CN103387576A - Aramide Raf kinase inhibitor based on purine structure and preparation method and application thereof - Google Patents
Aramide Raf kinase inhibitor based on purine structure and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a kind of new aramide compounds based on a purine structure, a preparation method thereof, a medicinal composition containing the compounds and a medical application thereof, and particularly relates to an application of the compounds serving as a Raf kinase inhibitor. The composition of the new compounds can be independently used or can be used together with at least one of other medicines for treating the diseases regulated by protein kinase such as cancers.
Description
Invention field
The present invention relates to a class based on the aryl amide new compound of purine structure, their preparation method, the medicinal compositions that contains these compounds and their medical use, particularly as the purposes of Raf kinase inhibitor.This new compound composition can use separately or be used for the treatment of at least a other medicines coupling that is subjected to the disorders such as cancers that protein kinase regulates.
Background technology
Along with the development of standard of living, medical level, the mankind have captured numerous disease, but cancer remains the difficult problem that medically can't capture fully, it has the distinguishing feature that is different from other diseases, as easy transfer and diffusion, and easily recurrence after treatment, mortality ratio is high etc.Modern biomedical research often trends towards the immediate cause of explaining that cancer occurs, to the treatment of cancer also mostly directly with cancer cells itself as striking target, be main as surgical operation, radiation cure and chemotherapy, but side effect is quite serious, overall curative ratio is also lower.Along with molecular biological development, people recognize that from molecular level normal cell is Protooncogene Activated to the conversion of malignant tumour, cancer suppressor gene inactivation, anti-apoptotic genes expression increased activity, the result of the combined factors effects such as short apoptogene reduced activity.If therefore can give strong treatment for the treatment target spot for the specific molecular that cancer occurs, will greatly improve curative effect, and killing off tumor cells and injuring normal cell not reduces toxic side effect only, this specificity therapeutic method, the i.e. targeted therapy of tumour.
The Raf kinases is a kind of protein serine/threonine, is playing the part of very important role in the Ras/Raf/MEK/ERK signal transduction pathway.At present, can activate this path by two paths.The one, the mode that relies on GTP is activated by upstream Ras, the Raf of activation makes kinase whose two the serine residue phosphorylations of MEK (MEK1/MEK2) and then activates MEK, the MEK that is activated follows phosphorylation activation downstream ERK (extracelluar signal-regulated kinase) kinases, cause the ERK kinases to enter in nucleus, cause the cytobiology reaction; The 2nd, activate by overexpression or the sudden change that forms this path albumen.In case its this path generation excessive activation, the acceleration of the cell proliferation that causes and the prolongation of cells survival phase can be led oncogenic formation and development., if suppress the Raf kinases, will suppress the MEK/ERK signal transduction pathway, thereby suppress the breeding of specific tumor cell, so the Raf kinases has become the important new target drone of clinical treatment tumour.
The kinase whose three kinds of hypotypes of Raf comprise Raf-1 (C-Raf), A-Raf and B-Raf, with cell proliferation, differentiation, survive, adhere to and the adjusting of vasculogenesis closely related, than A-Raf and C-Raf, B-Raf has stronger kinase activity, is the easiest albumen that is activated by Ras in this family.Frequent sudden change activation in human tumor provides potential theoretical basis for B-Raf for this.The activated mutant rate that it is found that B-Raf in mankind tumor tissue is quite high, is 60% in melanoma, is 40% in thyroid carcinoma, is 20% in colorectal carcinoma and ovarian cancer, makes it become the most attractive drug target.Suppress the B-Raf kinases and become one of effective way of targeted therapy of cancer.At present more and more for the kinase whose curative of Raf succeed in developing and be applied to clinical, as Xarelto, Wei Luofeini etc.
Summary of the invention
The present invention is by the crystal structure model of research Raf protein kinase, utilize the Computer-Aided Drug Design means to build structure activity relationship model and the medicine virtual screening model of Raf inhibitor, designed and synthesized the aryl amide compound based on the purine structure of a series of brand news, the preliminary pharmacological tests result shows: compound of the present invention has good Raf kinase inhibiting activity, thereby can suppress the growth of malignant tumour.
Compound general formula I of the present invention is as follows:
R wherein
1Be selected from hydrogen, hydroxyl, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
6Haloalkyl, C
1-C
6Alkylamino, C
1-C
6One or more in dialkyl amido or cyano group; Be preferably one or more in hydrogen, fluorine, chlorine, bromine, trifluoromethyl, sec.-propyl, methyl, methoxyl group, dimethylamino, cyano group;
R
2Be selected from hydrogen, hydroxyl, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group or C
1-C
6One or more in haloalkyl; Be preferably one or more in hydrogen, methyl, fluorine, chlorine;
X represents the connexons such as CONH, NHCO or NHCONH; Be preferably CONH, NHCO;
Y represents the connexons such as NH, O, S, CO; Be preferably NH.
According to the present invention, pharmacy acceptable salt comprises the acid salt that compound of Formula I and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, naphthene sulfonic acid, citric acid, tartrate, lactic acid, pyruvic acid, acetic acid, toxilic acid or succsinic acid, fumaric acid, Whitfield's ointment, phenylacetic acid, tussol.The acid salt that comprises in addition mineral alkali, as: basic metal positively charged ion, alkaline earth metal cation, ammonium cation salt contained.
The preferred following structural compounds of the compound of general formula I:
N-(4-chloro-3-trifluoromethyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-1)
N-(3-trifluoromethyl)-4-chloro-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-2)
N-(3-isopropyl phenyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-3)
N-(4-chloro-3-trifluoromethyl)-4-chloro-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-4)
N-(3-cyano-phenyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-5)
N-(3-fluorophenyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-6)
N-(3-methyl-4-chloro-phenyl-)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-7)
N-(3,4-dichlorophenyl)-4-chloro-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-8)
N-(3-trifluoromethyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-9)
N-(3-chloro-phenyl-)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-10)
N-(4-chloro-3-bromophenyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-11)
N-(4-trifluoromethyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-12)
N-(4-chloro-3-trifluoromethyl)-4-fluoro-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-13)
N-(3-isopropyl phenyl)-4-chloro-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-14)
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-3-(dimethylamino) benzamide (I-b-1)
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-3-methoxy benzamide (I-b-2)
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-3-chlorobenzamide (I-b-3)
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-3-trifluoromethyl benzamide (I-b-4)
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-4-chloro-3-trifluoromethyl benzamide (I-b-5)
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino] phenyl]-4-chloro-3-trifluoromethyl benzamide (I-b-6)
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-3-cyano group benzamide (I-b-7)
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-fluorophenyl]-4-chloro-3-trifluoromethyl benzamide (I-b-8)
Part of compounds preparation method of the present invention is as follows:
Method one:
Method two:
Method three:
The synthetic method of 6-(2-fluoro-3-pyridine)-9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine:
The compounds of this invention can prepare with above-mentioned or similar above-mentioned preparation method, according to the difference of substituent difference and substituting group position, selects corresponding raw material to get final product.
The pharmacology test result shows, the compound of general formula I and pharmacy acceptable salt thereof all have in various degree restraining effect to external Raf kinases, therefore, compound of Formula I and pharmacy acceptable salt thereof can be used for the treatment of the clinical disease relevant with the Raf kinase inhibitor.The described disease relevant with the Raf kinase inhibitor can be melanoma, liver cancer, kidney, acute leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome, the esophageal carcinoma, cancer of the stomach or mesothelioma.
1) be the materials and methods of vitro kinase pharmacology test:
[material]
Instrument Bole Westemblot electrophoresis apparatus (U.S. BIO-RAD company)
Black wall black matrix 384 orifice plates (U.S. Corning company)
Dull and stereotyped shaking table (the bright laboratory apparatus factory in Jiangsu Province)
Reagent B-Raf (truncated) (U.S. Sigma)
Lck(truncated)
MEKl unactive (U.S. Sigma)
Assay Dilution Bufferl (U.S. Sigma)
Magnesium/ATP Cocktail (U.S. Sigma)
Anti-phospho-MEKl (Ser218/222)/MEK2 (U.S. Sigma)
Goat anti-rabbit HRP conjugated lgG (U.S. Sigma)
DMSO (U.S. Sigma)
[method]
1, get EP pipe (50 μ L), add 20 μ L Magnesium/ATP Cocktail;
2, add 1 μ L B-Raf;
3, add medicine 2 μ L (1.0 * 10 to be sieved
-5Mol/mL);
4, add 0.84 μ L MEKl unactive, then add 14.16 μ L Assay Dilution Buffer1;
5, microcentrifuge centrifugal after, 30 ℃ of 30min on shaking table;
6, add again 40 μ L sample buffer, boiling water boiling 5min;
7, every hole 10 μ L, the SDS-PAGE electrophoresis, transferring film, tri-distilled water is washed film twice;
8, contain the TBST sealing of 5% skim-milk, shake gently 30min on the greenhouse shaking table;
9, incubate primary antibodie Anti-phospho-MEKl (Ser218/222)/MEK2,4 ℃ are spent the night;
10, tri-distilled water is washed film twice;
11, incubating Goat anti-rabbit HRP conjugated lgG two resists;
12, tri-distilled water is washed film twice;
13, wash film 3-5min with TBS-0.05%Tween-20;
14, tri-distilled water rinsing film is 4-5 time;
15, Westernblot chemiluminescence detection.
