichloromethane washs filter cake, and filtrate obtains yellow solid through removing solvent under reduced pressure, and ethyl alcohol recrystallization obtains Yellow needles solid 2.56g, yield 75.3%.

(b) preparation of 4- [2- (6,7- dimethoxy -3,4- dihydro -1H- isoquinolin-2-yls)-ethyl] aniline

6,7- dimethoxy -2- (4- nitrophenethyls) -1,2,3,4- tetrahydroquinolines (5g, 14.6mmol) be dissolved in ethanol/ The in the mixed solvent of dichloromethane (1: Isosorbide-5-Nitrae 0ml), lower hydrogen reducing reaction 24h is catalyzed in room temperature Pd/C (0.5g).Diatomite is made Matting layer filters, and dichloromethane repeatedly washs filter cake, and filtrate obtains faint yellow solid, ethanol/petroleum ether through removing solvent under reduced pressure It is recrystallized to give beige solid 3.84g, yield 84.2%.

(c) 2- (4- nitrine phenethyl) -6,7- dimethoxys -1,2, the preparation of 3,4- tetrahydroisoquinolines

Compound I-h (3.72g, 12mmol) is dissolved in the mixed solution of acetic acid and water (12ml/12ml) at room temperature.Cooling To 0~-5 DEG C, natrium nitrosum (1.2g, 17mmol) is repeatedly added portionwise on a small quantity, reaction solution is in claret, and temperature control stirs in 0~5 DEG C Mix 30min.Temperature is less than 0 DEG C in control, is repeatedly carefully added into Sodium azide (1.2g, 18mmol) on a small quantity, during heat up it is violent, and There are a large amount of bubbles to produce.Sodium azide is added and finished, and 0 DEG C is continued reaction 1 hour.Reaction is finished, and water is added into reaction solution (60ml) is diluted, and sodium carbonate regulation pH to 7~8, ethyl acetate extraction (60ml × 3), saturated aqueous common salt are added into reaction solution (60ml) is washed, anhydrous sodium sulfate drying, is filtered, and removing solvent under reduced pressure at 30 DEG C obtains pink solid 3.50g, yield 86.2%, mp：68-70℃.

(d) N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1, 2,3- triazole -4- bases) methyl) amino) phenyl) thiophene-2-carboxamide derivatives (27) preparation

With reference to the preparation method of (b) in embodiment 2, compound 27 is made, obtains faint yellow solid, yield 39.6%, M.p.107~109 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.73 (s, 1H), 8.59 (s, 1H), 8.00 (s, 1H), 7.82 (s, 1H), 7.74 (d, J=7.8Hz, 2H), 7.47 (d, J=7.4Hz, 2H), 7.21 (s, 1H), 7.19-7.03 (m, 2H), 6.86 (d, J=7.8Hz, 1H), 6.64 (d, J=7.4Hz, 3H), 5.70 (t, J=4.4Hz, 1H), 4.46 (d, J=4.4Hz, 2H), 3.70 (s, 6H), 3.55 (s, 2H), 2.90 (s, 2H), 2.70 (s, 6H)；¹³C NMR (75MHz, DMSO-d₆)δppm：160.53 147.12,146.82,143.36,141.22,134.68,131.29,130.01,129.19,127.93,127.57,127.26, 120.99,119.79,116.23,111.76,111.49,109.95,58.99,55.46,55.00,50.43,38.94, 38.59,32.26,28.21；ESI-MS m/z：595.5([M+H]⁺)。

Embodiment 26

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) thiophene -3- formamides (25) preparation

With reference in embodiment 25 24 preparation method, compound 25 is made, obtains faint yellow solid, yield 45.3%, M.p.104~106 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.55 (s, 1H), 8.58 (s, 1H), 8.32 (s, 1H), 7.80-7.68 (m, 2H), 7.63 (d, J=4.5Hz, 2H), 7.47 (d, J=6.3Hz, 2H), 7.13 (m, 2H), 6.86 (d, J=6.6Hz, 1H), 6.65 (d, J=6.0Hz, 3H), 5.58 (t, J=4.4Hz, 1H), 4.45 (d, J=4.4Hz, 2H), 3.70 (s, 6H), 3.55 (s, 2H), 2.90 (s, 2H), 2.70 (s, 6H)；¹³C NMR (75MHz, CDCl₃)δppm：162.12 147.51, 147.08,142.14,141.26,135.13,129.89,129.41,127.64,126.44,126.04,124.38,120.43, 120.10,118.78,113.85,111.30,109.40,59.76,56.18,55.54,51.04,40.10,33.50,28.67； ESI-MS m/z：595.5([M+H]⁺)。

Embodiment 27

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -2- methylthiophene -3- formamides (26) preparation

With reference in embodiment 25 24 preparation method, compound 26 is made, obtains faint yellow solid, yield 39.8%, M.p.89~91 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.21 (s, 1H), 8.62 (s, 1H), 7.75 (d, J=8.0Hz, 2H), 7.65 (d, J=5.0Hz, 1H), 7.47 (d, J=8.0Hz, 2H), 7.21 (d, J=6.8Hz, 1H), 7.08 (d, J=7.4Hz, 1H), 7.02 (d, J=5.0Hz, 1H), 6.86 (d, J=7.4Hz, 1H), 6.65 (d, J=8.0Hz, 3H), 5.58 (t, J= 5.4Hz, 1H), 4.45 (d, J=5.4Hz, 2H), 3.69 (s, 6H), 3.55 (s, 2H), 2.89 (d, J=6.8Hz, 2H), 2.70 (s, 6H), 2.48 (s, 3H)；¹³C NMR (75MHz, CDCl₃)δppm：161.70,147.12,142.86,142.60,142.34, 141.86,141.22,135.25,132.35,129.92,127.62,127.34,126.56,125.70,120.73,120.53, 120.29,119.05,114.06,111.32,109.41,76.89,59.76,55.81,51.04,40.26,33.52,28.65, 16.04；ESI-MS m/z：609.3([M+H]⁺)。

Embodiment 28

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -5- methylthiophene -2- formamides (27) preparation

