Research Article Design, Synthesis, and

Hindawi Publishing CorporationJournal of ChemistryVolume 2013 Article ID 107302 9 pageshttpdxdoiorg1011552013107302

Research ArticleDesign Synthesis and Acetylcholinesterase InhibitionAssay of Novel 9-(1-(Substituted-benzyl)piperidin-4-yl)-2-chloro-9H-purin-6-amine Derivatives

Dongwei Kang1 Yursquoning Song2 Peng Zhan1 Qingzhu Zhang2 and Xinyong Liu1

1 Department ofMedicinal Chemistry Key Laboratory of Chemical Biology (Ministry of Education) School of Pharmaceutical SciencesShandong University 44 West Culture Road Jinan Shandong 250012 China

2Department of Pharmacology Key Laboratory of Chemical Biology (Ministry of Education) School of Pharmaceutical SciencesShandong University 44 West Culture Road Jinan Shandong 250012 China

Correspondence should be addressed to Peng Zhan zhanpeng1982163com and Xinyong Liu xinyongllab163com

Received 22 May 2013 Revised 9 August 2013 Accepted 13 August 2013

Academic Editor Marco Radi

Copyright copy 2013 Dongwei Kang et alThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

A new series of 9-(1-(substituted-benzyl)piperidin-4-yl)-2-chloro-9H-purin-6-amine derivatives were designed synthesized andcharacterized on the basis of 1H-NMR 13C-NMR and mass spectra The newly synthesized compounds were evaluated for theinhibition activity against acetylcholinesterase (AChE) Biological results revealed that four compounds among them showedmoderate activities against AChEwith inhibitory percentagemore than 10 at 100 120583MFurther pharmacology investigation towardsother pathological routes in AD is currently underway

1 Introduction

Since a cholinergic hypothesis has been postulated as a crucialelement in Alzheimerrsquos disease (AD) symptoms etiologycatalytic acetylcholinesterase (AChE) inhibitors have con-stituted until today the main drugs used against AD [1]Reversible inhibition of brain AChE by anti-AD drugs suchas tacrine [2] donepezil (Figure 1) [3] and huperzine [4]increases theAChE levels and improves neurotransmission incholinergic synapses [5] Since AChE plays a proaggregating(noncatalytic) role to accelerating 120573-amyloid peptide (A120573)aggregation and deposition into the fibrils inhibition ofAChE is still the most successful therapeutic strategy forthe symptomatic treatment of AD and its progression [6]The search for novel AChE inhibitors with improved bio-logical profiles continues to be of great interest to medicinalchemists

In the past few years a group of 24-disubstituted pyrim-idine derivatives were reported as cholinesterase inhibitorsand agents targeting multiple pathological routes in ADParticularly compound PY-1 was identified as the lead

candidate with a dual ChE (AChE IC50

= 99 120583M BuChEIC50

= 114 120583M) A120573-aggregation (AChE-induced = 593self-induced = 174 at 100 120583M) and BACE-1 (34 inhi-bition at 10 120583M) inhibitory profile along with good cellviability (810 neuroblastoma cell viability at 40120583M) [7ndash10] Meanwhile o-fluorophenyl methyl derived triazolePU2012051296 effectively suppressed A120573-induced neuro-toxicity in hippocampal slice cultures Importantly the neu-roprotective effect of compound PU2012051296 is compara-ble to those of flavopiridol and roscovitine state of the artpharmaceuticals [11]

The refinement of the central core in bioactive moleculescombined with introducing privileged substituents is a com-mon practice in medicinal chemistry to find proprietary andnovel hits Based on the considerable similarities of theselead compounds a fragment-based design was employedto identify alternative chemotypes (Figure 2) Meanwhilein current drug research field substituted purines haveattracted considerable attention from the medicinal chemistsin recent years owing to the high number of positive hitsencountered with this heterocycle In this paper a novel

2 Journal of Chemistry

N

N

NS

N

N NN

N NN

N

N

NH

NHNH NH NH

NH

OO

N

PY-1

PY-2 PY-3 PY-4

N

NCl N

N

N NN

F

O

O

N

O

Donepezil

IC50 = 033120583M (AChE)230120583M (BuChE)

IC50 = 55 120583M (AChE) PU201205129659 inhibition of hAChE-induced aggregationof A120573(1ndash40) fibrils (at 100120583M)

AChE IC50 = 99 120583MBuChE IC50 = 114 120583M)A120573-aggregation (AChE-induced = 593self-induced = 174 at 100120583M)BACE-1 (34 inhibition at 10120583M)

Figure 1 Structure of donepezil 24-disubstituted pyrimidine AChE inhibitors and purine derivative PU2012051296

N

N N

N

NH

Cl

N N

N

F

N

N N

N

NH

Cl

Ar

N

Lead compound PU2012051296 Newly designed derivatives

R1

Figure 2The general structure formula of newly designed 9-(1-(substituted-benzyl)piperidin-4-yl)-2-chloro-9H- purin-6-amine derivatives

series of 9-(1-(substituted-benzyl)piperidin-4-yl)-2-chloro-9H-purin-6-amine derivatives were designed synthesizedand evaluated for the inhibition activity against AChE

2 Results and Discussion

21 Chemistry The synthetic route of the target compoundsis outlined in Scheme 1 whichwas started from commerciallyavailable materials and completed using well establishedmethods Initially N-(34-dimethoxybenzyl)-2-chloro-9H-purin-6-amine (2a) and N-(benzo[d][13]dioxol-5-ylme-thyl)-2-chloro-9H-purin-6-amine (2b) intermediates weresynthesized from the starting material 26-dichloro-9H-purine (1) by a nucleophilic aromatic substitution reaction atthe C-6 position using either (34-dimethoxyphenyl) meth-anamine or benzo[d][13]dioxol-5-ylmethanamine in thepresence of triethylamine (TEA) The reaction was run int-BuOH at 60∘C for 30min Intermediates 6 and 7 wereobtained in good yields ranging (905 and 897)

(Scheme 1) [7ndash10] In the meantime tert-butyl 4-hydroxypi-peridine-1-carboxylate (4) was synthesized according to thereported procedure [12] Then treatment of intermediate 4with compound 2a or 2b in the presence of NaH affordedtert-butyl 4-(6-(34-dimethoxybenzylamino)-2-chloro-9H-purin-9-yl)piperidine-1-carboxylate (5a) or tert-butyl4-(6-(benzo[d][13]dioxol-5-ylmethylamino)-2-chloro-9H-purin-9-yl)piperidine-1-carboxylate (5b) respectively Thedeprotection of the tert-butoxycarbonyl (t-Boc) group of 5aand 5b was accomplished using trifluoroacetic acid (TFA) indichloromethane (DCM) to yield N-(34-dimethoxybenzyl)-2-chloro-9-(piperidin-4-yl)-9H-purin-6-amine (6a) and N-(benzo[d][13]dioxol-5-ylmethyl)-2-chloro-9-(piperidin-4-yl)-9H-purin-6-amine (6b) respectively in good yield (91and 87) In the last step the alkylation reaction of piperidineat NH position with various substituted benzyl chloride(bromine) afforded the target compounds The newlysynthesized compounds were characterized by physico-chemical and spectral means and the MS and NMR spectral