2) be the materials and methods of cytoactive test,
[instrument]
Super clean bench: upper marine clean treating plant company limited produces
Electronic balance: METTLER TOLEDO ALl04 type
Whizzer: Anke/ flying pigeon TDL80-2B
Inverted microscope: Leica DMI3000B, use LAS V3.7 software
CO
2Incubator: Thermo
Microplate reader: TECAN GENion
[reagent]
Substratum (DMEM, RPMI1640): Gibco produces
Foetal calf serum: Gibco produces, and lot number is C2027050
Pancreatin: Amresco produces
MTT：Solarbio
DMSO：Amresco
[material]
Cell strain
Hepatoma cell strain HepG2, breast carcinoma cell strain MDA-MB-453, colon cancer cell line SW480, Prostatic cancer cell lines PC3, lung cancer cell line H522, breast cancer cell line mcf-7
Positive control drug
Sorafenib and Sorafenib salt
[method]
1, vitro culture human tumor cell line, Growth of Cells be to the logarithmic growth after date, collecting cell, and centrifugal 5 minutes of 1000rpm, abandon supernatant, and appropriate substratum suspends, and adjusts cell concn to 3.5～4.0 * 10
4Individual/mL;
2, with cell suspension inoculation in 96 porocyte culture plates, every hole 100 μ L, place cell culture incubator (37 ℃, 5%CO
2) the middle 24h that cultivates;
3, add medicine to be measured, it is 0.5%DMSO that negative control group adds final concentration, and each group is all established 3 multiple holes, cultivates 72h in incubator;
4, every hole adds the MTT20 μ L of 5mg/mL, places 4h for 37 ℃;
5, every hole adds 150 μ L DMSO, 37 ℃ of shaking table vibration 5min, and 492nm/620nm surveys absorbancy (OD).
3), following table is the result of external B-Raf activity and cytoactive test:
(in table, the compound code name is corresponding to the compound code name of front)
The pharmacology test result shows, the compounds of this invention has the Raf kinase inhibiting activity, can be used for preventing or clinical disease that treatment is relevant with the Raf kinase inhibitor, these diseases can be: melanoma, liver cancer, kidney, acute leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome, the esophageal carcinoma, cancer of the stomach or mesothelioma etc.
Embodiment
Fusing point is measured with b shape melting point tube, and medium is methyl-silicone oil, and thermometer is not proofreaied and correct; IR spectrum Nicolet Impact410 type determination of infrared spectroscopy, the KBr compressing tablet;
1HNMR completes (mark in TMS) with JEOL FX90Q type fourier transform NMR instrument, BRUKER ACF-300 type nuclear magnetic resonance analyser and BRUKER AM-500 type nuclear magnetic resonance analyser; MS measures with Nicolet2000 type Fourier transform mass spectrometer and MAT-212 type mass spectrograph.
Embodiment 1
6-chloro-9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine (P-1)
Add 6-chloro-9H-purine 2.0g (13mmol), 3 in the 100mL eggplant-shape bottle, 4-dihydro-2H-pyrans 3.3g (39mmol), p-methyl benzenesulfonic acid 50mg (0.3mmol) and anhydrous ethyl acetate 30mL, stir reflux 3 hours.Cooling, unnecessary ethyl acetate is removed in underpressure distillation, obtains light yellow oil (P-1) 3.0g, yield 96.7%, document yield 99.3%.Product need not purifying, directly casts single step reaction.
Embodiment 2
6-(2-fluoro-3-pyridine base)-9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine (P-2)
Add P-13.0g (13mmol), 2-fluoro-3-pyridine boric acid 2.7g (19.5mmol), NaCO in the 100mL three-necked bottle
35.5g (5lmmol), PdCl
2(dppf) 180mg (0.24mmol), water 5mL and Isosorbide-5-Nitrae-dioxane 35mL, stir lower logical N
2Protection, back flow reaction 14hr.After cooling, reaction solution is dissolved in 50mL water and 50mL ethyl acetate, standing, separatory, collected organic layer, water layer, with ethyl acetate extraction 3 times (50mL * 3), merges organic layer and uses the water washing of 50mL saturated common salt, anhydrous sodium sulfate drying, spend the night, suction filtration, concentrate to obtain crude product.(developping agent is ethyl acetate: sherwood oil=1:1) separates to obtain light yellow solid (P-2) 2.0g, yield 51.5%, mp::125～127 ℃ through silica gel column chromatography.MS(LR-ESI)：300.2[M+H]
+。
1HNMR(300MHz，CDCl
3)：δ1.70～2.23(6H，m，CH
2)，3.82(1H，t，CH
2O，J＝8.2Hz)，4.21(1H，d，CH
2O，J=9.9Hz)，5.87(1H，d，CH(N)O，J=9.9Hz)，7.40(1H，m，ArH)，8.38～8.40(2H，m，ArH)，8.53(1H，t，ArH，J=7.5Hz)，9.10(1H，s，ArH)。
Embodiment 3
4-methyl-3-nitro Benzoyl chloride (I-1)
Add 4-methyl-3-nitro phenylformic acid 725mg (4mmol), sulfur oxychloride 15mL and 2 DMFs (DMF) in the 100mL eggplant-shape bottle, stir lower back flow reaction 5hr.Cooling, remove sulfur oxychloride under reduced pressure and obtain light yellow oil (I-1) 790mg, yield 91.6%.
Embodiment 4
4-chloro-3-nitrobenzoyl chloride (I-2)
4-chloro-3-nitrobenzoic acid 800mg (4mmol), sulfur oxychloride 15mL and 2 DMF, the same I-1 of preparation method, obtain product (I-2) 820mg, yield 93.6%.
Embodiment 5
4-fluoro-3-nitrobenzoyl chloride (I-3)
4-fluoro-3-nitrobenzoic acid 740mg (4mmol), sulfur oxychloride 15mL and 2 DMF, the same I-1 of preparation method, obtain product (I-3) 800mg, yield 91.1%.
Embodiment 6
N-(4-chloro-3-trifluoromethyl)-4-methyl-3-nitro benzamide (I-4)
Add 4-chloro-3-5-trifluoromethylaniline 790mg (4mmol), anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL in the 100mL eggplant-shape bottle, stirring makes it to dissolve, then slowly drip the 10mL dichloromethane solution of 4-methyl-3-nitro Benzoyl chloride (I-1), room temperature reaction 1hr under condition of ice bath.Use saturated Na
2CO
3Regulate the pH value to 8-9, standing, separatory, collected organic layer, water layer, with dichloromethane extraction 3 times (50mL * 3), merges organic layer and uses the water washing of 50mL saturated common salt, and anhydrous sodium sulfate drying, spend the night, suction filtration, concentrate to obtain (I-4) 1.1g, yield 76.9%.Product need not purifying, directly casts single step reaction.
Embodiment 7
N-(3-trifluoromethyl)-4-chloro-3-nitrobenzamide (I-5)
3-5-trifluoromethylaniline 644mg (4mmol), 4-chloro-3-nitrobenzoyl chloride (I-2) 820mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-4), obtain yellow solid (I-5) 1.1g, yield 79.7%.Product need not purifying, directly casts single step reaction.
Embodiment 8
N-(3-isopropyl phenyl)-4-methyl-3-nitro benzamide (I-6)
3-isopropyl aniline 540mg (4mmol), 4-methyl-3-nitro Benzoyl chloride (I-1) 790mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-4), obtain yellow solid (I-6) 0.89g, yield 74.8%.Product need not purifying, directly casts single step reaction.
Embodiment 9
N-(4-chloro-3-trifluoromethyl)-4-chloro-3-nitrobenzamide (I-7)
4-chloro-3-5-trifluoromethylaniline 780mg (4mmol), 4-chloro-3-nitrobenzoyl chloride (I-2) 820mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-4), obtain yellow solid (I-7) 1.3g, yield 86.1%.Product need not purifying, directly casts single step reaction.
Embodiment 10
N-(3-cyano-phenyl)-4-methyl-3-nitro benzamide (I-8)
3-cyano-aniline 470mg (4mmol), 4-methyl-3-nitro Benzoyl chloride (I-1) 790mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-4), obtain yellow solid (I-8) 0.93g, yield 83.0%.Product need not purifying, directly casts single step reaction.
Embodiment 11
N-(3-fluorophenyl)-4-methyl-3-nitro benzamide (I-9)
3-fluoroaniline 440mg (4mmol), 4-methyl-3-nitro Benzoyl chloride (I-1) 800mg (4mmol), anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-4), obtain yellow solid (I-9) 0.83g, yield 75.5%.Product need not purifying, directly casts single step reaction.