With reference in embodiment 25 24 preparation method, compound 27 is made, obtains white solid, yield 45.3%, M.p.101~103 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.62 (s, 1H), 8.59 (s, 1H), 7.79 (s, 1H), 7.74 (d, J= 8.2Hz, 2H), 7.46 (d, J=8.1Hz, 2H), 7.11 (m, 2H), 6.91 (s, 1H), 6.85 (d, J=8.2Hz, 1H), 6.64 (d, J=7.8Hz, 3H), 5.65 (t, J=5.1Hz, 1H), 4.45 (d, J=5.1Hz, 2H), 3.70 (s, 6H), 3.56 (s, 2H), 2.90 (s, 2H), 2.71 (s, 6H), 2.49 (s, 3H)；¹³C NMR (75MHz, CDCl₃)δppm：161.19 147.14, 146.41,141.20,135.21,129.90,127.61,126.90-125.90,120.46,120.14,118.88,114.00, 111.32,109.42,59.75,56.29,55.54,51.03,40.21,33.49,28.64,15.74；ESI-MS m/z： 609.3([M+H]⁺)。

Embodiment 29

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) thiophene-2-carboxamide derivatives (28) preparation

With reference in embodiment 25 24 preparation method, compound 28 is made, obtains faint yellow solid, yield 43.1%, M.p.104~106 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.79 (s, 1H), 8.58 (s, 1H), 7.88 (s, 1H), 7.74 (d, J= 7.7Hz, 2H), 7.46 (d, J=7.0Hz, 2H), 7.26 (s, 1H), 7.10 (t, J=8.6Hz, 2H), 6.85 (d, J=8.0Hz, 1H), 6.64 (d, J=7.7Hz, 3H), 5.76 (t, J=5.0Hz, 1H), 4.45 (d, J=5.0Hz, 2H), 3.69 (s, 6H), 3.54 (s, 2H), 2.90 (s, 2H), 2.70 (s, 6H)；¹³C NMR (75MHz, DMSO-d₆)δppm：159.57 146.77, 143.45,141.24,137.24,134.90,133.22,130.01,129.10,128.75,127.88,126.55,125.87, 122.58,120.99,119.78,116.15,111.76,111.43,109.94,59.02,55.45,55.04,50.46, 36.68,32.27,28.26；ESI-MS m/z：629.3([M+H]⁺)。

Embodiment 30

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) picolinamide (29) preparation

With reference in embodiment 25 24 preparation method, compound 29 is made, obtains faint yellow solid, yield 33.6%, M.p.144~146 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：10.09 (s, 1H), 8.73 (d, J=4.1Hz, 1H), 8.60 (s, 1H), 8.15 (d, J=7.8Hz, 1H), 8.05 (t, J=7.3Hz, 1H), 7.74 (d, J=8.3Hz, 2H), 7.70-7.61 (m, 1H), 7.46 (d, J=8.3Hz, 3H), 7.07 (t, J=7.3Hz, 1H), 6.87 (d, J=8.3Hz, 1H), 6.71 (t, J=7.3Hz, 1H), 6.64 (d, J=7.8Hz, 2H), 5.71 (t, J=5.4Hz, 1H), 4.44 (d, J=5.4Hz, 2H), 3.70 (s, 6H), 3.55 (s, 2H), 2.88 (d, J=7.1Hz, 2H), 2.70 (s, 6H)；¹³C NMR (75MHz, DMSO-d₆)δppm：162.78 149.96,148.36,147.14,146.83,142.07,141.20,137.90,134.72,129.97,126.70,126.58, 126.47,125.90,125.45,125.21,124.29,122.23,121.01,119.74,117.00,112.32,111.78, 109.99,58.98,55.46,55.01,50.43,32.27,28.23；ESI-MS m/z：590.4([M+H]⁺)。

Embodiment 31

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) Pyrazinamide (30) preparation

With reference in embodiment 25 24 preparation method, compound 30 is made, obtains brown solid, yield 29.8%, M.p.178~180 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.92 (s, 1H), 8.58 (s, 1H), 7.74 (s, 3H), 7.46 (s, 3H), 7.30 (s, 1H), 7.16 (s, 2H), 7.11 (s, 2H), 6.84 (s, 1H), 6.65 (s, 4H), 5.79 (t, J=5.4Hz, 1H), 4.45 (d, J=5.4Hz, 2H), 3.70 (s, 6H), 2.90 (d, J=7.1Hz, 2H), 2.73 (s, 6H)；¹³C NMR (75MHz, DMSO-d₆)δppm：164.19,150.07,147.14,146.85,145.49,143.28,141.59,127.38, 126.23,125.78,122.90,121.78 (s), 115.86 (s), 111.74 (s), 111.27,109.84,56.76,55.43, 54.87,50.04,46.97,40.82-40.53,40.14,39.59,39.18,39.18,28.02；ESI-MS m/z：590.3 ([M+H]⁺)。

Embodiment 32

The chloro- N- of 2- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H- 1,2,3- triazole -4- bases) methyl) amino) phenyl) niacinamide (31) preparation

With reference in embodiment 25 24 preparation method, compound 31 is made, obtains white solid, yield 34.5%, M.p.129~131 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.88 (s, 1H), 8.63 (s, 1H), 8.52 (s, 1H), 8.17 (d, J= 7.5Hz, 1H), 7.75 (d, J=6.3Hz, 2H), 7.57 (s, 1H), 7.47 (d, J=6.4Hz, 2H), 7.34 (d, J=7.5Hz, 1H), 7.12 (s, 1H), 6.88 (d, J=6.4Hz, 1H), 6.69 (s, 1H), 6.65 (m, 2H), 5.47 (t, J=5.4Hz, 1H), 4.47 (d, J=5.4Hz, 2H), 3.70 (s, 6H), 3.55 (s, 2H), 2.90 (s, 2H), 2.71 (s, 6H)；¹³C NMR (75MHz, CDCl₃)δppm：159.23,146.32,143.37,142.81,142.62,141.83,137.19,136.62,134.83, 130.37,126.77,125.20,123.41,121.91,121.69,121.43,118.70,118.06,115.72,115.26, 114.07,108.80,106.59,104.69,54.97,51.49,50.77,46.28,35.32,28.73,23.89；ESI-MS m/z：624.3([M+H]⁺)。

Embodiment 33

The chloro- N- of 2- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H- 1,2,3- triazole -4- bases) methyl) amino) phenyl) -1H- indole 2-carboxamides (32) preparation