Journal of Chemistry 3

N

N NH

NN

N NH

N

N

OH

NBoc

Boc

Boc

O

NH

NH NH NH1

3 4

SO

O

N

N N

N

N

(i)

(ii)

(iii)2a2b

5a5b

6a6b

N

N N

N

NH

N

N N

N

N

(iv) (v)

Cl

Cl Cl Cl

Cl

Cl

Ar

Ar

Ar Ar Ar

R1

2a 5a 6a

2b 5b 6b

7a1ndasha13 Ar =

7b1ndashb13

7a1ndash137b1ndash13

Ar = benzo[d][

34-dimethoxyphenyl

NH2

13]dioxol-5-yl

Scheme 1 Reagents and Conditions (i) t-BuOH Et3N (ii) methanesulfonyl chloride (MsCl) DCM Et

3N and 4-DMAP (iii) NaH DMF

(iv) TFA DCM (v) substituted benzyl chloride (bromine fluorine) DMF and K2CO3

data are found in agreement with the assigned molecularstructures

22 Cholinesterase Inhibition All the newly synthesizedcompounds (7a1-a13 7b1-b13) were evaluated for theirinhibitory activities toward AChE using an in vitro assaybased on the reported protocol [7ndash10] in comparison withdonepezil as standard drug The anticholinesterase activitiesare summarized in Table 1 Preliminary results in Table 1revealed that compound 7b9 with a 3-cyanobenzyl groupin the benzo[d][13]dioxol-5-yl series displayed the highestAChE inhibitory activity (1542 at 100120583M) among all thetested compounds Besides compounds 7a1 7a7 and 7b10with inhibitory percentage more than 10 at 100 120583M showedsimilar activities with compound 7b9 against AChE Gen-erally all the compounds in both 34-dimethoxyphenyl andbenzo[d][13]dioxol-5-yl series demonstrated much lowerinhibitory activity toward AChE than the reference drugdonepezil (8007 at 100 120583M) Obviously the activity of thecompounds depends upon the nature of the substituentsattached with purine ring Even small modifications in everyseries can decrease and even lost their activity against AChETherefore the coherent structure-activity relationship willbe afforded by further pharmacology investigation which iscurrently underway in our lab

3 Conclusion

In summary a novel series of 9-(1-(substituted-benzyl) pip-eridin-4-yl)-2-chloro-9H-purin-6-amine derivatives weredesigned and synthesized and their AChE inhibitoryactivities were preliminary examined Biological assay dem-onstrated that four compounds showed moderate activitiesagainst AChE with inhibitory percentage more than 10at 100 120583M Further investigation of other bioactivitiesassociated with AD of this series is ongoing work within ourgroup and will be reported in due course

4 Experimental Section

41 Chemistry All melting points were determined on amicromelting point apparatus and are uncorrected 1H-NMRand 13C-NMR spectrawere obtained on aBrukerAvance-400NMR-spectrometer in the indicated solvents Chemical shiftsare expressed in 120575 units and TMS as internal reference Massspectra were taken on an LC Autosampler Device StandardG1313A instrument TLC was performed on Silica Gel GF254for TLC (Merck) and spots were visualized by iodin evapoursor by irradiation with UV light (120582 = 254 nm) Flash columnchromatography was performed on column packed withSilica Gel60 (230ndash400mesh) Solvents were reagent gradeand when necessary were purified and dried by standardmethods Concentration of the reaction solutions involvedthe use of rotary evaporator at reduced pressure

411 General Procedure for the Preparation of 2a and2b 26-Dichloro-9-H-purine (189 g 10mmol) and Et

3N

(16mL 11mmol) was dissolved in t-BuOH (50mL) and themixed solution of 34-dimethoxybenzylamine (1a 150mL10mmol) and t-BuOH (20mL) or benzo[d][13]dioxol-5-ylmethanamine (1b 127 mL 10 mmol) and t-BuOH (20mL)was slowly added to the previous solution in 20min at 60∘CThe resulting mixture was stirred at 60∘C for 30min Thenthe reactionmixture was poured into cold H

2O (100mL) the

resulting precipitate was collected by filtration underreducedpressure andwashed sequentially withH

2O then dried to give

the corresponding product 2a as a white power with yield of905 or 2b as a white power with yield of 897

412 General Procedure for the Preparation of 4 N-Boc-4-hydroxypiperidine (3 805 g and 40mmol) was dissolvedin DCM (50mL) then methanesulfonyl chloride (34mL44mmol) Et

3N (67mL 48mmol) and 4-DMAP (005 g

40mmol) were added to the above solution slowly in turn at0∘CThemixed solution ofmethanesulfonyl chloride (34mL


Table 1 Cholinesterase inhibition activity of 9-(1-(substituted-benzyl)piperidin-4-yl)-2-chloro-9H-purin-6-amine derivativesa

HN

N N

NN

Cl

NAr

R1

Compd Ar R1 Cholinesterase inhibition at 100120583M7a1 34-Dimethoxyphenyl 3-Chlorobenzyl 11037a2 34-Dimethoxyphenyl 3-bromobenzyl 0247a3 34-Dimethoxyphenyl 4-Cyanobenzyl 0477a4 34-Dimethoxyphenyl 4-Nitrobenzyl 3847a5 34-Dimethoxyphenyl 3-Fluorobenzyl 3487a6 34-Dimethoxyphenyl Pyridine-4-yl-methyl NAb

7a7 34-Dimethoxyphenyl Benzyl 14577a8 34-Dimethoxyphenyl 4-Bromobenzyl NA7a9 34-Dimethoxyphenyl 3-Cyanobenzyl 6107a107a11

34-Dimethoxyphenyl34-Dimethoxyphenyl

4-Methoxybenzyl26-Dicholobenzyl

NANA

7a12 34-Dimethoxyphenyl 246-Trimethylbenzyl NA7a13 34-Dimethoxyphenyl 2-Fluorobenzyl 4027b1 Benzo[d][1 3]dioxol-5-yl 3-Chlorobenzyl NA7b2 Benzo[d][1 3]dioxol-5-yl 3-Bromobenzyl 0097b3 Benzo[d][1 3]dioxol-5-yl 4-Cyanobenzyl NA7b4 Benzo[d][1 3]dioxol-5-yl 4-Nitrobenzyl NA7b5 Benzo[d][1 3]dioxol-5-yl 3-Fluorobenzyl 0147b6 Benzo[d][1 3]dioxol-5-yl Pyridine-4-yl-methyl NA7b7 Benzo[d][1 3]dioxol-5-yl Benzyl 7557b8 Benzo[d][1 3]dioxol-5-yl 4-Bromobenzyl 7297b9 Benzo[d][1 3]dioxol-5-yl 3-Cyanobenzyl 15427b10 Benzo[d][1 3]dioxol-5-yl 4-Methoxybenzyl 11217b11 Benzo[d][1 3]dioxol-5-yl 26-Dicholobenzyl 3807b12 Benzo[d][1 3]dioxol-5-yl 246-Trimethylbenzyl 1517b13 Benzo[d][1 3]dioxol-5-yl 2-Fluorobenzyl 614Donepezil 8007aSee the experimental section for assay details bNot active