Embodiment 12
N-(3-methyl-4-chloro-phenyl-)-4-methyl-3-nitro benzamide (I-10)
3-methyl-4-chloroaniline 565mg (4mmol), 3-nitro-4-methyl Benzoyl chloride (I-1) 790mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-4), obtain yellow solid (I-10) 0.91g, yield 74.6%.Product need not purifying, directly casts single step reaction.
Embodiment 13
N-(3,4-dichlorophenyl)-4-chloro-3-nitrobenzamide (I-11)
3,4-dichlorphenamide bulk powder 644mg (4mmol), 4-chloro-3-nitrobenzoyl chloride (I-2) 820mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method, with (I-4), obtains yellow solid (I-11) 1.12g, yield 81.2%.Product need not purifying, directly casts single step reaction.
Embodiment 14
N-(3-trifluoromethyl)-4-methyl-3-nitro benzamide (I-12)
3-5-trifluoromethylaniline 644mg (4mmol), 4-methyl-3-nitro Benzoyl chloride (I-1) 790mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-4), obtain yellow solid (I-12) 0.98g, yield 75.4%.Product need not purifying, directly casts single step reaction.
Embodiment 15
N-(3-chloro-phenyl-)-4-methyl-3-nitro benzamide (I-13)
3-chloroaniline 508mg (4mmol), 4-methyl-3-nitro Benzoyl chloride (I-1) 790mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-4), obtain yellow solid (I-13) 0.90g, yield 77.6%.Product need not purifying, directly casts single step reaction.
Embodiment 16
N-(4-chloro-3-bromophenyl)-4-methyl-3-nitro benzamide (I-14)
4-chloro-3-bromaniline 820mg (4mmol), 4-methyl-3-nitro Benzoyl chloride (I-1) 790mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-4), obtain yellow solid (I-14) 1.23g, yield 83.7%.Product need not purifying, directly casts single step reaction.
Embodiment 17
N-(4-trifluoromethyl)-4-methyl-3-nitro benzamide (I-15)
4-5-trifluoromethylaniline 644mg (4mmol), 4-methyl-3-nitro Benzoyl chloride (I-1) 790mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-4), obtain yellow solid (I-15) 1.02g, yield 78.5%.Product need not purifying, directly casts single step reaction.
Embodiment 18
N-(4-chloro-3-trifluoromethyl)-4-fluoro-3-nitrobenzamide (I-16)
4-chloro-3-5-trifluoromethylaniline 780mg (4mmol), 4-fluoro-3-nitrobenzoyl chloride (I-3) 800mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-4), obtain yellow solid (I-16) 1.06g, yield 73.1%.Product need not purifying, directly casts single step reaction.
Embodiment 19
N-(3-isopropyl phenyl)-4-chloro-3-nitrobenzamide (I-43)
Add 4-chloro-3-nitrobenzoic acid 800mg (4mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) 1.15g (6mmol), DMAP (DMAP) 50mg (0.4mmol), triethylamine 1.2g (12mmol) and anhydrous methylene chloride 40mL in the eggplant-shape bottle of 100mL.Slowly add 3-isopropyl aniline 540mg (4mmol) after stirring 10min, room temperature reaction, spend the night.Add the remaining EDCI of 40mL water destruct in reaction solution, dichloromethane extraction 3 times (40mL * 3), merge organic layer and use the water washing of 40mL saturated common salt once, anhydrous sodium sulfate drying, spend the night, suction filtration, concentrated yellow solid (I-43) 1.1g, the productive rate 86.6% of obtaining.Product need not purifying, directly casts single step reaction.
Embodiment 20
N-(4-chloro-3-trifluoromethyl)-4-methyl-3-AB (I-17)
Add I-41.43g (4mmol), iron powder 0.9g (16mmol), NH in the 250mL three-necked bottle
4Cl0.64g (12mmol) and 75% ethanol (100mL), back flow reaction 5hr.Suction filtration while hot, filter cake is with a small amount of washing with alcohol.Remove the most of solvent in filtrate under reduced pressure, ethyl acetate extraction 3 times (40mL * 3), merge organic layer and use the water washing of 40mL saturated common salt once, remove solvent under reduced pressure and obtain yellow oil, (developping agent is ethyl acetate: sherwood oil=1:4) separates to obtain off-white color solid phase prod (I-17) 0.87g to crude product through column chromatography, yield is 66.3%, mp:161～162 ℃.
1HNMR(300MHz，CDCl
3)：δ2.24(3H，s，ArCH
3)，3.80(2H，brs，ArNH
2)，7.13(2H，m，ArH)，7.21(1H，s，ArH)，7.48(1H，d，ArH，J=8.8Hz)，7.88(1H，d，ArH，J=8.8Hz)，7.94(1H，s，ArH)，7.95(1H，s，CONH).
Embodiment 21
N-(3-trifluoromethyl)-4-chloro-3-AB (I-18)
I-51.38g (4mmol), iron powder 0.9g (16mmol), NH
4C10.64g (12mmol) and 75% ethanol (100mL), the preparation method, with (I-17), obtains off-white color solid phase prod (I-18) 1.02g, and yield is 81.0%, mp:124～126 ℃.
1HNMR(300MHz，CDCl
3)：δ4.15(2H，brs，ArNH
2，+D
2Odisappear)，7.1l(1H，d，ArH，J=4.9Hz)，?7.33(1H，s，ArH)，7.37(1H，d，ArH，J5.0Hz)，7.42(1H，d，ArH，J＝4.6Hz)，7.51(1H，t，ArH，J＝4.8Hz)，7.8l(1H，brs，CONH，+D
2Odisappear)，7.86(1H，d，ArH，J＝4.7Hz)，7.92(1H，s，ArH).
Embodiment 22
N-(3-isopropyl phenyl)-4-methyl-3-AB (I-19)
I-61.19g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the preparation method, with (I-17), obtains off-white color solid phase prod (I-19) 0.71g, and yield is 66.2%, mp:152～154 ℃.
1HNMR(300MHz，CDCl
3)：δ1.25(6H，s，(CH
3)
2CH)，2.20(3H，s，ArCH
3)，2.90(1H，m，(CH
3)
2CH，J＝6.8Hz)，3.77(2H，brs，ArNH
2，+D20disappear)，7.00(1H，d，ArH，J=7.7Hz)，7.11(2H，t，ArH，J=8.2Hz)，7.22～7.29(2H，m，ArH)，7.45(1H，d，ArH，J=8.0Hz)，7.50(1H，s，ArH)，7.82(1H，brs，CONH).
Embodiment 23
N-(4-chloro-3-trifluoromethyl)-4-chloro-3-AB (I-20)
I-71.51g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the preparation method, with (I-17), obtains off-white color solid phase prod (I-20) 1.0g, and yield is 71.8%, mp:136～138 ℃.
1HNMR(300MHz，CDCl
3)：δ5.64(2H，s，ArNH
2)，7.12(1H，d，ArH，J＝8.2Hz)，7.34～7.37(2H，m，ArH)，7.70(1H，t，ArH，J=8.8Hz)，8.09(1H，d，ArH，J=8.8Hz)，8.33(1H，s，ArH)，10.54(1H，brs，CONH).
Embodiment 24
N-(3-cyano-phenyl)-4-methyl-3-AB (I-21)
I-81.12g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the preparation method, with (I-17), obtains off-white color solid phase prod (I-21) 0.76g, and yield is 75.7%, mp:l80～182 ℃.
1HNMR(300MHz，CDCl
3)：δ2.12(3H，s，ArCH
3)，5.10(2H，s，ArNH
2)，7.08(2H，m，ArH)，7.17(1H，s，ArH)，7.51～7.58(2H，m，ArH)，8.02～8.06(1H，m，ArH)，8.24(1H，s，ArH)，10.3l(1H，s，CONH).
Embodiment 25
N-(3-fluorophenyl)-4-methyl-3-AB (I-22)
I-91.10g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the preparation method, with (I-17), obtains off-white color solid phase prod (I-22) 0.64g, and yield is 71.4%, mp:142～144 ℃.
1HNMR(300MHz，CDCl
3)：δ2.12(3H，s，ArCH
3)，5.08(2H，s，ArNH
2)，6.85～6.92(1H，m，ArH)，7.06(2H，s，ArH)，7.16(1H，s，ArH)，7.35(1H，q，ArH，J＝8.2Hz)，7.55(1H，d，ArH，J＝9.2Hz)，7.71～7.77(1H，m，ArH)，10.18(1H，s，CONH).
Embodiment 26
N-(3-methyl-4-chloro-phenyl-)-4-methyl-3-AB (I-23)
I-101.22g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the preparation method, with (I-17), obtains off-white color solid phase prod (I-23) 0.76g, and yield is 69.3%, mp:156～157 ℃.
1HNMR(300MHz，CDCl
3)：δ2.25(3H，s，ArCH
3)，2.39(3H，s，ArCH
3)，7.14(2H，s，ArH)，7.29～7.32(2H，m，ArH)，7.40(1H，dd，ArH，J＝8.8Hz)，7.57(1H，s，ArH)，7.80(1H，brs，CONH).