With reference in embodiment 25 24 preparation method, compound 32 is made, obtains orange solids, yield 38.1%, M.p.126~128 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：11.70 (s, 1H), 9.74 (s, 1H), 8.61 (s, 1H), 7.74 (s, 2H), 7.68 (s, 1H), 7.47 (d, J=7.4Hz, 3H), 7.37 (s, 1H), 7.28-7.16 (m, 2H), 7.16-6.99 (m, 2H), 6.90 (s, 1H), 6.65 (d, J=7.4Hz, 3H), 5.80-5.58 (t, J=5.4Hz, 1H), 4.47 (d, J=5.4Hz, 2H), 3.70 (s, 6H), 3.57 (s, 2H), 2.90 (s, 2H ,-CH₂Ar), 2.72 (s, 6H ,-CH₂-)；¹³C NMR (75MHz, CDCl₃)δppm：153.14,142.15,141.32,139.05,137.45,136.60,131.72,130.59,129.60, 124.76,123.26,121.09,120.81,118.83,118.18,116.29,115.31,114.91,106.49,106.10, 104.48,98.73,54.41,51.04,50.29,45.76,35.69,28.25,23.40；ESI-MS m/z：626.9([M+H ]⁺)。

Embodiment 34

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) quinoline -3- formamides (33) preparation

With reference in embodiment 25 24 preparation method, compound 33 is made, obtains faint yellow solid, yield 37.2%, M.p.109~111 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：10.02 (s, 1H), 9.43 (s, 1H), 9.01 (s, 1H), 8.61 (s, 1H), 8.18-8.09 (m, 2H), 7.93-7.85 (m, 1H), 7.74 (d, J=8.2Hz, 3H), 7.46 (d, J=8.2Hz, 2H), 7.25 (d, J=7.4Hz, 1H), 7.12 (t, J=7.4Hz, 1H), 6.88 (d, J=7.9Hz, 1H), 6.69 (d, J=7.0Hz, 1H), 6.64 (d, J=7.9Hz, 2H), 5.91 (t, J=5.2Hz, 1H), 4.49 (d, J=5.2Hz, 2H), 3.69 (s, 6H), 3.54 (s, 2H), 2.94-2.84 (m, 2H), 2.70 (s, 6H)；¹³C NMR (75MHz, DMSO-d₆)δppm：164.52 153.30,149.38,148.40,147.01,143.30,141.24,138.59,136.16,134.71,131.21,130.00, 129.10,128.93,127.50,127.37,126.57,125.88,123.24,121.00,119.77,116.14,111.75, 111.42,109.95,59.02,55.50,55.26,50.44,38.52,32.28,28.26；ESI-MS m/z：640.4([M+ H]⁺)。

Embodiment 35

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) quinoline-2-formamide (34) preparation

With reference in embodiment 25 24 preparation method, compound 34 is made, obtains yellow solid, yield 39.5%, M.p.136~138 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：10.28 (s, 1H), 8.63 (m, 2H), 8.25 (d, J=8.4Hz, 1H), 8.15 (d, J=8.4Hz, 2H), 7.83 (d, J=7.2Hz, 1H), 7.75 (s, 3H), 7.55 (d, J=7.2Hz, 1H), 7.47 (d, J=7.6Hz, 2H), 7.11 (s, 1H), 6.92 (d, J=7.6Hz, 1H), 6.76 (s, 1H), 6.65 (d, J=7.2Hz, 2H), 5.79 (t, J=5.2Hz, 1H), 4.46 (d, J=5.2Hz), 3.70 (s, 6H), 3.56 (s, 2H), 2.91 (s, 2H), (2.71 s, 6H)；¹³C NMR (75MHz, DMSO-d₆)δppm：162.90,150.14,147.05,145.85,142.07, 141.21,137.96,134.75,130.47,129.99,129.27,128.87,128.11,126.58,126.50,125.90, 125.22,124.55,121.04,119.78,118.73,117.23,112.64,111.83,110.02,58.99,55.49, 55.03,50.44,38.98,32.27,28.25；ESI-MS m/z：640.4([M+H]⁺)。

Embodiment 36

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) furans -2- formamides (35) preparation

With reference in embodiment 25 24 preparation method, compound 35 is made, obtains faint yellow solid, yield 29.6%, M.p.94~96 DEG C；

¹H NMR (300MHz, DMSO-d₆)δppm：9.57 (s, 1H), 8.57 (s, 1H), 7.90 (s, 1H), 7.74 (d, J= 8.3Hz, 2H), 7.46 (d, J=8.3Hz, 2H), 7.29 (s, 1H), 7.17 (d, J=7.4Hz, 1H), 7.09 (t, J=7.4Hz, 1H), 6.84 (d, J=8.0Hz, 1H), 6.73-6.59 (m, 4H), 5.66 (t, J=5.4Hz, 1H), 4.45 (d, J=5.4Hz, 2H), 3.70 (s, 6H), 3.55 (s, 2H), 2.89 (d, J=7.4Hz, 2H), 2.70 (s, 6H)；¹³CNMR (75MHz, DMSO-d₆) δppm：162.44,147.77,146.88,145.28,143.16,138.59,136.82130.00,127.19,126.50, 125.98,125.71,122.96,121.00,119.78,116.86,116.30,114.34,111.89,110.02,59.00, 55.47,55.03,50.45,37.04,32.29,28.24；ESI-MS m/z：579.3([M+H]⁺)。

Embodiment 37

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) benzamide (36) preparation

With reference in embodiment 25 24 preparation method, compound 36 is made, obtains faint yellow solid, yield 77.8%, M.p.162~164 DEG C；

¹H NMR (300MHz, DMSO-d₆)δ：9.72 (s, 1H), 8.60 (s, 1H), 7.88 (dd, J=83.5,7.3Hz, 5H), 7.61-7.34 (m, 5H), 7.23-7.00 (m, 2H), 6.85 (d, J=7.9Hz, 1H), 6.65 (t, J=8.9Hz, 3H), 5.71 (s, 1H), 4.46 (s, 2H), 3.69 (s, 6H), 3.54 (s, 2H), 2.88 (s, 2H), 2.69 (s, 6H)；¹³C NMR (75MHz, DMSO-d₆)δ：165.60,143.16,141.21,134.71,131.39,130.01,128.21,127.81, 127.37,127.03,125.83,120.98,119.75,116.21,111.68,111.44,109.87,55.41,50.42, 32.25 28.24；ESI-MS m/z：589.3([M+H]⁺)。

Embodiment 38

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -2- methyl benzamides (37) preparation