44mmol) and DCM (20mL) was slowly added to the mixedsolution in 30 min at 60∘C The mixtures were stirred at0∘C overnight Then the reaction solution was alkalized toPH = 9 with NaHCO

3 The solution was washed by water

(50mL) then extracted with DCM (3 times 15mL) Combinedorganic phase dried over anhydrous Na

2SO4 filtered and

concentrated under reduced pressure to give the product 4as white solid Yield 943

413 General Procedure for the Preparation of 5a and 5b2-Chloro-N-(34-dimethoxbenzyl)-9H-purin-6-amine(2a320 g 10mmol) or N-(benzo[d][13]dioxol-5-ylmethyl)-2-chloro-9-(piperidin-4-yl)-9H-purin-6-amine(2b 303 g10mmol) was dissolved in DMF (60 mL) and added 60dispersion NaH (048 g 12mmol) to the solution at roomtemperature Then it slowly added the intermediate 4 (310 g

11mmol) that dissolved in DMF (20mL) to the previousmixed solution in 20min at 60∘C The reaction mixturewasrapid stirred at 100∘C for 16 h (monitored by TLC) Afterremoval of the solvent under reduced pressure water(30mL) was added and extracted with ethyl acetate (3 times10mL) Combined organic phase was washed with brineand dried over anhydrous Na

2SO4to give the corresponding

crude product which was purified by flash columnchromatography to afford compounds 5a as a pink crystalwith yield of 315 or 5b as a pink crystal with yield of 297

414 General Procedure for the Preparation of 6a and 6b To asolution of 5a (600mg 119mmol) or 5b (600mg 123mmol)in DCM (20mL) TFAwas added (3mL) at room temperatureand the solutionwas stirred for 5 hThen the reaction solutionwas alkalized to PH = 9 with NaHCO

3 The solution was


washed by water (50mL) and then extracted with DCM (3times 15mL) Combined organic phase dried over anhydrousNa2SO4 filtered and concentrated under reduced pressure to

give the product 6a or 6b

2-Chloro-N-(34-dimethoxbenzyl)-9-(piperidin-4-yl)-9H-purin-6-amine (6a)White crystal yield 91 mp 157ndash160∘C1H NMR (400MHz DMSO-d6 ppm) 120575 873 (1H s)825(1H s) 707(1H s) 687 (2H d J = 404Hz) 508 (1H sNH) 455 (2H d J = 536Hz) 436 (1H dt J

1= 1080Hz

J2= 512Hz) 374 (3H s OCH

3) 371 (3H s OCH

3) 308

(2H d J = 888Hz) 265 (2H dt J1= 1428Hz J

2= 352Hz)

192ndash194 (4H m) 13C NMR (100MHz DMSO-d6 ppm) 1205751553 1532 1498 1490 1483 1400 1321 1201 1189 11241121 560 558 533 456 (2C) 435 330 (2C) ESI-MS mz4035 (M + 1) 4055 (M + 3) 5253 (M + Na) C

19H23ClN6O2

(40216)

N-(Benzo[d][13]Dioxol-5-ylmethyl)-2-chloro-9-(piperidin-4-yl)-9H-purin-6-amine (6b) White crystal yield 87 mp205ndash209∘C 1H NMR (400MHz DMSO-d6 ppm) 120575 873(1H s) 826 (1H s) 693 (1H s) 683 (2H d J = 768Hz) 597(2H s OCH

2O) 505 (1H s NH) 454 (2H d J = 492Hz)

435 (1H dt J1= 1048Hz J

2= 540Hz) 305 (2H d J =

1232Hz) 260 (2H dt J1= 1476Hz J

2= 360Hz) 196 (4H

dd J1= 1664Hz J

2= 280Hz) 13CNMR (100MHz DMSO-

d6 ppm) 120575 1553 1532 1499 1476 1466 1401 1337 12111189 1013 553 534 457 (2C) 434 332 (2C) ESI-MSmz3873 (M + 1) 3893 (M + 3) 4094 (M + Na) C

18H19ClN6O2

(38613)

415 General Procedure for the Target Compounds 7a and7b Compound 6a (or 6b) was dissolved in anhydrous DMF(10mL) in the presence of anhydrous K

2CO3(12 eq) fol-

lowed by addition of appropriate substituted benzyl chloride(bromine fluorine) (11 eq) The reaction mixture was stirredat room temperature overnight The solvent was removedunder reduced pressure and then water (20mL) was addedExtracted with ethyl acetate (3 times 10mL) and the organicphase was washed with saturated sodium chloride (10mL)then dried over anhydrous Na


crude product which was purified by flash column chro-matography to afford compounds 7a1-13 (or 7b1-13)

2-Chloro-9-(1-(3-chlorobenzyl)piperidin-4-yl)-N-(34-dime-thoxbenzyl)-9H-purin-6-amine (7a1) Recrystallized fromEAPE as a white crystal yield 623 mp 176ndash180∘C 1HNMR (400MHz DMSO-d6 ppm) 120575 830 (1H s) 729ndash739(4H m) 706 (1H s) 686 (2H d J = 432Hz) 507 (1H sNH) 455 (2H d J = 724Hz) 430 (1H dt J

1= 832Hz J

2

= 327Hz) 373 (3H s OCH3) 371 (3H s OCH

3) 354 (2H

s) 292 (2H d J = 780Hz) 211ndash219 (4H m) 193 (2H d J= 880Hz) 13C NMR (100MHz DMSO-d6 ppm) 120575 15531532 1500 1490 1483 1417 1401 1334 1322 1305 12891279 1274 1201 1189 1125 1122 614 560 559 529 525(2C) 435 319 (2C) ESI-MS mz 5273 (M + 1) 5292 (M +3) 5493 (M + Na) C

26H28Cl2N6O2(52617)

2-Chloro-9-(1-(3-bromobenzyl)piperidin-4-yl)-N-(34-dime-thoxbenzyl)-9H-purin-6-amine (7a2) Recrystallized from

EAPE as a white crystal yield 572 mp 187ndash190∘C 1HNMR (400MHz DMSO-d6 ppm) 120575 831 (1H s) 761 (1H ddJ1= 796 J

2= 10Hz) 752 (1H dd J

1= 764Hz J

2= 152Hz)

740 (1H dt J1= 748Hz J

2= 10Hz) 723 (1H dt J

1= 776Hz

J2= 168Hz) 706 (1H s) 686 (2H d J = 826Hz) 507 (1H

s NH) 454 (2H d J = 544Hz) 434 (1H dt J1= 1172Hz

J2= 384Hz) 373 (3H s OCH

3) 371 (3H s OCH

3) 360

(2H s) 296 ( 2H d J = 1152Hz) 227 (2H t J = 1168Hz)208ndash217 (2H m) 195ndash199 (2H d J = 728Hz) 13C NMR(100MHz DMSO-d6 ppm) 120575 1553 1532 1500 1490 14831400 1380 1330 1322 1313 1294 1280 1244 1201 11901125 1122 614 560 559 528 527 (2C) 435 319 (2C)ESI-MS mz 5732 (M + 3) 5744 (M + 4) 5762 (M + 6)C26H28BrClN