Embodiment 27
N-(3,4-dichlorophenyl)-4-chloro-3-AB (I-24)
I-111.38g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the preparation method, with (I-17), obtains off-white color solid phase prod (I-24) 0.92g, and yield is 73.2%, mp:181～182 ℃.
1HNMR(300MHz，CDCl
3)：δ5.63(2H，s，ArNH
2)，7.10(1H，dd，ArH，J=8.2Hz)，7.32～7.37(2H，m，ArH)，7.60(1H，d，ArH，J＝8.8Hz)，7.73(1H，dd，ArH，J＝9.0Hz)，8.13(1H，d，ArH，J＝2.4Hz)，10.40(1H，s，CONH).
Embodiment 28
N-(3-trifluoromethyl)-4-methyl-3-AB (I-25)
I-121.30g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the preparation method, with (I-17), obtains off-white color solid phase prod (I-25) 0.79g, and yield is 67.2%, mp:119～121 ℃.
1HNMR(300MHz，CDCl
3)：δ2.12(3H，s，ArCH
3)，5.09(2H，s，ArNH
2)，7.05～7.12(2H，m，ArH)，7.18(1H，s，ArH)，7.41(1H，d，ArH，J＝7.7Hz)，7.57(1H，t，ArH，J＝7.7Hz)，8.04(1H，d，ArH，J＝8.8Hz)，8.24(1H，s，ArH)，10.30(1H，s，CONH).
Embodiment 29
N-(3-chloro-phenyl-)-4-methyl-3-AB (I-26)
I-131.16g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the preparation method, with (I-17), obtains off-white color solid phase prod (I-26) 0.77g, and yield is 74.0%, mp:136～138 ℃.
1HNMR(300MHz，CDCl
3)：δ2.12(3H，s，ArCH
3)，5.08(2H，s，ArNH
2)，7.06～7.16(4H，m，ArH)，?7.35(1H，t，ArH，J=8.0Hz)，7.69(1H，d，ArH，J=8.2Hz)，7.96(1H，s，ArH)，10.15(1H，s，CONH).
Embodiment 30
N-(4-chloro-3-bromophenyl)-4-methyl-3-AB (I-27)
I-141.47g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the preparation method, with (I-17), obtains off-white color solid phase prod (I-27) 1.02g, and yield is 75.4%, mp:188～190 ℃.
1HNMR(300MHz，CDCl
3)：δ2.12(3H，s，ArCH
3)，5.10(2H，brs，ArNH
2)，7.06(2H，s，ArH)，7.15(1H，s，ArH)，7.58(1H，d，ArH，J=8.8Hz)，7.79(1H，dd，ArH，J=8.8Hz)，8.28(1H，s，ArH)，10.23(1H，s，CONH).
Embodiment 31
N=(4-trifluoromethyl)-4-methyl-3-AB (I-28)
I-151.30g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the preparation method, with (I-17), obtains off-white color solid phase prod (I-28) 0.89g, and yield is 74.2%, mp:125～127 ℃.
1HNMR(300MHz，CDCl
3)：δ2.12(3H，s，ArCH
3)，5.10(2H，s，ArNH
2)，7.05～7.11(2H，m，ArH)，7.18(1H，s，ArH)，7.69(2H，d，ArH，J＝8.6Hz)，8.00(2H，d，ArH，J＝8.6Hz)，10.34(1H，s，CONH)。
Embodiment 32
N-(4-chloro-3-trifluoromethyl)-4-fluoro-3-AB (I-29)
I-161.45g (4mmol), iron powder 0.9g (16mmol), NH
4C10.64g (12mmol) and 75% ethanol (100mL), the preparation method, with (I-17), obtains off-white color solid phase prod (I-29) 0.94g, and yield is 72.3%, mp:130～132 ℃.
1HNMR(300MHz，CDCl
3)：δ5.67(2H，s，ArNH
2)，7.18(1H，d，ArH，J=8.1Hz)，7.36～7.40(2H，m，ArH)，7.69(1H，t，ArH，J=8.8Hz)，8.12(1H，d，ArH，J=8.8Hz)，8.34(1H，s，ArH)，10.68(1H，brs，CONH)。
Embodiment 33
N-(3-isopropyl phenyl)-4-chloro-3-AB (I-44)
I-431.27g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the preparation method, with (I-17), obtains off-white color solid phase prod (I-44) 0.78g, and yield is 67.7%, mp:147～148 ℃.MS(LR-ESI)：287.1[M-H]
+。
Embodiment 34 N-(4-chloro-3-trifluoromethyl)-4-methyl-3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino] benzamide (I-30)
Add I-17720mg (2.2mmol), P-2600mg (2mmol) and anhydrous tetrahydro furan (40mL) in the 100mL three-necked bottle, stir, logical N
2Protection, after 10min, drip LiHMDS (1mol/L THF) 10mL, room temperature reaction 2hr under ice bath.Reaction solution is dissolved in 40mL ethyl acetate and 40mL NaHCO
3(10%) in solution, standing, separatory, collected organic layer, water layer, with ethyl acetate extraction 3 times (40mL * 3), merges organic layer and uses the water washing of 40mL saturated common salt, and anhydrous sodium sulfate drying, spend the night, suction filtration, concentrate to obtain (I-30) 0.58g, and yield is 47.9%.Product need not purifying, directly casts single step reaction.
Embodiment 35
N-(3-trifluoromethyl)-4-chloro-3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino] benzamide (I-31)
I-18690mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/L THF) 10mL, preparation method, with (I-30), obtain (I-31) 0.6g, and yield is 50.4%.Product need not purifying, directly casts single step reaction.
Embodiment 36
N-(3-isopropyl phenyl)-4-methyl-3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino] benzamide (I-32)
I-19590mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/LTHF) 10mL, preparation method, with (I-30), obtain (I-32) 0.43g, and yield is 39.4%.Product need not purifying, directly casts single step reaction.
Embodiment 37
N-(4-chloro-3-trifluoromethyl)-4-chloro-3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino] benzamide (I-33)
I-20760mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/LTHF) 10mL, preparation method, with (I-30), obtain (I-33) 0.5lg, and yield is 40.8%.Product need not purifying, directly casts single step reaction.
Embodiment 38
N-(3-cyano-phenyl)-4-methyl-3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino] benzamide (I-34)
I-21550mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/L THF) 10mL, preparation method, with (I-30), obtain (I-34) 0.50g, and yield is 47.2%.Product need not purifying, directly casts single step reaction.
Embodiment 39
N-(3-fluorophenyl)-4-methyl-3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino] benzamide (I-35)
I-22540mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/L THF) 10mL, preparation method, with (I-30), obtain (I-35) 0.48g, and yield is 45.7%.Product need not purifying, directly casts single step reaction.
Embodiment 40
N-(3-methyl-4-chloro-phenyl-)-4-methyl-3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino] benzamide (I-36)
I-23600mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/L THF) 10mL, preparation method, with (I-30), obtain (I-36) 0.56g, and yield is 50.5%.Product need not purifying, directly casts single step reaction.
Embodiment 41
N-(3,4-dichlorophenyl)-4-chloro-3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino] benzamide (I-37)
I-24690mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/L THF) 10mL, preparation method, with (I-30), obtain (I-37) 0.54g, and yield is 45.4%.Product need not purifying, directly casts single step reaction.
Embodiment 42
The N-3-trifluoromethyl)-4-methyl-3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino] benzamide (I-38)
I-25650mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/L THF) 10mL, preparation method, with (I-30), obtain (I-38) 0.5lg, and yield is 44.3%.Product need not purifying, directly casts single step reaction.
Embodiment 43
N-(3-chloro-phenyl-)-4-methyl-3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino] benzamide (I-39)
I-26570mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/L THF) 10mL, preparation method, with (I-30), obtain (I-39) 0.49g, and yield is 49.1%.Product need not purifying, directly casts single step reaction.
Embodiment 44
N-(4-chloro-3-bromophenyl)-4-methyl-3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino] benzamide (I-40)
I-27740mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/L THF) 10mL, preparation method, with (I-30), obtain (I-40) 0.58g, and yield is 47.2%.Product need not purifying, directly casts single step reaction.
Embodiment 45
N-(4-trifluoromethyl)-4-methyl-3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino] benzamide (I-41)
I-28650mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/L THF) 10mL, preparation method, with (I-30), obtain (I-41) 0.52g, and yield is 45.2%.Product need not purifying, directly casts single step reaction.
Embodiment 46
N-(4-chloro-3-trifluoromethyl)-4-fluoro-3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino] benzamide (I-42)
I-29732mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/L THF) 10mL, preparation method, with (I-30), obtain (I-42) 0.55g, and yield is 47.0%.Product need not purifying, directly casts single step reaction.
Embodiment 47
N-(3-isopropyl phenyl)-4-chloro-3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino] benzamide (I-45)
I-44630mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/L THF) 10mL, preparation method, with (I-30), obtain (I-45) 0.46g, and yield is 40.7%.Product need not purifying, directly casts single step reaction.