With reference in embodiment 25 24 preparation method, compound 37 is made, obtains faint yellow solid, yield 79.5%, m.p.133-135℃；

¹H NMR (300MHz, DMSO-d₆)δ：9.61 (s, 1H), 8.64 (s, 1H), 7.73-7.58 (m, 2H), 7.44- 7.29 (m, 7H), 7.08 (s, 1H), 6.85-6.63 (m, 4H), 5.56 (s, 1H), 4.45 (s, 2H), 3.69 (s, 8H), 2.87- 2.69 (m, 8H), 2.40 (s, 3H)；¹³C NMR (75MHz, DMSO-d₆)δ：168.31,147.13,146.88,146.57, 142.29,141.25,135.44,134.71,130.45,130.01,129.50,127.42,126.71,126.57,126.35, 125.88,125.46,123.88,121.00,119.78,116.43,111.77,111.58,109.96,59.00,55.44, 55.03,50.44,32.28,28.25,19.45；ESI-MS m/z：603.6([M+H]⁺)。

Embodiment 39

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -3- methyl benzamides (38) preparation

With reference in embodiment 25 24 preparation method, compound 41 is made, obtains yellow solid, yield 81.6%, M.p.149~151 DEG C；

¹H NMR (300MHz, DMSO-d₆)δ：9.65 (s, 1H), 8.59 (s, 1H), 7.81-7.75 (m, 4H), 7.46 (d, J =8.5Hz, 2H), 7.39 (d, J=4.5Hz, 2H), 7.18 (d, J=7.2Hz, 1H), 7.09 (t, J=7.3Hz, 1H), 6.65 (t, J=9.0Hz, 3H), 5.64 (t, J=5.7Hz, 1H), 4.45 (d, J=5.7Hz, 2H), 3.69 (d, J=1.6Hz, 6H), 3.54 (s, 2H), 2.89 (t, J=7.1Hz, 2H), 2.70 (s, 6H), 2.38 (s, 3H)；¹³C NMR (75MHz, DMSO-d₆)δ： 165.61,147.12,146.84,143.09,141.23,137.48,134.64,131.94,130.00,128.36,128.11, 127.24,126.95,126.57,125.88,124.95,123.92,120.99,119.76,116.29,111.76,111.53, 109.95,59.01,55.45,55.03,50.44,32.27,28.26,20.93；ESI-MS m/z：603.4([M+H]⁺)。

Embodiment 40

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -4- methyl benzamides (39) preparation

With reference in embodiment 25 24 preparation method, compound 42 is made, obtains yellow solid, yield 75.9%, M.p.96~97 DEG C；

¹H NMR (300MHz, DMSO-d₆)δ：9.62 (s, 1H), 8.59 (s, 1H), 7.91 (d, J=8.0Hz, 2H), 7.73 (d, J=8.4Hz, 2H), 7.46 (d, J=8.4Hz, 2H), 7.31 (d, J=8.0Hz, 2H), 7.17 (d, J=7.6Hz, 1H), 7.08 (t, J=7.7Hz, 1H), 6.84 (d, J=7.7Hz, 1H), 6.65 (t, J=8.2Hz, 3H), 5.64 (t, J=5.7Hz, 1H), 4.45 (d, J=5.7Hz, 2H), 3.70 (s, 6H), 3.54 (s, 2H), 2.89 (t, J=7.2Hz, 2H), 2.71 (s, 6H), 2.38 (s, 3H)；¹³C NMR (75MHz, DMSO-d₆)δ：165.62,147.12,146.84,143.12,141.27,134.71, 131.73,129.99,128.72,127.85,127.30,126.92,126.58,125.88,123.96,120.97,119.75, 116.28,111.63,109.95,59.01,55.43,55.04,50.45,32.28,28.25,20.96；ESI-MS m/z： 603.1([M+H]⁺)。

Embodiment 41

4- (tert-butyl group)-N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) benzene Base) -1H-1,2,3- triazole -4- bases) methyl) amino) phenyl) benzamide (40) preparation

With reference in embodiment 25 24 preparation method, compound 43 is made, obtains pale solid, yield 82.0%, M.p.150~152 DEG C；

¹H NMR (300MHz, DMSO-d₆)δ：9.63 (s, 1H), 8.60 (s, 1H), 7.95 (d, J=7.8Hz, 2H), 7.74 (d, J=8.0Hz, 2H), 7.54-7.45 (m, 4H), 7.19 (d, J=6.7Hz, 1H), 7.08 (d, J=7.0Hz, 1H), 6.85 (d, J=7.3Hz, 1H), 6.64 (d, J=7.6Hz, 3H), 5.66 (s, 1H), 4.45 (s, 2H), 3.69 (s, 6H), 3.54 (s, 2H), 2.89 (s, 2H), 2.70 (s, 6H), 1.31 (s, 9H)；¹³C NMR (75MHz, DMSO-d₆)δ：165.68 154.28, 147.01,143.08,141.21,134.72,131.80,129.99,127.71,127.46,126.93,126.58,125.88, 124.97,123.96,120.97,119.75,116.29,111.63,109.96,59.02,55.43,55.04,50.45, 34.60,32.28,30.90,28.26；ESI-MS m/z：645.7([M+H]⁺)。

Embodiment 42

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -2- methoxy benzamides (41) preparation

With reference in embodiment 25 24 preparation method, compound 41 is made, obtains yellow-brown solid, yield 78.2%, M.p.79~81 DEG C；

¹H NMR (300MHz, DMSO-d₆)δ：9.64 (s, 1H), 8.67 (s, 1H), 8.05-7.82 (m, 3H), 7.64- 7.35 (m, 6H), 7.30-6.96 (m, 3H), 6.64 (d, J=7.3Hz, 3H), 5.48 (s, 1H), 4.45 (s, 2H), 3.83 (s, 3H), 3.69 (s, 6H), 3.55 (s, 2H), 2.92 (s, 2H), 2.71 (s, 6H)；¹³C NMR (75MHz, DMSO-d₆)δ： 164.61,157.33,147.97,147.44,146.97,142.84,141.85,135.20,134.47,132.86,130.66, 127.00,126.64,126.36,125.68,125.25,124.09,121.68,121.03,120.27,117.45,112.52, 112.15,110.34,59.49,56.31,55.88,55.53,50.93,32.75,28.74；ESI-MS m/z：619.6([M+ H]⁺)。

Embodiment 43

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -3- methoxy benzamides (42) preparation