6O2(57011)

2-Chloro-9-(1-(4-cyanobenzyl)piperidin-4-yl)-N-(34-dime-thoxbenzyl)-9H-purin-6-amine (7a3) Recrystallized fromEAPE as a white crystal yield 665 mp 193ndash196∘C 1HNMR (400MHz DMSO-d6 ppm) 120575 830 (1H s) 782 (2Hd J = 410Hz) 754 (2H d J = 408Hz) 706 (1H s) 687 (2Hdd J1= 864Hz J

2= 326Hz) 507 (1H s NH) 454 (2H

d J = 520Hz) 432 (1H dt J1= 862Hz J

2= 356Hz) 374

(3H s OCH3) 371 (3H s OCH

3) 362 (2H s) 290 (2H

d J = 928Hz) 217 (4H dd J1= 1660 J

2= 888Hz) 195

(2H d J = 1156Hz) 13C NMR (100MHz DMSO-d6 ppm)120575 1553 1532 1499 1490 1483 1451 1401 1326 (2C) 13211300 (2C) 1201 1193 1189 1124 1121 1102 616 560 558528 526 (2C) 435 318 (2C) ESI-MS mz 5184 (M + 1)5404 (M + Na) C

27H28ClN7O2(51720)

2-Chloro-9-(1-(4-nitrobenzyl)piperidin-4-yl)-N-(34-dime-thoxbenzyl)-9H-purin-6-amine (7a4) Recrystallized fromEAPE as a yellow crystal yield 534 mp 209ndash212∘C 1HNMR (400MHz DMSO-d6 ppm) 120575 829 (1H s) 821 (2Hd J = 812Hz) 762 (2H d J = 808Hz) 706 (1Hs) 689 (2Hd J = 468Hz) 507 (1H s NH) 455 (2H d J = 632Hz) 432(1H dt J

1= 1132 J

2= 328Hz) 374 (3H s OCH

3) 371 (3H

s OCH3) 367 (2H s) 292 (2H t J = 908Hz) 214ndash225 (4H

m) 197 (2H d J = 458Hz) 13CNMR (100MHz DMSO-d6ppm) 120575 1553 1532 1500 1490 1483 1473 1471 1401 13211302 (2C) 1240 (2C) 1201 1189 1124 1121 613 560 558528 526 (2C) 435 318 (2C) ESI-MS mz 5384 (M + 1)5404 (M + 3) 5603 (M + Na) C

26H28ClN7O4(53719)

2-Chloro-9-(1-(3-fluorobenzyl)piperidin-4-yl)-N-(34-dime-thoxbenzyl)-9H-purin-6-amine (7a5) Recrystallized fromEAPE as a white crystal yield 497 mp 183ndash185∘C 1HNMR (400MHz DMSO-d6 ppm) 120575 830 (1H s) 738 (1Hdt J1= 804Hz J

2= 616Hz) 717 (2H dd J

1= 936Hz J

2

= 628Hz) 709 (2H s) 687 (2H d J = 326Hz) 507 (1H sNH) 455 (2H d J = 556Hz) 431 (1H dt J

1= 1028Hz J

2

= 368Hz) 374 (3H s OCH3) 371 (3H s OCH

3) 355 (2H

s) 293 (2H d J = 716Hz) 211ndash217 (4H m) 193 (2H d J= 888Hz) 13C NMR (100MHz DMSO-d6 ppm) 120575 16391615 1553 1532 1499 1490 1483 1420 1400 1321 13051252 1201 1189 1157 1143 1124 615 560 558 528 525(2C) 435 318 (2C) ESI-MSmz 5115 (M + 1) 5134 (M + 3)5154 (M + 5) 5333 (M + Na) C

26H28ClFN6O2(51019)


2-Chloro-9-(1-(pyridine-4-yl-methyl)piperidin-4-yl)-N-(34-dimethoxbenzyl)-9H-purin-6-amine (7a6) Recrystallizedfrom EAPE as a yellow crystal yield 612 mp 158ndash161∘C1H NMR (400MHz DMSO-d6 ppm) 120575 853 (2H dd J

1=

456Hz J2= 136Hz) 830 (1H s) 735 (2H d J = 580Hz)

706 (1H s) 686 (2H d J = 228Hz) 506 (1H s NH) 453(2H d J = 544Hz) 432 (1H dt J

1= 728Hz J

2= 376Hz)

373 (3H s OCH3) 370 (3H s OCH

3) 357 (2H s) 292

(2H d J = 940Hz) 213ndash220 (4H m) 194 (2H d J =112Hz) 13C NMR (100MHz DMSO-d6 ppm) 120575 15531532 1503 (2C) 1490 1483 1480 1401 1322 1242 (2C)1202 1193 1189 1125 1122 609 560 559 527 526 (2C)435 318 (2C) ESI-MS mz 4944 (M + 1) 4964 (M + 3)5165 (M + Na) C

25H28ClN7O2(49320)

2-Chloro-9-(1-benzylpiperidin-4-yl)-N-(34-dimethoxbenzyl)-9H-purin-6-amine (7a7) Recrystallized from EAPE asa white crystal yield 557 mp 179ndash182∘C 1H NMR(400MHz DMSO-d6 ppm) 120575 829 (1H s) 733 (4H t J =468Hz) 727 (1H t J = 424Hz) 706 (1H s) 687 (2H d J =506Hz) 507 (1H s NH) 455 (2H d J = 516Hz) 431 (1Hdt J1= 926Hz J

2= 404Hz) 373 (3H s OCH

3) 370 (3H s

OCH3) 352 (2H s) 293 (2H d J = 624Hz) 212ndash214 (4H

m) 194 (2H d J = 643Hz) 13CNMR (100MHz DMSO-d6ppm) 120575 1553 1532 1500 1490 1483 1401 1389 13211293(2C) 1287(2C) 1274 1201 1189 1123 1121 623 560558 529 526 (2C) 435 318 (2C) ESI-MSmz 4934 (M +1) 4953 (M + 3) 5154 (M + Na) C

26H29ClN6O2(49220)

2-Chloro-9-(1-(4-bromobenzyl)piperidin-4-yl)-N-(34-dime-thoxbenzyl)-9H-purin-6-amine (7a8) Recrystallized fromEAPE as a white crystal yield 525 mp 209ndash212∘C 1HNMR (400MHz DMSO-d6 ppm) 120575 830(1H s) 752 (2Hd J = 160Hz) 729 (2H d J = 836Hz) 707 (1H s) 687 (2Hd J = 438Hz) 507 (1H s NH) 455 (2H d J = 576Hz)429 (1H dt J

1= 837Hz J

2= 576Hz) 374 (3H s OCH

3)

371 (3H s OCH3) 349 (2H s) 291 (2H d J = 636Hz)

199ndash214 (4H m) 193 (2H d J = 624Hz) 13C NMR(100MHz DMSO-d6 ppm) 120575 1553 1532 1500 1490 14831401 1384 1321 1315 (2C) 1314 (2C) 1204 1201 11891124 1121 614 560 558 528 525 (2C) 435 318 (2C) ESI-MSmz 5713 (M + 1) 5732 (M + 3) 5753 (M + 5) 5953 (M+ Na) C