Embodiment 48
N-(4-chloro-3-trifluoromethyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-1)
Add I-30300mg (0.5mmol) and methyl alcohol 30mL in the 100mL eggplant-shape bottle, slowly drip concentrated hydrochloric acid 2mL (36mmol), room temperature reaction 3h under stirring at room.Use saturated Na
2CO
3Regulate the pH value to 8-9, standing, separatory, collected organic layer, water layer ethyl acetate extraction 3 times (40mL * 3), merge organic layer and use the water washing of 40mL saturated common salt, anhydrous sodium sulfate drying, suction filtration, filtrate concentrates to obtain crude product, (developping agent is ethyl acetate: sherwood oil=1:1) separate to obtain light yellow solid product I-a-1 160mg, yield is 61.2%, m.p.＞300 ℃ to crude product through column chromatography.MS(LR-ESI)：522.0[M-H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ2.54(3H，s，ArCH
3)，7.05～8.40(7H，m，ArH)，8.73(1H，s，ArH)，8.95(1H，s，ArH)，9.10(1H，s，purine-2-H)，9.83(1H，s，purine-8-H)，10.56(1H，s，NH，+D
2Odisappear)，12.45(1H，s，CONH，+D
2Odisappear)，13.86(1H，s，purine-9-H，+D
2Odisappear).IR(KBr，cm
-1)：3186，3092，?2989，2837，1674，1593，1541，1381，924，761.
Embodiment 49
N-(3-trifluoromethyl)-4-chloro-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-2)
I-31298mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the preparation method, with (I-a-1), obtains light yellow solid (I-a-2) 150mg, and yield is 58.9%, m.p.＞300 ℃.MS(LR-ESI)：508.1[M-H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ7.16～8.48(8H，m，ArH)，8.74(1H，s，ArH)，9.14(1H，s，ArH)，9.38(1H，s，purine-2-H)，9.85(1H，s，purine-8-H)，10.61(1H，s，NH，+D
2Odisappear)，13.18(1H，s，CONH，+D
2Odisappear)，13.89(1H，s，purine-9-H，+D
2Odisappear).IR(KBr，cm
-1)：3090，2988，2922，2847，1666，1607，1564，1526，1332，924，793.
Embodiment 50
N-(3-isopropyl phenyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-3)
I-32272mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the preparation method, with (I-a-1), obtains light yellow solid (I-a-3) 130mg, and yield is 56.2%, m.p.＞300 ℃.MS(LR-ESI)：462.2[M-H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ1.22(6H，d，(CH
3)
2CH，J=7.0Hz)，2.53(3H，s，ArCH
3)，2.87(1H，m，(CH
3)
2CH，J=6.6Hz)，6.96～7.68(7H，m，ArH)，8.37(1H，d，ArH，J=4.6Hz)，8.72(1H，s，ArH)，8.88(1H，s，ArH)，9.10(1H，s，purine-2-H)，9.82(1H，s，purine-8-H)，10.07(1H，s，NH，)，12.40(1H，s，CONH)，13.85(1H，s，purine-9-H).IR(KBr，cm
-1)：3082，2959，2918，2849，1626，1587，1568，1530，926，768.
Embodiment 51
N-(4-chloro-3-trifluoromethyl)-4-chloro-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-4)
I-33313mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the preparation method, with (I-a-1), obtains light yellow solid (I-a-4) 160mg, and yield is 58.9%, m.p.＞300 ℃.MS(LR-ESI)：544.1[M+H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ7.17～8.48(7H，m，ArH)，8.74(1H，s，ArH)，9.14(1H，s，ArH)，9.38(1H，s，purine-2-H)，9.86(1H，d，purine-8-H，J=7.3Hz)，10.69(1H，s，NH，)，13.19(1H，s，CONH)，13.89(1H，s，purine-9-H).IR(KBr，cm
-1)：3192，3102，2992，2839，1674，1593，1570，1522，858，768.
Embodiment 52
N-(3-cyano-phenyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-5)
I-34265mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the preparation method, with (I-a-1), obtains light yellow solid (I-a-5) 120mg, and yield is 53.8%, m.p.＞300 ℃.MS(LR-ESI)：445.1[M-H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ2.49(3H，s，ArCH3)，7.05-8.38(8H，m，ArH)，8.73(1H，s，ArH)，8.94(1H，s，ArH)，9.10(1H，s，purine-2-H)，9.84(1H，d，purine-8-H，J＝6.8Hz)，10.47(1H，s，NH)，12.46(1H，s，CONH)，13.86(1H，s，purine-9-H).IR(KBr，cm
-1)：3431，3084，2986，2822，1699，1578，1483，858，791，762.
Embodiment 53
N-(3-fluorophenyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-6)
I-35263mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the preparation method, with (I-a-1), obtains light yellow solid (I-a-6) 110mg, and yield is 50.1%, m.p.＞300 ℃.MS(LR-ESI)：440.2[M+H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ2.54(3H，s，ArCH
3)，6.89～8.39(8H，m，ArH)，8.73(1H，s，ArH)，8.91(1H，s，ArH)，9.10(1H，s，purine-2-H)，9.83(1H，s，purine-8-H)，10.35(1H，s，NH，)，12.43(1H，s，CONH)，13.85(1H，s，purine-9-H).IR(KBr，cm
-1)：3433，3098，2990，2847，1674，1599，1570，1530，860，760.
Embodiment 54
N-(3-methyl-4-chloro-phenyl-)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-7)
I-36278mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the preparation method, with (I-a-1), obtains light yellow solid (I-a-7) 130mg, and yield is 55.4%, m.p.＞300 ℃.MS(LR-ESI)：468.3[M-H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ2.33(3H，s，ArCH
3)，2.53(3H，s，ArCH
3)，7.04～8.38(7H，m，ArH)，8.73(1H，s，ArH)，8.90(1H，s，ArH)，9.10(1H，s，purine-2-H)，9.82(1H，s，purine-8-H)，10.20(1H，s，NH，)，12.42(1H，s，CONH)，13.86(1H，s，purine-9-H).IR(KBr，cm
-1)：3431，3341，3092，2972，2824，1657，1572，1535，827，764。
Embodiment 55
N-(3,4-dichlorophenyl)-4-chloro-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-8)
I-37298mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the preparation method, with (I-a-1), obtains light yellow solid (I-a-8) 150mg, and yield is 58.9%, m.p.＞300 ℃.MS(LR-ESI)：508.2[M-H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ7.16～8.47(7H，m，ArH)，8.75(1H，s，ArH)，9.13(1H，s，ArH)，9.36(1H，s，purine-2-H)，9.85(1H，s，purine-8-H)，10.56(1H，s，NH，)，12.18(1H，s，CONH)，13.89(1H，s，purine-9-H).IR(KBr，cm
-1)：3335，3092，2986，2824，1659，1578，1522，827，762.
Embodiment 56
N-(3-trifluoromethyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-9)
I-38289mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the preparation method, with (I-a-1), obtains light yellow solid (I-a-9) 140mg, and yield is 57.3%, m.p.＞300 ℃.MS(LR-ESI)：490.2[M+H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ2.54(3H，s，ArCH
3)，7.05～8.39(8H，m，ArH)，8.73(1H，s，ArH)，8.94(1H，s，ArH)，9.11(1H，s，purine-2-H)，9.82(1H，s，purine-8-H)，10.47(1H，s，NH，)，12.44(1H，s，CONH)，13.85(1H，s，purine-9-H).IR(KBr，cm
-1)：3428，3088，2988，2826，1670，1576，1483，799，758，706.
Embodiment 57
N-(3-chloro-phenyl-)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-10)
I-39270mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the preparation method, with (I-a-1), obtains light yellow solid (I-a-10) 130mg, and yield is 57.1%, m.p.＞300 ℃.MS(LR-ESI)：456.1[M+H]
+1H-NMR[300MHz，DMSO-d
6]：δ2.53(3H，s，ArCH
3)，7.05～8.38(8H，m，ArH)，8.73(1H，s，ArH)，8.91(1H，s，ArH)，9.10(1H，s，purine-2-H)，9.83(1H，s，purine-8-H)，10.32(1H，s，NH，)，12.43(1H，s，CONH)，13.85(1H，s，purine-9-H)。IR(KBr，cm
-1)：3430，3088，2988，2834，1667，1595，1526，858，768.
Embodiment 58
N-(4-chloro-3-bromophenyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-11)
I-40308mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the preparation method, with (I-a-1), obtains light yellow solid (I-a-11) 160mg, and yield is 60.0%, m.p.＞300 ℃.MS(LR-ESI)：532.0[M-H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ2.53(3H，s，ArCH
3)，7.05～8.38(10H，m，ArH)，8.73(1H，s，ArH)，8.92(1H，s，ArH)，9.10(1H，s，purine-2-H)，9.83(1H，s，purine-8-H)，10.40(1H，s，NH)，12.44(1H，s，CONH)，13.85(1H，s，purine-9-H).IR(KBr，cm
-1)：3343，3088，2969，2828，1659，1580，1528，866，800，762.