With reference in embodiment 25 24 preparation method, compound 42 is made, obtains yellow solid, yield 77.1%, M.p.80~82 DEG C；

¹H NMR (300MHz, DMSO-d₆)δ：9.70 (s, 1H), 8.61 (s, 1H), 8.38 (s, 1H), 7.98 (s, 1H), 7.74 (d, J=8.0Hz, 1H), 7.59-7.35 (m, 3H), 7.26-7.04 (m, 3H), 6.85 (d, J=8.0Hz, 2H), 6.66 (t, J=8.9Hz, 3H), 5.68 (s, 1H), 4.51-4.44 (m, 2H), 3.82 (s, 3H), 3.68 (s, 6H), 3.54 (s, 2H), 2.89 (s, 2H), 2.70 (s, 6H)；¹³C NMR (75MHz, DMSO-d6) δ：166.03,154.18,149.65,148.86, 147.56,143.67,136.45,135.34,130.51,129.85,127.72,127.02,126.32,124.24,121.50, 120.58,120.24,117.72,116.82,113.50,112.08,110.35,59.53,55.82,50.94,43.45, 32.75 28.75；ESI-MS m/z：619.6([M+H]⁺)。

Embodiment 44

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -4- methoxy benzamides (43) preparation

With reference in embodiment 25 24 preparation method, compound 43 is made, obtains yellow-brown solid, yield 72.9%, M.p.123~125 DEG C；

¹H NMR (300MHz, DMSO-d₆)δ：9.55 (s, 1H), 8.59 (s, 1H), 7.99 (d, J=8.6Hz, 2H), 7.74 (d, J=8.3Hz, 2H), 7.46 (d, J=8.2Hz, 2H), 7.17 (d, J=7.2Hz, 1H), 7.10-7.03 (m, 3H), 6.84 (d, J=8.0Hz, 1H), 6.65 (t, J=8.1Hz, 3H), 5.62 (s, 1H), 4.45 (d, J=5.4Hz, 2H), 3.83 (s, 3H), 3.69 (s, 6H), 3.54 (s, 2H), 2.88 (d, J=6.9Hz, 2H), 2.70 (s, 6H)；¹³C NMR (75MHz, DMSO- d₆)δ：165.25,161.78,147.12,146.87,143.17,141.20,134.71,129.99,129.71,127.34, 126.87,126.67,126.58,125.87,124.10,120.98,119.75,116.30,113.43,111.63,109.96, 59.00,55.45,55.02,50.44,32.27,28.25；ESI-MS m/z：619.6([M+H]⁺)。

Embodiment 45

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -3,4- dimethoxybenzarnides (44) preparation

With reference in embodiment 25 24 preparation method, compound 44 is made, obtains faint yellow solid, yield 88.5%, M.p.76~77 DEG C；

¹H NMR (300MHz, DMSO-d₆)δ：9.60 (s, 1H), 8.61 (s, 1H), 7.75 (d, J=8.3Hz, 2H), 7.70-7.51 (m, 2H), 7.47 (d, J=8.4Hz, 2H), 7.26-6.96 (m, 3H), 6.87 (d, J=7.7Hz, 1H), 6.66 (t, J=9.6Hz, 3H), 5.76 (s, 1H), 4.46 (d, J=5.2Hz, 2H), 3.83 (s, 6H), 3.70 (s, 6H), 3.55 (s, 2H), 2.90 (s, 2H), 2.70 (s, 6H)；¹³C NMR (75MHz, DMSO-d₆)δ：165.27,151.50,148.19,147.12, 146.80,143.24,141.23,134.71,129.99,127.33,126.94,127.33,126.62,125.87,124.08, 121.09,119.77,116.35,111.67 (d, J=14.1Hz), 111.75,111.57,111.04,109.94,59.01, 55.62,55.57,55.02,50.44,32.27,28.24；ESI-MS m/z：649.7([M+H]⁺)。

Embodiment 46

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -3,5- dimethoxybenzarnides (45) preparation

With reference in embodiment 25 24 preparation method, compound 45 is made, obtains yellow solid, yield 76.5%, M.p.89~91 DEG C；

¹H NMR (300MHz, DMSO-d₆)δ：9.66 (s, 1H), 8.59 (s, 1H), 7.73 (d, J=8.4Hz, 2H), 7.46 (d, J=8.5Hz, 2H), 7.24-6.92 (m, 4H), 6.85 (d, J=8.0Hz, 1H), 6.75-6.49 (m, 4H), 5.61 (s, 1H), 4.45 (d, J=5.5Hz, 2H), 3.80 (s, 6H), 3.69 (d, J=1.4Hz, 6H), 3.54 (s, 2H), 3.00-2.81 (m, 2H), 2.72-2.69 (m, 6H)；¹³C NMR (75MHz, DMSO-d₆)δ：160.27 146.87,143.17,141.24, 136.63,129.99,127.33,126.58,125.88,123.75,120.99,119.77,116.30,111.65,109.95, 105.78,103.32,59.02,55.43,55.02,50.44,32.27,28.26；ESI-MS m/z：649.5([M+H]⁺)。

Embodiment 47

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -3, the preparation of 4,5- trimethoxy-benzamides (46)

With reference in embodiment 25 24 preparation method, compound 46 is made, obtains yellow solid, yield 80.7%, M.p.171~173 DEG C

¹H NMR (300MHz, DMSO-d₆)δ：δ 9.70 (s, 1H), 8.61 (s, 1H), 7.74 (d, J=6.9Hz, 2H), 7.47 (d, J=7.1Hz, 2H), 7.35 (s, 2H), 7.21-7.06 (m, 2H), 6.88 (d, J=7.3Hz, 1H), 6.64 (d, J= 6.8Hz, 3H), 5.60 (s, 1H), 4.46 (s, 2H), 3.85 (s, 6H), 3.75-3.64 (m, 9H), 3.54 (s, 2H), 2.90 (s, 2H), 2.70 (s, 6H)；¹³C NMR (75MHz, DMSO-d₆)δ：165.18,152.52,147.12,146.87,146.76, 143.29,141.26,134.71,130.00,129.63,127.24,126.58,125.88,123.83,121.00,119.78, 116.34,111.76,111.59,109.95,105.47,60.08,59.01,56.02,55.43,55.03,50.45,32.27, 28.25；ESI-MSm/z：679.4([M+H]⁺)。