26H28BrClN

6O2(57011)

2-Chloro-9-(1-(3-cyanobenzyl)piperidin-4-yl)-N-(34-dime-thoxbenzyl)-9H-purin-6-amine (7a9) Recrystallized fromEAPE as a white crystal yield 621 mp 209ndash210∘C 1HNMR (400MHz DMSO-d6 ppm) 120575 830 (1H s) 777 (1Hdd J1= 2548Hz J

2= 760Hz) 768 (2H d J = 780Hz) 756

(1H t J = 768Hz) 706 (1H s) 687 (2H d J = 984Hz) 507(1H s NH) 455 (2H d J = 516Hz) 433 (1H dt J

1= 1084 J

2

= 326Hz) 373 (3H s OCH3) 371 (3H s OCH

3) 359 (2H

s) 293 (2H d J = 916Hz) 211ndash218 (4H m) 193 (2H d J =1280Hz) 13C NMR (100MHz DMSO-d6 ppm) 120575 15531532 1500 1490 1483 1408 1401 1341 1326 1321 13131299 1201 1194 1189 1124 1117 611 560 558 527 525(2C) 435 318 (2C) ESI-MS mz 5184 (M + 1) 5203 (M +3) 5226 (M + 5) 5403 (M + Na) C

27H28ClN7O2(51720)

2-Chloro-9-(1-(4-methoxybenzyl)piperidin-4-yl)-N-(34-dimethoxbenzyl)-9H-purin-6-amine (7a10) Recrystallizedfrom EAPE as a white crystal yield 563 mp 202ndash205∘C1H NMR (400MHz DMSO-d6 ppm) 120575 828 (1H s) 724(2H d J = 856Hz) 706 (1H s) 690 (2H d J = 860Hz)686 (2H d J = 456Hz) 507 (1H s NH) 454 (2H d J =548Hz) 427 (1H dt J

1= 862Hz J

2= 364Hz) 374 (3H s

OCH3) 373 (3H s OCH

3) 370 (3H s) 344 (2H s) 292

(2H d J = 632Hz) 207ndash209 (4H m) 192 (2H s) 13CNMR (100MHz DMSO-d6 ppm) 120575 1588 1553 1532 14991490 1483 1401 1321 1306 1305 (2C) 1201 1189 1140(2C) 1124 1121 617 560 558 555 530 524 (2C) 435318 (2C) ESI-MSmz 5235 (M + 1) 5254 (M + 3) 5453 (M+ Na) C

27H31ClN6O3(52221)

2-Chloro-9-(1-(26-dicholobenzyl)piperidin-4-yl)-N-(34-dimethoxbenzyl)-9H-purin-6-amine (7a11) Recrystallizedfrom EAPE as a white crystal yield 583 mp 196ndash198∘C1H NMR (400MHz DMSO-d6 ppm) 120575 828 (1H s) 734(2H dt J

1= 1722Hz J

2= 720Hz) 734 (1H dd J

1= 856Hz

J2= 748Hz) 706 (1H s) 686 (2H d J= 382Hz) 506 (1H

s NH) 455 (2H d J = 456Hz) 429 (1H dt J1= 1026 J

2=

432Hz) 374 (3H s OCH3) 372 (2H s) 370 (3H s OCH

3)

293 (2H d J = 1168Hz) 240 (2H dt J1= 992Hz J

2=

180Hz) 193ndash206 (4H m) 13C NMR (100MHz DMSO-d6ppm) 120575 1553 1532 1500 1490 1483 1401 1365(2C) 13431320 1304 1292 (2C) 1201 1189 1124 1121 623 563560 558 525 (2C) 432 318 (2C) ESI-MS mz 5612 (M +1) 5632 (M + 3) 5653 (M + 5) C

26H27Cl3N6O2(56013)

2-Chloro-9-(1-(246-trimethylbenzyl)piperidin-4-yl)-N-(34-dimethoxbenzyl)-9H-purin-6-amine (7a12) Recrystallizedfrom EAPE as a white crystal yield 633 mp 203ndash206∘C1H NMR (400MHz DMSO-d6 ppm) 120575 827(1H s) 706(1H s) 686 (2H s) 680 (2H s) 507 (1H s NH) 454 (2Hd J = 548Hz) 440 (1H dt J

1= 1124Hz J

2= 548Hz)

373 (3H s OCH3) 370 (3H s OCH

3) 343 (2H s) 286

(2H d J = 114Hz) 232ndash233 (6H m) 219ndash221 (5H m)192ndash194 (4H m) 13C NMR (100MHz DMSO-d6 ppm)1205751553 1532 1499 1490 1483 1399 1379(2C) 1360 13221321 1291 (2C) 1201 1189 1124 1121 560 558 554 530523 (2C) 435 321 (2C) 210 202 (2C) ESI-MS mz 5353(M + 1) 5374 (M + 3) C

29H35ClN6O2(53425)


2= 180Hz) 734 (1H dt J

1= 548Hz J

2=

172Hz) 715ndash722 (2H m) 706 (1H s) 686 (2H d J =432Hz) 507 (1H s NH) 455 (2H d J = 496Hz) 429 (1Hdt J1= 1126Hz J

2= 740Hz) 373 (3H s OCH

3) 371 (3H s

OCH3) 358 (2H s) 295 ( 2H d J = 1052Hz) 209ndash222 (4H

m) 193 (2H d J = 828Hz) 13C NMR (100MHz DMSO-d6 ppm) 120575 1625 1601 1553 1532 1499 1490 1483 14011321 1296 1251 1246 1201 1189 1157 1155 1123 560 558549 528 524 (2C) 435 318 (2C) ESI-MS mz 5114 (M +1) 5134 (M + 3) 5333 (M + Na) C

26H28ClFN6O2(51019)


N-(Benzo[d][13]dioxol-5-ylmethyl)-2-chloro-9-(1-(3-chloro-benzyl)piperidin-4-yl)-9H-purin-6-amine (7b1) Recrystal-lized from EAPE as a white crystal yield 559 mp 146ndash150∘C 1H NMR (400MHz DMSO-d6 ppm) 120575 832 (1H s)738 (1H d J = 1044Hz) 733 (3H dd J = 996Hz 828Hz)693 (1H s) 683 (2H dd J

1= 838Hz J

2= 283Hz) 596

(2H s OCH2O) 504 (1H s NH) 453 (2H d J = 520Hz)

432 (1H dt J1= 924 J

2= 364Hz) 354 (2H s) 292 (2H d

J = 792Hz) 215 (4H t J = 972Hz) 196 (2H t J = 888Hz)13C NMR (100MHz DMSO-d6 ppm) 120575 1553 1532 15001476 1466 1415 1400 1336 1334 1305 1289 1279 12741267 1211 1189 1085 1013 614 528 525 (2C) 434 318(2C) ESI-MS mz 5113 (M + 1) 5134 (M + 3) 5332 (M +Na) C

25H24Cl2N6O2(51013)