Embodiment 59
N-(4-trifluoromethyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-12)
I-41289mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the preparation method, with (I-a-1), obtains light yellow solid (I-a-12) 140mg, and yield is 57.3%, m.p.＞300 ℃.MS(LR-ESI)：490.2[M+H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ2.54(3H，s，ArCH
3)，7.05～8.39(8H，m，ArH)，8.73(1H，s，ArH)，8.94(1H，s，ArH)，9.11(1H，s，purine-2-H)，9.83(1H，s，purine-8-H)，10.50(1H，s，NH，)，12.45(1H，s，CONH)，13.86(1H，s，purine-9-H).IR(KBr，cm
-1)：3437，3111，2992，2839，1595，1570，1528，845，766.
Embodiment 60
N-(4-chloro-3-trifluoromethyl)-4-fluoro-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-13)
I-42306mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the preparation method, with (I-a-1), obtains light yellow solid (I-a-13) 157mg, and yield is 59.5%, m.p.＞300 ℃.MS(LR-ESI)：527.1[M+H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ7.24～8.53(7H，m，ArH)，8.80(1H，s，ArH)，9.19(1H，s，ArH)，9.43(1H，s，purine-2-H)，9.90(1H，d，purine-8-H，J=7.2Hz)，10.72(1H，s，NH)，13.34(1H，s，CONH)，13.89(1H，s，purine-9-H).IR(KBr，cm
-1)：3192，3102，2992，2839，1674，1593，1570，1522，858，768.
Embodiment 61
N-(3-isopropyl phenyl)-4-chloro-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-14)
I-45283mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the preparation method, with (I-a-1), obtains light yellow solid (I-a-14) 140mg, and yield is 58.0%, m.p.＞300 ℃.MS(LR-ESI)：484.1[M+H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ1.22(6H，d，(CH
3)
2CH，J=7.0Hz)，2.88(1H，m，(CH
3)
2CH，J=6.8Hz)，6.98～8.48(8H，m，ArH)，8.75(1H，s，ArH)，9.14(1H，s，ArH)，9.32(1H，s，purine-2-H)，9.86(1H，d，purine-8-H，J=7.5Hz)，10.23(1H，s，NH)，13.15(1H，s，CONH)，13.89(1H，s，purine-9-H)。IR(KBr，cm
-1)：3192，3088，2963，2868，2835，1653，1603，1576，1526，762，702.
Embodiment 62
3-(dimethylamino) Benzoyl chloride (I-46)
Add 3-(dimethylamino) phenylformic acid 661mg (4mmol), sulfur oxychloride 15mL and 2 DMFs (DMF) in the 100mL eggplant-shape bottle, stir lower back flow reaction 5hr.The same I-1 of preparation method.Cooling, remove sulfur oxychloride under reduced pressure and obtain light yellow oil (I-46) 680mg, yield 92.6%.
Embodiment 63
3-methoxy benzoyl chloride (I-47)
3-methoxybenzoic acid 605mg (4mmol), sulfur oxychloride 15mL and 2 DMFs (DMF), the same I-1 of preparation method, obtain light yellow oil (I-47) 585mg, yield 89.7%.
Embodiment 64
3-chloro-benzoyl chloride (I-48)
3-chloro-benzoic acid 626mg (4mmol), sulfur oxychloride 15mL and 2 N, N-METHYLFORMAMIDE (DMF), the same I-1 of preparation method, obtain light yellow oil (I-48) 610mg, yield 87.1%.
Embodiment 65
3-trifluoromethyl benzoyl chloride (I-49)
3-trifluoromethylbenzoic acid 760mg (4mmol), sulfur oxychloride 15mL and 2 DMFs (DMF), the same I-1 of preparation method, obtain light yellow oil (I-49) 735mg, yield 88.2%.
Embodiment 66
4-chloro-3-trifluoromethyl benzoyl chloride (I-50)
4-chloro-3-trifluoromethylbenzoic acid 898mg (4mmol), sulfur oxychloride 15mL and 2 DMFs (DMF), the same I-1 of preparation method, obtain light yellow oil (I-50) 810mg, yield 97.1%.
Embodiment 67
3-cyano-benzoyl chloride (I-51)
3-cyanobenzoic acid 589mg (4mmol), sulfur oxychloride 15mL and 2 DMFs (DMF), the same I-1 of preparation method, obtain light yellow oil (I-51) 588mg, yield 94.5%.
Embodiment 68
3-(dimethylamino)-N-(4-methyl-3-nitro phenyl) benzamide (I-52)
4-methyl-3-nitro aniline 608mg (4mmol), 3-(dimethylamino) Benzoyl chloride (I-46) 680mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-3), obtain yellow solid (I-52) 0.96g, yield 80.7%.Product need not purifying, directly casts single step reaction.
Embodiment 69
3-methoxyl group-N-(4-methyl-3-nitro phenyl) benzamide (I-53)
4-methyl-3-nitro aniline 608mg (4mmol), 3-methoxy benzoyl chloride (I-47) 585mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-3), obtain yellow solid (I-53) 0.94g, yield 82.6%.Product need not purifying, directly casts single step reaction.
Embodiment 70
3-chloro-N-(4-methyl-3-nitro phenyl) benzamide (I-54)
4-methyl-3-nitro aniline 608mg (4mmol), 3-chloro-benzoyl chloride (I-48) 610mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-3), obtain yellow solid (I-54) 0.95g, yield 81.6%.Product need not purifying, directly casts single step reaction.
Embodiment 71
3-trifluoromethyl-N-(4-methyl-3-nitro phenyl) benzamide (I-55)
4-methyl-3-nitro aniline 608mg (4mmol), 3-trifluoromethyl benzoyl chloride (I-49) 735mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-3), obtain yellow solid (I-55) 1.07g, yield 82.6%.Product need not purifying, directly casts single step reaction.
Embodiment 72
4-chloro-3-trifluoromethyl-N-(4-methyl-3-nitro phenyl) benzamide (I-56)
4-methyl-3-nitro aniline 608mg (4mmol), 4-chloro-3-trifluoromethyl benzoyl chloride (I-50) 810mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-3), obtain yellow solid (I-56) 1.24g, yield 86.7%.Product need not purifying, directly casts single step reaction.
Embodiment 73
4-chloro-3-trifluoromethyl-N-(3-nitrophenyl) benzamide (I-57)
3-N-methyl-p-nitroaniline 553mg (4mmol), 4-chloro-3-trifluoromethyl benzoyl chloride (I-50) 810mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-3), obtain yellow solid (I-57) 1.22g, yield 88.4%.Product need not purifying, directly casts single step reaction.
Embodiment 74
3-cyano group-N-(4-methyl-3-nitro phenyl) benzamide (I-58)
4-methyl-3-nitro aniline 608mg (4mmol), 3-cyano-benzoyl chloride (I-51) 588mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-3), obtain yellow solid (I-58) 0.95g, yield 84.1%.Product need not purifying, directly casts single step reaction.
Embodiment 75
4-chloro-3-trifluoromethyl-N-(4-fluoro-3-nitrophenyl) benzamide (I-59)
4-fluoro-3-N-methyl-p-nitroaniline 624mg (4mmol), 4-chloro-3-trifluoromethyl benzoyl chloride (I-50) 810mg, anhydrous triethylamine 1.0g (10mmol) and methylene dichloride 40mL, the preparation method is with (I-3), obtain yellow solid (I-59) 1.27g, yield 87.6%.Product need not purifying, directly casts single step reaction.
Embodiment 76
3-(dimethylamino)-N-(4-methyl-3-aminophenyl) benzamide (I-60)
I-521.20g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the same I-17 of preparation method, obtain off-white color solid phase prod I-600.88g, and yield is 81.3%.
Embodiment 77
3-methoxyl group-N-(4-methyl-3-aminophenyl) benzamide (I-61)
I-531.15g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the same I-17 of preparation method, obtain off-white color solid phase prod I-610.82g, and yield is 80.1%.
1HNMR(300MHz，CDCl
3)：δ2.15(3H，s，ArCH
3)，3.65(2H，brs，ArNH
2)，3.87(3H，s，OCH
3)，6.70～6.74(1H，dd，ArH，J=2.2Hz，J=7.9Hz)，7.02～6.99(1H，d，ArH，J=8.0Hz)，7.04～7.09(1H，m，ArH)，7.29(1H，d，ArH，J=2.0Hz)，7.36～7.40(2H，m，ArH，J=8.2Hz)，7.41～7.43(1H，m，ArH)，7.67(1H，s，CONH).
Embodiment 78
3-chloro-N-(4-methyl-3-aminophenyl) benzamide (I-62)
I-541.16g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the same I-17 of preparation method, obtain off-white color solid phase prod I-620.84g, and yield is 81.0%.
Embodiment 79
3-trifluoromethyl-N-(4-methyl-3-aminophenyl) benzamide (I-63)
I-551.30g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the same I-17 of preparation method, obtain off-white color solid phase prod I-630.97g, and yield is 83.4%.