Embodiment 48

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -2- (3,4- Dimethoxyphenyl) acetamides (47) preparation

With reference in embodiment 25 24 preparation method, compound 47 is made, obtains faint yellow solid, yield 79.3%, M.p.89~91 DEG C

¹H NMR (300MHz, DMSO-d₆)δ：9.35 (s, 1H), 8.59 (s, 1H), 7.75 (d, J=8.0Hz, 2H), 7.47 (d, J=8.2Hz, 2H), 7.23-6.92 (m, 4H), 6.85-6.81 (m, 3H), 6.65 (d, J=7.3Hz, 3H), 5.42 (s, 1H), 4.43 (s, 2H), 3.69 (d, J=5.7Hz, 12H), 3.57 (d, J=7.9Hz, 4H), 2.91 (s, 2H), 2.71 (s, 6H)；¹³C NMR (75MHz, DMSO-d6) δ：170.33,148.91,147.41,146.95,142.49,141.73,135.17, 130.51,129.05,126.65,124.37,121.41,120.22,116.86,113.33,112.01,110.30,59.58, 55.81,55.53,50.96,42.76,32.76,28.76；ESI-MS m/z：663.7([M+H]⁺)。

Embodiment 49

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -2- (3,4- Dimethoxyphenyl) benzamides (48) preparation

With reference in embodiment 25 24 preparation method, compound 48 is made, obtains yellow solid, yield 81.4%, M.p.99~101 DEG C；

¹H NMR (300MHz, DMSO-d₆)δ：9.60 (s, 1H), 8.59 (s, 1H), 7.74 (d, J=8.3Hz, 2H), 7.46 (d, J=8.3Hz, 2H), 7.28-7.10 (m, 5H), 6.92-6.79 (m, 2H), 6.64 (d, J=7.7Hz, 3H), 5.56 (s, 1H), 4.45 (d, J=4.8Hz, 2H), 3.70 (d, J=1.3Hz, 6H), 3.55 (s, 2H), 2.94 (s, 8H), 2.70 (s, 6H) ；¹³C NMR (75MHz, DMSO-d₆)δ：166.94,150.73,147.57,147.31,143.59,141.71,135.70, 135.20,130.50,129.25,127.73,127.41,127.01,126.32,124.58,121.50,120.25,116.85, 115.99,115.65,112.07,110.34,59.54,55.90,55.53,50.94,32.76,28.75；ESI-MS m/z： 632.7([M+H]⁺)。

Embodiment 50

The chloro- N- of 2- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H- 1,2,3- triazole -4- bases) methyl) amino) phenyl) benzamide (49) preparation

With reference in embodiment 25 24 preparation method, compound 49 is made, obtains yellow solid, yield 84.8%, M.p.110~112 DEG C

¹H NMR (300MHz, DMSO-d₆)δ：9.81 (s, 1H), 8.65 (s, 1H), 7.81-7.61 (m, 3H), 7.59- 7.40 (m, 5H), 7.34 (d, J=7.0Hz, 1H), 7.11 (t, J=7.3Hz, 1H), 6.86 (d, J=8.1Hz, 1H), 6.71- 6.62 (m, 3H), 5.47 (t, J=5.3Hz, 1H), 4.46 (d, J=5.2Hz, 2H), 3.69 (s, 6H), 3.54 (s, 2H), 2.91-2.87 (m, 2H), 2.69 (s, 6H)；¹³C NMR (75MHz, DMSO-d₆)δ：165.53,146.39,142.23, 141.26,136.86,134.69,130.95,130.03,129.53,129.11,127.10,126.42,125.82,123.09, 121.08,119.77,116.35,111.55,109.85,59.03,55.38,55.02,50.43,32.24,28.23；ESI-MS m/z：623.6([M+H]⁺).

Embodiment 51

The chloro- N- of 3- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H- 1,2,3- triazole -4- bases) methyl) amino) phenyl) benzamide (50) preparation

With reference in embodiment 25 24 preparation method, compound 50 is made, obtains yellow solid, yield 71.8%, M.p.94~96 DEG C

¹H NMR (300MHz, DMSO-d₆)δ：9.78 (s, 1H), 8.57 (s, 1H), 8.06 (s, 1H), 7.95 (d, J= 6.7Hz, 1H), 7.74 (d, J=7.9Hz, 2H), 7.63 (d, J=8.2Hz, 1H), 7.57-7.32 (m, 3H), 7.19-7.01 (m, 2H), 6.82 (d, J=7.8Hz, 1H), 6.65 (d, J=9.3Hz, 3H), 5.75 (s, 1H), 4.44 (d, J=5.4Hz, 2H), 3.69 (s, 8H), 2.99-2.64 (m, 8H)；¹³C NMR (75MHz, DMSO-d₆)δ：164.23,146.96,143.30, 136.63,134.85,133.04,131.16,130.12,127.69,127.54,127.26,126.60,123.31,121.00, 119.83,116.09,111.72,111.38,109.89,55.45,50.18,32.24,28.23；ESI-MS m/z：623.4 ([M+H]⁺)。

Embodiment 52

The chloro- N- of 4- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H- 1,2,3- triazole -4- bases) methyl) amino) phenyl) benzamide (51) preparation

With reference in embodiment 25 24 preparation method, compound 51 is made, obtains yellow solid, yield 83.0%, M.p.164~166 DEG C

¹H NMR (300MHz, DMSO-d₆)δ：9.76 (s, 1H), 8.59 (s, 1H), 8.03 (d, J=7.2Hz, 2H), 7.74 (d, J=7.4Hz, 2H), 7.59 (d, J=7.4Hz, 2H), 7.46 (d, J=7.6Hz, 2H), 7.28-7.00 (m, 2H), 6.84 (d, J=7.7Hz, 1H), 6.64 (d, J=7.5Hz, 3H), 5.75 (s, 1H), 4.46 (s, 2H), 3.69 (s, 6H), 3.54 (s, 2H), 2.89 (s, 2H), 2.70 (s, 6H)；¹³C NMR (75MHz, DMSO-d₆)δ：164.73,146.86,143.25,141.22, 129.90,128.25,128.25,127.47,127.20,125.85,123.46,120.98,119.75,116.15,111.74, 111.41,109.92,59.03,55.44,55.03,50.44,32.27,28.26；ESI-MS m/z：623.6([M+H]⁺)。

Embodiment 53

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -4- chlorobenzamides (52) preparation