N-(Benzo[d][13]dioxol-5-ylmethyl)-2-chloro-9-(1-(3-bromo-benzyl)piperidin-4-yl)-9H-purin-6-amine (7b2) Recrystal-lized from EAPE as a white crystal yield 621 mp 174ndash178∘C 1H NMR (400MHz DMSO-d6 ppm) 120575 831 (1H s)761 (1H d J = 792Hz) 752 (1H d J = 748Hz) 739 (1H tJ = 736Hz) 721 (1H t J = 744Hz) 692 (1H s) 683 (2Hdd J1= 1216 J

2= 428Hz) 597 (2H s OCH

2O) 504 (1H

s NH) 453 (2H d J = 528Hz) 432 (1H dt J1= 792Hz J

2

= 448Hz) 361 (2H s) 296 (2H d J = 1140Hz) 227 (2H tJ = 1144Hz) 214 (2H dd J

1= 2184Hz J

2= 1172Hz) 196

(2H d J = 1024Hz) 13C NMR (100MHz DMSO-d6 ppm)120575 1552 1532 1500 1476 1466 1401 1379 1336 1330 13131294 1281 1244 1211 1203 1189 1085 1013 614 553 526(2C) 434 318 (2C) ESI-MS mz 5552 (M + 1) 5582 (M +4) 5791 (M + Na) C

25H24BrClN

6O2(55408)

N-(Benzo[d][13]dioxol-5-ylmethyl)-2-chloro-9-(1-(4-cyano-benzyl)piperidin-4-yl)-9H-purin-6-amine (7b3) Recrystal-lized from EAPE as a white crystal yield 584 mp 221ndash225∘C 1H NMR (400MHz DMSO-d6 ppm) 120575 830 (1Hs) 780 (2H d J = 804Hz) 754 (2H d J = 806Hz) 683(2H dd J

1= 1088Hz J

2= 784Hz) 693 (1H s) 597 (2H s

ndashOCH2Ondash) 503 (1H s NH) 453 (2H d J = 468Hz) 432

(1H dt J1= 1088Hz J

2= 426Hz) 362 (2H s) 292 (2H d J

= 920Hz) 217 (4H t J = 944Hz) 197 (2H t J = 1160Hz)13C NMR (100MHz DMSO-d6 ppm) 120575 1553 1532 15001476 1466 1451 1432 1401 1336 (2C) 1326 1300 (2C)1284 1211 1194 1102 1085 1013 659 616 525 (2C) 433318 (2C) ESI-MSmz 5023 (M + 1) 5043 (M + 3) 5063 (M+ 5) 5244 (M + Na) C

26H24ClN7O2(50117)

N-(Benzo[d][13]dioxol-5-ylmethyl)-2-chloro-9-(1-(4-nitro-benzyl)piperidin-4-yl)-9H-purin-6-amine (7b4) Recrystal-lized from EAPE as a yellow crystal yield 495 mp 137ndash141∘C 1H NMR (400MHz DMSO-d6 ppm) 120575 830 (1H s)822 (2H dd J

1= 708Hz J

2= 168Hz) 762 (2H d J =

868Hz) 692 (1H s) 683 (2H dd J1= 838Hz J

2= 283Hz)

596 (2H s ndashOCH2Ondash) 504 (1H s NH) 453 (2H d J =

520Hz) 432 (1H dt J1= 1140 J

2= 388Hz) 367 (2H s)

293 (2H d J = 1044Hz) 217 (4H t J = 1044Hz) 196 (2Ht J = 384Hz) 13CNMR (100MHz DMSO-d6 ppm) 120575 15521532 1497 1476 1473 1471 1466 1402 1336 1302 (2C)1286 1241 (2C) 1211 1189 1085 1013 613 528 526 (2C)

433 318 (2C) ESI-MS mz 5223 (M + 1) 5244 (M + 3)5444 (M + Na) C

25H24ClN7O4(52116)

N-(Benzo[d][13]dioxol-5-ylmethyl)-2-chloro-9-(1-(3-fluoro-benzyl)piperidin-4-yl)-9H-purin-6-amine (7b5) Recrystal-lized from EAPE as a white crystal yield 641 mp 144ndash148∘C 1H NMR (400MHz DMSO-d6 ppm) 120575 831 (1H s)738 (1H dt J

1= 804Hz J

2= 648Hz) 717 (2H dt J

1=

796Hz J2= 212Hz) 708 (1H dt J

1= 864Hz J

2= 223Hz)

693 (1H s) 683 (2H t J = 772Hz) 597 (2H s ndashOCH2Ondash

) 505 (1H s NH) 454 (2H d J = 572Hz) 432 (1H dtJ1= 724Hz J

2= 426Hz) 355 (2H s) 293 (2H d J =

692Hz) 216 (4H t J = 896Hz) 194 (2H d J = 772Hz)13C NMR (400MHz DMSO-d6 ppm) 120575 1639 1615 15531532 1500 1476 1466 1421 1401 1336 1306 1251 12111189 1157 1142 1085 1012 615 528 525 (2C) 434 318(2C) ESI-MS mz 4953 (M + 1) 4974 (M + 3) 5174 (M +Na) C

25H24ClFN6O2(49416)

N-(Benzo[d][13]dioxol-5-ylmethyl)-2-chloro-9-(1-(pyridine-4-yl-methyl)piperidin-4-yl)-9H-purin-6-amine (7b6) Recrys-tallized from EAPE as a yellow crystal yield 623 mp154ndash157∘C 1H NMR (400MHz DMSO-d6 ppm) 120575 853(2H dd J

1= 448Hz J

2= 144Hz) 831 (1H s) 735 (2H d

J = 584Hz) 692 (1H s) 683 (2H dd 1198691= 1012Hz J

2=

780Hz) 597 (2H s ndashOCH2Ondash) 504 (1H s NH) 453 (2H

d J = 576Hz) 432 (1H dt J1= 1048Hz 119869

2= 362Hz) 357

(2H s) 293 (2H d J = 920Hz) 217 (4H t J = 1216Hz)195 (2H d J = 1064Hz) 13C NMR (100MHz DMSO-d6ppm) 120575 1552 1532 1500 (2C) 1480 1476 1470 1466 14011336 1242 (2C) 1211 1203 1189 1085 1013 609 526 491(2C) 434 318 (2C) ESI-MS mz 4783 (M + 1) 4803 (M +3) 4824 (M + 5) 5002 (M + Na) C

24H24ClN7O2(47717)

N-(Benzo[d][13]dioxol-5-ylmethyl)-2-chloro-9-(1-benzylpi-peridin-4-yl)-9H-purin-6-amine (7b7) Recrystallized fromEAPE as a white crystal yield 585 mp 169ndash172∘C 1HNMR (400MHz DMSO-d6 ppm) 120575 830 (1H s) 733 (4Ht J = 460Hz) 725 (1H dd J

1= 852Hz J

2= 428Hz) 692

(1H s) 683 (2H dd J1= 100Hz J

2= 780Hz) 596 (2H s


(1H dt J1= 781 J

2= 388Hz) 352 (2H s) 292 (2H d J =

636Hz) 213 (4H dt J1= 1136 J

2= 7 40Hz) 194 (2H s)

13C NMR (100MHz DMSO-d6 ppm) 120575 1552 1531 15001476 1466 1402 1389 1336 1293 (2C) 1286 (2C) 12741211 1203 1189 1085 1013 623 529 526 (2C) 434 318(2C) ESI-MSmz 4773 (M + 1) 4793 (M + 3) 5814 (M + 5)5993 (M + Na) C