1HNMR(300MHz，CDCl
3)：δ2.03(3H，s，ArCH
3)，4.87(2H，s，ArNH
2)，6.80～6.89(2H，m，ArH)，7.10(1H，d，ArH，J=2.0Hz)，7.73～7.78(1H，t，ArH，J＝7.68Hz)，7.92～7.95(2H，d，ArH，J=7.9Hz)，8.21～8.24(2H，d，ArH，J=9.5Hz)，10.13(1H，s，CONH).
Embodiment 80
4-chloro-3-trifluoromethyl-N-(4-methyl-3-aminophenyl) benzamide (I-64)
I-561.43g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the same I-17 of preparation method, obtain off-white color solid phase prod I-641.12g, and yield is 84.8%.
Embodiment 81
4-chloro-3-trifluoromethyl-N-(3-aminophenyl) benzamide (I-65)
I-571.38g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the same I-17 of preparation method, obtain off-white color solid phase prod I-651.12g, and yield is 84.8%.
Embodiment 82
3-cyano group-N-(4-methyl-3-aminophenyl) benzamide (I-66)
I-581.13g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the same I-17 of preparation method, obtain off-white color solid phase prod I-661.04g, and yield is 82.5%.
Embodiment 83
4-chloro-3-trifluoromethyl-N-(4-fluoro-3-aminophenyl) benzamide (I-67)
I-591.45g (4mmol), iron powder 0.9g (16mmol), NH
4Cl0.64g (12mmol) and 75% ethanol (100mL), the same I-17 of preparation method, obtain off-white color solid phase prod I-671.09g, and yield is 82.0%.
Embodiment 84
N-[3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino]-the 4-aminomethyl phenyl]-3-(dimethylamino) benzamide (I-68)
I-60590mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/LTHF) 10mL, the preparation method, with (I-30), obtains I-680.51g, and yield is 46.8%.Product need not purifying, directly casts single step reaction.
Embodiment 85
N-[3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino]-the 4-aminomethyl phenyl]-3-methoxy benzamide (I-69)
I-61563mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/LTHF) 10mL, the preparation method, with (I-30), obtains I-690.51g, and yield is 47.5%.Product need not purifying, directly casts single step reaction.
Embodiment 86
N-[3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-[pyridine is amino]-the 4-aminomethyl phenyl]-3-chlorobenzamide (I-70)
I-62573mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/LTHF) 10mL, the preparation method, with (I-30), obtains I-700.53g, and yield is 48.8%.Product need not purifying, directly casts single step reaction.
Embodiment 87
N-[3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino]-the 4-aminomethyl phenyl]-3-trifluoromethyl benzamide (I-71)
I-63647mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/LTHF) 10mL, the preparation method, with (I-30), obtains I-710.52g, and yield is 45.5%.Product need not purifying, directly casts single step reaction.
Embodiment 88
N-[3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino]-the 4-aminomethyl phenyl]-4-chloro-3-trifluoromethyl benzamide (I-72)
I-64723mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/LTHF) 10mL, the preparation method, with (I-30), obtains I-720.63g, and yield is 47.0%.Product need not purifying, directly casts single step reaction.
Embodiment 89
N-[3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino] phenyl]-4-chloro-3-trifluoromethyl benzamide (I-73)
I-65692mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/LTHF) 10mL, the preparation method, with (I-30), obtains I-730.60g, and yield is 45.8%.Product need not purifying, directly casts single step reaction.
Embodiment 90
N-[3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino]-the 4-aminomethyl phenyl]-3-cyano group benzamide (I-74)
I-66553mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/LTHF) 10mL, the preparation method, with (I-30), obtains I-740.43g, and yield is 43.9%.Product need not purifying, directly casts single step reaction.
Embodiment 91
N-[3-[3-[9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl]-the 2-pyridine is amino]-the 4-fluorophenyl]-4-chloro-3-trifluoromethyl benzamide (I-75)
I-67732mg (2.2mmol), P-2600mg (2mmol), anhydrous tetrahydro furan (40mL) and LiHMDS (1mol/LTHF) 10mL, the preparation method, with (I-30), obtains I-750.69g, and yield is 51.1%.Product need not purifying, directly casts single step reaction.
Embodiment 92
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-3-(dimethylamino) benzamide (I-b-1)
I-68274mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the same I-a-1 of preparation method, light yellow solid (I-b-1) 143mg, yield is 61.7%, m.p.＞300 ℃.MS(LR-ESI)：464.1[M+H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ2.42(3H，s，ArCH
3)，3.00(6H，s，(CH
3)
2N)，6.90～6.93(4H，m，ArH)，7.00～7.04(1H，m，ArH)，7.20～7.33(4H，m，ArH)，7.41～7.45(1H，dd，ArH，J＝2.0Hz，J＝8.1Hz)，8.33～8.35(1H，dd，ArH，J=2.0Hz，J＝4.7Hz)，8.61(1H，d，ArH，J=2.2Hz)，8.71(1H，s，ArH)，9.08(1H，s，ArH)，9.80～9.83(1H，dd，purine-8-H，J＝2.0Hz，J＝7.9Hz)，10.05(1H，s，purine-2-H)，12.26(1H，s，CONH)，13.85(1H，s，purine-9-H).
Embodiment 93
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-3-methoxy benzamide (I-b-2)
I-69267mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the same I-a-1 of preparation method, obtain light yellow solid (I-b-2) 140mg, and yield is 62.0%, m.p.＞300 ℃.MS(LR-ESI)：451.1[M+H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ2.43(3H，s，ArCH
3)，3.81(3H，s，CH
3O)，7.00～7.05(1H，m，ArH)，7.13～7.16(1H，m，ArH)，7.21～7.23(1H，d，ArH，J＝8.6Hz)，7.40～7.57(4H，m，ArH)，8.33～8.36(1H，dd，ArH，J=2.0Hz，J＝4.7Hz)，8.63～8.64(1H，d，ArH，J＝2.2Hz)，8.71(1H，s，ArH)，9.08(1H，s，ArH)，9.80(1H，s，purine-8-H)，10.02(1H，s，purine-2-H)，12.27(1H，s，CONH)，13.83(1H，s，purine-9-H).
Embodiment 94
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-3-chlorobenzamide (I-b-3)
I-70270mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the same I-a-1 of preparation method, obtain light yellow solid (I-b-3) 137mg, and yield is 62.0%, m.p.＞300 ℃.MS(LR-ESI)：455.1[M+H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ2.43(3H，s，ArCH
3)，7.02～7.06(1H，m，ArH)，7.22～7.25(1H，d，ArH，J=8.4Hz)，7.45～7.67(3H，m，ArH)，7.92～7.95(1H，d，ArH，J＝7.7Hz)，8.02～8.03(4H，m，ArH)，8.35～8.37(1H，m，ArH)，8.66(1H，d，ArH，J＝2.2Hz)，8.72(1H，s，ArH)，9.09(1H，s，ArH)，9.82(1H，s，purine-8-H)，10.30(1H，s，purine-2-H)，12.30(1H，s，CONH)，13.84(1H，s，purine-9-H).
Embodiment 95
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-3-trifluoromethyl benzamide (I-b-4)
I-71287mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the same I-a-1 of preparation method, obtain light yellow solid (I-b-4) 151mg, and yield is 61.9%, m.p.＞300 ℃.MS(LR-ESI)：455.1[M+H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ2.44(3H，s，ArCH
3)，7.01～7.05(1H，m，ArH)，7.23～7.26(1H，d，ArH，J＝8.2Hz)，?7.46～7.48(1H，d，ArH，J＝8.0Hz)，7.75～7.86(1H，t，ArH，J＝7.9Hz)，7.94～7.97(1H，d，ArH，J＝7.9Hz)，8.27～8.36(3H，m，ArH)，8.67(1H，m，ArH)，8.71(1H，s，ArH)，9.08(1H，s，ArH)，9.79(1H，s，purine-8-H)，10.42(1H，s，purine-2-H)，12.29(1H，s，CONH)，13.83(1H，s，purine-9-H).
Embodiment 96
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-4-chloro-3-trifluoromethyl benzamide (I-b-5)
I-72304mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the same I-a-1 of preparation method, light yellow solid (I-b-5) 165mg, yield is 63.0%, m.p.＞300 ℃.MS(LR-ESI)：523.1[M+H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ2.45(3H，s，ArCH
3)，7.05～7.09(1H，dd，ArH，J＝4.6Hz，7.9Hz)，7.43～7.46(1H，d，ArH，J＝8.9Hz)，7.59～7.61(1H，d，ArH，J＝8.9Hz)，7.70～7.72(1H，d，ArH，J＝8.9Hz)，8.11～8.15(1H，dd，ArH，J＝2.4Hz，9.0Hz)，8.37～8.40(2H，m，ArH)，8.73(1H，m，ArH)，8.95(1H，s，ArH)，9.11(1H，s，ArH)，9.85(1H，s，purine-8-H)，10.56(1H，s，purine-2-H)，12.45(1H，s，CONH)，13.86(1H，s，purine-9-H).