With reference in embodiment 25 24 preparation method, compound 52 is made, obtains gray solid, yield 80.1%, M.p.110~112 DEG C

¹H NMR (300MHz, DMSO-d₆)δ：9.75 (s, 1H), 8.60 (s, 1H), 8.09 (s, 2H), 7.74 (d, J= 6.6Hz, 2H), 7.47 (s, 2H), 7.35 (s, 2H), 7.17-7.09 (m, 2H), 6.86 (s, 1H), 6.65 (s, 2H), 5.75 (s, 1H), 4.46 (s, 2H), 3.69 (s, 6H), 3.54 (s, 2H), 2.89 (s, 2H), 2.70 (s, 6H)；¹³C NMR (75MHz, DMSO- d₆)δ：164.72,147.12,146.87,143.25,141.21,131.06,130.52,130.00,127.47,127.12, 126.55,125.87,123.62,120.97,119.75,116.17,115.24,114.95,111.76,111.42,109.95, 59.00,55.42,55.01,50.42,32.25,28.22；ESI-MS m/z：607.6([M+H]⁺)。

Embodiment 54

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -3- nitrobenzamides (53) preparation

With reference in embodiment 25 24 preparation method, compound 53 is made, obtains yellow solid, yield 73.7%, M.p.126~128 DEG C

¹H NMR (300MHz, DMSO-d₆)δ：10.08 (s, 1H), 8.85 (s, 1H), 8.59 (s, 1H), 8.44 (t, J= 6.7Hz, 2H), 7.82 (t, J=8.0Hz, 1H), 7.73 (d, J=8.4Hz, 2H), 7.45 (d, J=8.4Hz, 2H), 7.20- 7.01 (m, 2H), 6.85 (d, J=8.0Hz, 1H), 6.67-6.62 (m, 3H), 5.87 (t, J=5.5Hz, 1H), 4.46 (d, J= 5.5Hz, 2H), 3.69 (d, J=1.4Hz, 6H), 3.54 (s, 2H), 2.90 (d, J=6.7Hz, 2H), 2.69 (s, 6H)；¹³C NMR (75MHz, DMSO-d₆)δ：¹³C NMR (75MHz, DMSO) δ 164.22,155.32,147.11,146.85,143.59, 141.58,137.92,134.47,132.31,130.02,128.59,127.02,126.54,125.85,124.81,122.52, 121.23,120.90,120.01,113.69,111.74,109.92,62.20,58.98,55.42,55.03,50.43, 32.28 28.23；ESI-MS m/z：634.6([M+H]⁺)。

Embodiment 55

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- Triazole -4- bases) methyl) amino) phenyl) -4- nitrobenzamides (54) preparation

With reference in embodiment 25 24 preparation method, compound 54 is made, obtains brown solid, yield 81.3%, M.p.147~149 DEG C

¹H NMR (300MHz, DMSO-d₆)δ：10.00 (s, 1H), 8.59 (s, 1H), 8.36 (d, J=7.2Hz, 2H), 8.26 (s, 2H), 7.75 (s, 2H), 7.47 (s, 2H), 7.28-7.00 (m, 2H), 6.87 (s, 1H), 6.65 (s, 3H), 5.84 (s, 1H), 4.47 (s, 2H), 3.69 (s, 6H), 3.54 (s, 2H), 2.89 (s, 2H), 2.70 (s, 6H)；¹³C NMR (75MHz, DMSO-d₆)δ：164.26,149.02,146.93,141.21,140.33,130.02,129.36,127.55,125.79, 123.34,119.73,116.07,111.50,109.81,55.38,54.92,50.36,32.24,28.20；ESI-MS m/z： 634.4([M+H]⁺)。

Embodiment 56

4- cyano group-N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) - 1H-1,2,3- triazole -4- bases) methyl) amino) phenyl) benzamide (55) preparation

With reference in embodiment 25 24 preparation method, compound 55 is made, obtains yellow-brown solid, yield 76.8%, M.p.174~176 DEG C

¹H NMR (300MHz, DMSO-d₆)δ：9.90 (s, 1H), 8.58 (s, 1H), 8.17 (d, J=7.5Hz, 2H), 8.02 (d, J=7.5Hz, 2H), 7.74 (d, J=7.5Hz, 2H), 7.47 (d, J=7.5Hz, 2H), 7.26-7.02 (m, 2H), 6.85 (d, J=7.1Hz, 1H), 6.65 (d, J=7.8Hz, 3H), 5.80 (s, 1H), 4.46 (s, 2H), 3.69-3.59 (m, 8H), 2.90 (s, 2H), 2.72 (s, 6H)；¹³C NMR (75MHz, DMSO-d₆)δ：164.98,147.62,147.35,143.77, 141.50,139.12,135.24,132.76,130.53,129.19,127.91,126.18,123.54,121.55,120.25, 118.89,116.56,114.15,112.00,110.32,59.22,55.89,55.89,50.82,32.59,28.68；ESI-MS m/z：614.7([M+H]⁺)。

Embodiment 57

N- (2- (((1- (4- (2- ((the 1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H- 1,2,3- triazole -4- bases) methyl) acid amides) phenyl) -4- oxo -4H- chromene -2- formamides (56) preparation

With reference in embodiment 25 24 preparation method, compound 56 is made, obtains faint yellow solid, yield 39.6%, M.p.104~107 DEG C

¹H NMR (300MHz, DMSO-d6) δ ppm：10.29 (s, 1H), 8.60 (s, 1H), 8.10 (d, J=8.1Hz, 1H), 7.98-7.87 (m, 2H), 7.83 (d, J=8.1Hz, 1H), 7.75 (d, J=8.4Hz, 3H), 7.57 (t, J=7.6Hz, 1H), 7.48 (d, J=8.3Hz, 2H), 7.18 (d, J=7.6Hz, 2H), 6.98 (s, 1H), 6.89 (d, J=7.8Hz, 1H), 6.65 (d, J=7.8Hz, 2H), 5.99 (s, 1H), 4.48 (d, J=5.6Hz, 2H), 3.71 (s, 6H), 3.58 (s, 2H), 2.92 (s, 3H), 2.73 (s, 6H)¹³C NMR (75MHz, DMSO-d6) δ ppm：179.54,161.09,155.17,153.96, 149.41,148.19,146.70,138.59,136.82,136.48,133.85,128.13,127.01,125.88,125.52, 124.74,123.85,123.30,121.78,119.78,117.79,116.19,112.58,111.35,109.72,56.73, 54.70,51.36,36.68,33.42,28.76；ESI-MS m/z：657.6([M+H]⁺)。

Embodiment 58

Tablet containing activating agent 3：

Supplementary material is mixed according to a conventional method, pelletized, is dried, tabletting.