25H25ClN6O2(47617)

N-(Benzo[d][13]dioxol-5-ylmethyl)-2-chloro-9-(1-(4-bromo-benzyl)piperidin-4-yl)-9H-purin-6-amine (7b8) Recrystal-lized from EAPE as a white crystal yield 543 mp 204ndash208∘C 1H NMR (400MHz DMSO-d6 ppm) 120575 830 (1H s)754 (2H d J = 160Hz) 728 (2H d J = 832Hz) 693 (1Hs) 683 (2H dd J

1= 726Hz J

2= 184Hz) 597 (2H s ndash

OCH2Ondash) 504 (1H s NH) 454 (2H d J = 580Hz) 430

(1H dt J1= 728Hz J

2= 428Hz) 350 (2H s) 292 (2H d J =

66Hz) 220 (4H dt J1= 1236 J

2= 860Hz) 194 (2H s) 13C

NMR (100MHz DMSO-d6 ppm) 120575 1552 1532 1500 14761467 1402 1384 1336 1315 (2C) 1314 (2C) 1211 1209


1204 1189 1085 1012 614 529 525 (2C) 434 318 (2C)ESI-MS mz 5571 (M + 3) 5591 (M + 5) C

25H24BrClN

6O2

(55408)

N-(Benzo[d][13]dioxol-5-ylmethyl)-2-chloro-9-(1-(3-cyano-benzyl)piperidin-4-yl)-9H-purin-6-amine (7b9) Recrystal-lized from EAPE as a white crystal yield 484 mp 200ndash204∘C 1H NMR (400MHz DMSO-d6 ppm) 120575 831 (1H s)776 (1H dd J

1= 1084Hz J

2= 764Hz) 769 (2H d J =

784Hz) 657 (1H t J = 768Hz) 693 (1H s) 683 (2H ddJ1= 976 J

2= 780Hz) 597 (2H s ndashOCH

2Ondash) 504 (1H s

NH) 453 (2H d J = 540Hz) 431 (1H dt J1= 812 J

2=

384Hz) 360 (2H s) 293 (2H d J = 928Hz) 217 (4H dt J1

= 1204Hz J2= 968Hz) 194 (2H d J = 1104Hz) 13CNMR

(400MHz DMSO-d6 ppm) 120575 1552 1532 1500 1476 14661408 1401 1341 1336 1325 1313 1299 1211 1194 11881117 1085 1013 611 554 527 525 (2C) 434 318 (2C) ESI-MSmz 5023 (M + 1) 5043 (M+3) 5063 (M + 5) 5244 (M+ Na) C

26H24ClN7O2(50117)

N-(Benzo[d][13]dioxol-5-ylmethyl)-2-chloro-9-(1-(4-metho-xybenzyl)piperidin-4-yl)-9H-purin-6-amine (7b10) Recrys-tallized from EAPE as a white crystal yield 594 mp 182ndash185∘C 1H NMR (400MHz DMSO-d6 ppm) 120575 830 (1H s)724 (2H d J = 852Hz) 690 (3H t J = 692Hz) 683 (2Hdd J1= 752Hz J


2Ondash) 504

(1H s NH) 454 (2H d J = 592Hz) 428 (1H dt J1= 825 J

2

= 332Hz) 374 (3H s) 344 (2H s) 292 (2H d J = 624Hz)207 (4H t J = 788Hz) 193 (2H s) 13C NMR (100MHzDMSO-d6 ppm) 120575 1588 1553 1532 1500 1476 1466 14011345 1336 1307 1305 (2C) 1211 1189 1140 (2C) 10851013 617 555 530 524 (2C) 434 318 (2C) ESI-MS mz5073 (M + 1) 5093 (M + 3) 5293 (M + Na) C

26H27ClN6O3

(50618)

N-(Benzo[d][13]dioxol-5-ylmethyl)-2-chloro-9-(1-(26-dich-olobenzyl)piperidin-4-yl)-9H-purin-6-amine (7b11) Recrys-tallized from EAPE as a white crystal yield 568 mp 199ndash203∘C 1H NMR (400MHz DMSO-d6 ppm) 120575 828(1H s)748 (2H dt J

1= 840Hz J

2= 076Hz) 734 (1H dd J

1=

754Hz J1= 862Hz) 692 (1H s) 683 (2H dd J

1= 1174

J1= 79Hz) 597 (2H s ndashOCH

2Ondash) 504 (1H s NH) 454

(2H d J = 576Hz) 454 (2H d J = 604Hz) 432 (1H dt J1

= 782Hz J2= 426Hz) 374 (2H s) 295 (2H d J = 116Hz)

239 (2H t J = 16Hz) 199 (4H dt J1= 1151Hz J

2= 962Hz)

13C NMR (100MHz DMSO-d6 ppm) 120575 1552 1532 15001476 1466 1401 1366 (2C) 1343 1336 1319 1304 1291(2C) 1211 1189 1085 1013 623 563 527 (2C) 433 318(2C) ESI-MS mz 5472 (M + 3) 5492 (M + 5) 5512 (M +7) C25H23Cl3N6O2(54409)

N-(Benzo[d][13]dioxol-5-ylmethyl)-2-chloro-9-(1-(246-trimethylbenzyl)piperidin-4-yl)-9H-purin-6-amine (7b12)Recrystallized from EAPE as a white crystal yield 634mp 164ndash167∘C 1H NMR (400MHz DMSO-d6 ppm) 120575828 (1H s) 692 (1H s) 680ndash685 (4H m) 596 (2H sndashOCH

2Ondash) 503 (1H s NH) 453 (2H d J = 520Hz) 429

(1H dt J1= 1028Hz J

2= 480Hz) 344 (2H s) 286 (2H d

J = 1140Hz) 232 (6H s) 219ndash221 (5H m) 194ndash196 (4Hm) 13C NMR (100MHz DMSO-d6 ppm) 120575 1552 1532

1500 1476 1466 1400 1381 1379 1360 1336 1322 1291(2C) 1210 1188 1085 1012 619 554 523 (2C) 433 321(2C) 210 202 197 ESI-MS mz 5194 (M + 1) 5213 (M +3) 5235 (M + 5) 5414 (M + Na) C

28H31ClN6O2(51822)


1= 80 J

2= 156Hz) 733 (1H dt J

1= 564 J

2

= 192Hz) 718 (2H dd J1= 142Hz J

2= 64Hz) 692 (1H

s) 685 (2H t J = 78Hz) 597 (2H s ndashOCH2Ondash) 504 (1H

s NH) 454 (2H d J = 576Hz) 430 (1H dt J1= 1152Hz

J2= 416Hz) 359 (2H s) 295 (2H d J = 102Hz) 215 (4H

dt J1= 232Hz J

2= 1172Hz) 194 (2H t J = 1288Hz) 13C

NMR (100MHz DMSO-d6 ppm) 120575 1624 1600 1552 15321499 1476 1467 1402 1336 1321 1296 1252 1246 12111189 1157 1085 1013 549 528 524 (2C) 434 318 (2C)ESI-MS mz 4953 (M + 1) 4974 (M + 3) 5174 (M + Na)C25H24ClFN6O2(49416)