Embodiment 97
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino] phenyl]-4-chloro-3-trifluoromethyl benzamide (I-b-6)
I-73297mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the same I-a-1 of preparation method, obtain light yellow solid (I-b-6) 155mg, and yield is 60
-8%, m.p.＞300 ℃.MS(LR-ESI)：509.1[M+H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ7.01～7.05(1H，dd，ArH，J＝4.7Hz，J＝7.9Hz)，7.29～7.34(1H，m，ArH)，7.45～7.47(1H，d，ArH，J＝7.9Hz)，7.55～7.57(1H，d，ArH，J＝7.9Hz)，7.90～7.93(1H，d，ArH，J＝8.6Hz)，8.24(1H，s，ArH)，8.26～8.29(1H，dd，ArH，J＝2.0Hz，8.4Hz)，8.35～8.38(1H，dd，ArH，J＝2.1Hz，J=4.8Hz)，8.40(1H，m，ArH)，8.70(1H，s，ArH)，9.09(1H，s，ArH)，9.77(1H，s，purine-8-H)，10.51(1H，s，purine-2-H)，12.55(1H，s，CONH)，13.83(1H，s，purine-9-H).
Embodiment 98
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-3-cyano group benzamide (I-b-7)
I-74265mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the same I-a-1 of preparation method, obtain light yellow solid (I-b-7) 137mg, and yield is 61.4%, m.p.＞300 ℃.MS(LR-ESI)：446.2[M+H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ2.50(3H，s，ArCH
3)，7.02～7.06(1H，m，ArH)，7.23～7.26(1H，d，ArH，J＝8.4Hz)，7.47～7.50(1H，dd，ArH，J＝2.1Hz，8.1Hz)，7.72～7.77(1H，t，ArH，J＝10.2Hz)，8.04～8.07(1H，m，?ArH)，8.26～8.28(1H，m，ArH)，8.35～8.37(1H，dd，ArH，J＝2.1Hz，4.8Hz)，8.42～8.43(1H，d，ArH，J＝1.5Hz)，8.68～8.72(2H，m，ArH)，9.07～9.09(1H，d，ArH，J＝4.8Hz)，9.82(1H，s，purine-8-H)，10.38(1H，s，purine-2-H)，12.32(1H，s，CONH)，13.85(1H，s，purine-9-H).
Embodiment 99
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-fluorophenyl]-4-chloro-3-trifluoromethyl benzamide (I-b-8)
I-75306mg (0.5mmol), methyl alcohol 30mL and concentrated hydrochloric acid 2mL (36mmol), the same I-a-1 of preparation method, obtain light yellow solid (I-b-8) 151mg, and yield is 57.2%, m.p.＞300 ℃.MS(LR-ESI)：527.1[M+H]
+。
1H-NMR[300MHz，DMSO-d
6]：δ7.01～7.05(1H，m，ArH)，7.29～7.32(1H，d，ArH，J＝8.2Hz)，7.46～7.48(1H，d，ArH，J=8.0Hz)，7.55～7.57(1H，d，ArH，J＝7.9Hz)，7.90～7.93(1H，d，ArH，J＝8.6Hz)，8.24(1H，s，ArH)，8.26～8.29(1H，dd，ArH，J＝2.0Hz，8.4Hz)，8.35～8.38(1H，dd，ArH，J-＝2.1Hz，J＝4.8Hz)，8.72(1H，s，ArH)，8.92～8.93(1H，d，ArH，J＝1.8Hz)，9.10(1H，s，ArH)，9.83(1H，s，purine-8-H)，10.40(1H，s，purine-2-H)，12.44(1H，s，CONH)，13.85(1H，s，purine-9-H)。
Claims (8)
1. the compound of general formula (I) or its pharmacy acceptable salt:
R wherein
1Be selected from hydrogen, hydroxyl, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
6Haloalkyl, C
1-C
6Alkylamino, C
1-C
6One or more in dialkyl amido or cyano group;
R
2Be selected from hydrogen, hydroxyl, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group or C
1-C
6One or more in haloalkyl;
X represents the connexons such as CONH, NHCO or NHCONH;
Y represents the connexons such as NH, O, S, CO.
2. according to claim 1 general formula (I) compound or its pharmacy acceptable salt, wherein R
1Be selected from one or more in hydrogen, fluorine, chlorine, bromine, trifluoromethyl, sec.-propyl, methyl, methoxyl group, dimethylamino, cyano group; R wherein
2Be selected from one or more in hydrogen, methyl, chlorine, fluorine.
3. according to claim 1 general formula (I) compound or its pharmacy acceptable salt, wherein X represents NHCO, CONH; Y represents NH.
4. according to claim 1 general formula (I) compound or its pharmacy acceptable salt is wherein following arbitrary compound or its pharmacy acceptable salt:
N-(4-chloro-3-trifluoromethyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-1),
N-(3-trifluoromethyl)-4-chloro-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-2),
N-(3-isopropyl phenyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-3),
N-(4-chloro-3-trifluoromethyl)-4-chloro-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-4),
N-(3-cyano-phenyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-5),
N-(3-fluorophenyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-6),
N-(3-methyl-4-chloro-phenyl-)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-7),
N-(3,4-dichlorophenyl)-4-chloro-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-8),
N-(3-trifluoromethyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-9),
N-(3-chloro-phenyl-)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-10),
N-(4-chloro-3-bromophenyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-11),
N-(4-trifluoromethyl)-4-methyl-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-12),
N-(4-chloro-3-trifluoromethyl)-4-fluoro-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-13),
N-(3-isopropyl phenyl)-4-chloro-3-[3-(9H-purine-6-yl)-2-pyridine is amino] benzamide (I-a-14),
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-3-(dimethylamino) benzamide (I-b-1),
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-3-methoxy benzamide (I-b-2),
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-3-chlorobenzamide (I-b-3),
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-3-trifluoromethyl benzamide (I-b-4),
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-4-chloro-3-trifluoromethyl benzamide (I-b-5),
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino] phenyl]-4-chloro-3-trifluoromethyl benzamide (I-b-6),
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-aminomethyl phenyl]-3-cyano group benzamide (I-b-7),
N-[3-[3-(9H-purine-6-yl)-2-pyridine is amino]-the 4-fluorophenyl]-4-chloro-3-trifluoromethyl benzamide (I-b-8).
5. according to claim 1 general formula (I) compound or its pharmacy acceptable salt, wherein pharmacy acceptable salt comprises the acid salt that general formula (I) compound and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, tosic acid, naphthene sulfonic acid, citric acid, tartrate, lactic acid, pyruvic acid, acetic acid, toxilic acid or Phenylsulfonic acid, succsinic acid, fumaric acid, Whitfield's ointment, phenylacetic acid or tussol.The acid salt that comprises in addition mineral alkali, as: basic metal positively charged ion, alkaline earth metal cation, ammonium cation salt contained.
6., according to a kind of pharmaceutical composition, wherein contain general formula (I) compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.
7. according to claim 1 the compound of general formula (I) or the purposes of its pharmacy acceptable salt in the medicine for the preparation of prevention or the treatment disease relevant with the Raf kinase inhibitor.
8. according to claim 7 purposes, wherein the disease relevant with the Raf kinase inhibitor is melanoma, liver cancer, kidney, acute leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome, the esophageal carcinoma, cancer of the stomach or mesothelioma.
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| CN106146503A (en) * | 2015-04-16 | 2016-11-23 | 上海医药工业研究院 | A kind of preparation method of Idelalisib |
| CN106279171A (en) * | 2015-06-09 | 2017-01-04 | 南京安源生物医药科技有限公司 | A kind of preparation method of Idelalisib |
| WO2017135589A1 (en) * | 2016-02-03 | 2017-08-10 | 삼진제약주식회사 | Pyridine derivative inhibiting raf kinase and vascular endothelial growth factor receptor, method for preparing same, pharmaceutical composition containing same, and use thereof |
| CN108794326A (en) * | 2018-08-03 | 2018-11-13 | 上海华堇生物技术有限责任公司 | The preparation method of 3- methoxy benzoyl chlorides |
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| CN106146503A (en) * | 2015-04-16 | 2016-11-23 | 上海医药工业研究院 | A kind of preparation method of Idelalisib |
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| CN109071543B (en) * | 2016-02-03 | 2021-07-16 | 三进制药株式会社 | Pyridine derivatives inhibiting RAF kinase and vascular endothelial growth factor receptor, process for their preparation, pharmaceutical compositions containing them and their use |
| CN109071534A (en) * | 2016-04-15 | 2018-12-21 | 艾伯维公司 | Bu Luomo structural domain inhibitor |
| CN109071534B (en) * | 2016-04-15 | 2021-11-23 | 艾伯维公司 | Bromodomain inhibitors |
| CN108794326A (en) * | 2018-08-03 | 2018-11-13 | 上海华堇生物技术有限责任公司 | The preparation method of 3- methoxy benzoyl chlorides |
| WO2022178256A1 (en) * | 2021-02-18 | 2022-08-25 | Black Diamond Therapeutics, Inc. | 6-substituted-9h-purine derivatives and related uses |
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