Embodiment 59

Tablet containing activating agent 50：

Claims

1. the compound and its officinal salt of logical formula (I)：

Wherein X is selected from：- NHCO- or-CONH- groups；

Wherein L is selected from：-CH₂- or-Ph- groups；

Wherein R₁It is selected from：Substitution or unsubstituted C₁~C₅Alkyl, substitution or unsubstituted C₁~C₅Alkoxy, substitution or unsubstituted fragrance Base, aromatic heterocyclic, cycloalkyl；

Wherein R₂And R₃It is identical or different, it is respectively selected from：H, halogen, substitution or unsubstituted C₁-C₅Alkyl, substitution or unsubstituted C₁- C₅Alkoxy, nitro work as R₄And R₅It is substituted in the carbon atom that when on adjacent carbon atom and they are connected and forms phenyl ring together Or methylene dioxy substituent.

2. the compound of logical formula (I) according to claim 1 or its pharmaceutically useful salt, it is the chemical combination shown in logical formula (II) Thing or its pharmaceutically useful salt：

Wherein X is selected from：- NHCO- ,-CONH- ,-SO₂NH- or-NHSO₂- group；

Wherein L is selected from：-CH₂- or-Ph- groups；

Wherein R₁It is selected from：Substitution or unsubstituted C₁~C₅Alkyl, substitution or unsubstituted C₁~C₅Alkoxy, substitution or unsubstituted fragrance Base, aromatic heterocyclic, cycloalkyl.

3. lead to formula (I) compound according to defined in claim 1-4 and its officinal salt, the compound are selected from：

2- (((1- (2- (6,7- dimethoxy -3,4- dihydro-isoquinoline -2- bases) ethyl) 1H-1,2,3- triazole -4- bases) amine Base) methyl)-N phenylbenzamaides；

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) first Base) amino)-N- (3,4,5- trimethoxyphenyl) benzamide；

N- (4- (tert-butyl group) phenyl) -2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1, 2,3- triazole -4- bases) methyl) amino) benzamide；

N- (4- chlorphenyls) -2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- tri- Nitrogen azoles -4- bases) methyl) amino) benzamide；

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) first Base) amino))-N- (4- fluorophenyls) benzamide；

(2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) first Base) amino) phenyl) (morpholine) ketone；

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) first Base) amino)-N- (3,4- Dimethoxyphenethyl) benzamide；

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) first Base) amino)-N- (4- (trifluoromethoxy) phenyl) benzamide；

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) first Base) amino)-N- (4- methoxyphenyls) benzamide；

N- (benzo [1,3] 5- dioxa cyclopentenyls) -2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) Ethyl) -1H-1,2,3- triazole -4- bases) methyl) amino) benzamide；

2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) first Base) amino) isobutyl-benzene formamide；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) Methyl) amino) phenyl) thiophene-2-carboxamide derivatives；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) Methyl) amino) phenyl) thiophene -3- formamides；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) Methyl) amino) phenyl) -3 methyl thiophene -2- formamides；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) Methyl) amino) phenyl) -5- thiophene-2-carboxamide derivatives；

The chloro- N- of 5- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) -2- thenoyl amines；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) Methyl) amino) phenyl) picolinamide；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) Methyl) amino) phenyl) Pyrazinamide；

The chloro- N- of 2- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) amino) phenyl) niacinamide；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) Methyl) amino) phenyl) -1H- indole 2-carboxamides；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) Methyl) amino) phenyl) quinoline -3- formamides；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) Methyl) amino) phenyl) quinoline-2-formamide；

N- (2- (((1- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) -1H-1,2,3- triazole -4- bases) Methyl) amino) phenyl) furans -2- formamides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) thiophene-2-carboxamide derivatives；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) thiophene -3- formamides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) -2- methylthiophene -3- formamides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) -5- methylthiophene -2- formamides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) picolinamide；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) Pyrazinamide；

The chloro- N- of 2- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2, 3- triazole -4- bases) methyl) amino) phenyl) niacinamide；

The chloro- N- of 2- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2, 3- triazole -4- bases) methyl) amino) phenyl) -1H- indole 2-carboxamides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) quinoline -3- formamides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) quinoline-2-formamide；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) furans -2- formamides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) benzamide；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) -2- methyl benzamides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) -3- methyl benzamides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) -4- methyl benzamides；

4- (tert-butyl group)-N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) - 1H-1,2,3- triazole -4- bases) methyl) amino) phenyl) benzamide；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) -2- methoxy benzamides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) -3- methoxy benzamides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) -4- methoxy benzamides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) -3,4- dimethoxybenzarnides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) -3,5- dimethoxybenzarnides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) -3,4,5- trimethoxy-benzamides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) -2- (3,4- Dimethoxyphenyl) acetamide；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) -2- (3,4- Dimethoxyphenyl) benzamide；

The chloro- N- of 2- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2, 3- triazole -4- bases) methyl) amino) phenyl) benzamide；

The chloro- N- of 3- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2, 3- triazole -4- bases) methyl) amino) phenyl) benzamide；

The chloro- N- of 4- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2, 3- triazole -4- bases) methyl) amino) phenyl) benzamide；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) -4- chlorobenzamides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) -3- nitrobenzamides；

N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2,3- tri- nitrogen Azoles -4- bases) methyl) amino) phenyl) -4- nitrobenzamides；

4- cyano group-N- (2- (((1- (4- (2- (base of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1, 2,3- triazole -4- bases) methyl) amino) phenyl) benzamide；

N- (2- (((1- (4- (2- ((the 1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline -2) ethyl) phenyl) -1H-1,2, 3- triazole -4- bases) methyl) acid amides) phenyl) -4- oxo -4H- chromene -2- formamides.

4. the compound and its pharmaceutically acceptable salt described in claim 1-5 any one are resistance in preparation treatment tumour multiple medicine Application in the medicine of medicine and the medicine of preparation treatment tumour.

A kind of 5. pharmaceutical composition, it is characterised in that the chemical combination described in the claim 1-5 any one containing therapeutically effective amount Thing and pharmaceutically acceptable auxiliary material.