42 Acetylcholinesterase Inhibition Assay The ability ofderivatives 7a1-7a13 and 7b1-7b13 to inhibit human acetyl-cholinesterase (hAChE) (Sigma-Aldrich USA) was exam-ined using the 551015840-dithiobis-(2-nitrobenzoic acid) (DTNB)method (to generate a yellow chromophore (5-mercapto-2-nitrobenzoic acid) detectable at the 405ndash412 nm range)with the acetylcholinesterase assay kit (Keygen China) Theassay was carried out as a previously described protocol [10]using donepezil as controls (119899 = 4) Stock solutions of testcompounds were dissolved in a minimum volume of DMSO(1) and were diluted using saline In 96-well plates 50120583L ofAChE (022UmL diluted using saline) was incubated with10 120583L of various concentrations of test compounds (10 100100 120583M) at room temperature for 10min followed by theaddition of relative agents according to the kit instructionThe absorbance was measured at a wavelength of 405 nmwith Thermo MK3 microplate reader Percent inhibition wascalculated by the comparison of compound-treated to variouscontrol incubations

Conflict of Interests

The authors declare no conflict of interests

Acknowledgments

The financial support from the National Natural ScienceFoundation of China (NSFC no 81102320 no 81273354)Key Project of NSFC for International Cooperation (no30910103908) the Natural Science Foundation of ShandongProvince (ZR2009CM016) and China Postdoctoral ScienceFoundation funded project (no 20100481282 2012T50584) isgratefully acknowledged

References

[1] A Enz R Amstutz H Boddeke G Gmelin and JMalanowskildquoBrain selective inhibition of acetylcholinesterase a novel


approach to therapy for Alzheimerrsquos diseaserdquo Progress in BrainResearch vol 98 pp 431ndash438 1993

[2] G R Proctor and A L Harvey ldquoSynthesis of tacrine analoguesand their structure-activity relationshipsrdquo Current MedicinalChemistry vol 7 no 3 pp 295ndash302 2000

[3] H Sugimoto Y Iimura Y Yamanishi and K YamatsuldquoSynthesis and structure-activity relationships of acetylcholin-esterase inhibitors 1-benzyl-4-[(56-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride and related compoundsrdquoJournal of Medicinal Chemistry vol 38 no 24 pp 4821ndash48291995

[4] D L Bai X C Tang and X C He ldquoHuperzine A a potentialtherapeutic agent for treatment of Alzheimerrsquos diseaserdquo CurrentMedicinal Chemistry vol 7 no 3 pp 355ndash374 2000

[5] J Winkler L J Thal F H Gage and L J Fisher ldquoCholin-ergic strategies for Alzheimerrsquos diseaserdquo Journal of MolecularMedicine vol 76 no 8 pp 555ndash567 1998

[6] A Musiał M Bajda and B Malawska ldquoRecent developmentsin cholinesterases inhibitors for Alzheimerrsquos disease treatmentrdquoCurrent Medicinal Chemistry vol 14 no 25 pp 2654ndash26792007

[7] T Mohamed and P P Rao ldquoDesign synthesis and evaluationof 24-disubstituted pyrimidines as cholinesterase inhibitorsrdquoBioorganic amp Medicinal Chemistry Letters vol 20 no 12 pp3606ndash3609 2010

[8] T Mohamed X Zhao L K Habib J Yang and P P RaoldquoDesign synthesis and structure-activity relationship (SAR)studies of 24-disubstituted pyrimidine derivatives dual activityas cholinesterase and A120573-aggregationinhibitorsrdquo Bioorganic ampMedicinal Chemistry Letters vol 19 no 7 pp 2269ndash2281 2011

[9] T Mohamed J C Yeung and P P Rao ldquoDevelopmentof 2-substituted-N-(naphth-1-ylmethyl) and N-benzhydrylpyr-imidin-4-amines as dual cholinesterase and A120573-aggregationinhibitors synthesis and biological evaluationrdquo Bioorganic ampMedicinal Chemistry Letters vol 21 pp 5881ndash5887 2011

[10] T Mohamed J C Yeung M S Vasefi M A Beazely and PP Rao ldquoDevelopment and evaluation of multifunctional agentsfor potential treatment of Alzheimerrsquos disease application toa pyrimidine-24-diamine templaterdquo Bioorganic amp MedicinalChemistry Letters vol 22 no 14 pp 4707ndash4712 2012

[11] P V Reddy N G Nair M A Smith and W Kudo ldquoPurine-based triazolesrdquo WO2012051296A2

[12] J J Cui M Tran-Dube H Shen et al ldquoStructure based drugdesign of crizotinib (PF-02341066) a potent and selective dualinhibitor of mesenchymal-epithelial transition factor (c-MET)kinase and anaplastic lymphoma kinase (ALK)rdquo Journal ofMedicinal Chemistry vol 54 no 18 pp 6342ndash6363 2011

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

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Chemistry


Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


N

N

NS

N

N NN

N NN

N

N

NH

NHNH NH NH

NH

OO

N

PY-1

PY-2 PY-3 PY-4

N

NCl N

N

N NN

F

O

O

N

O

Donepezil

IC50 = 033120583M (AChE)230120583M (BuChE)

IC50 = 55 120583M (AChE) PU201205129659 inhibition of hAChE-induced aggregationof A120573(1ndash40) fibrils (at 100120583M)

AChE IC50 = 99 120583MBuChE IC50 = 114 120583M)A120573-aggregation (AChE-induced = 593self-induced = 174 at 100120583M)BACE-1 (34 inhibition at 10120583M)

Figure 1 Structure of donepezil 24-disubstituted pyrimidine AChE inhibitors and purine derivative PU2012051296

N

N N

N

NH

Cl

N N

N

F

N

N N

N

NH

Cl

Ar

N

Lead compound PU2012051296 Newly designed derivatives

R1

Figure 2The general structure formula of newly designed 9-(1-(substituted-benzyl)piperidin-4-yl)-2-chloro-9H- purin-6-amine derivatives

series of 9-(1-(substituted-benzyl)piperidin-4-yl)-2-chloro-9H-purin-6-amine derivatives were designed synthesizedand evaluated for the inhibition activity against AChE

2 Results and Discussion

21 Chemistry The synthetic route of the target compoundsis outlined in Scheme 1 whichwas started from commerciallyavailable materials and completed using well establishedmethods Initially N-(34-dimethoxybenzyl)-2-chloro-9H-purin-6-amine (2a) and N-(benzo[d][13]dioxol-5-ylme-thyl)-2-chloro-9H-purin-6-amine (2b) intermediates weresynthesized from the starting material 26-dichloro-9H-purine (1) by a nucleophilic aromatic substitution reaction atthe C-6 position using either (34-dimethoxyphenyl) meth-anamine or benzo[d][13]dioxol-5-ylmethanamine in thepresence of triethylamine (TEA) The reaction was run int-BuOH at 60∘C for 30min Intermediates 6 and 7 wereobtained in good yields ranging (905 and 897)

(Scheme 1) [7ndash10] In the meantime tert-butyl 4-hydroxypi-peridine-1-carboxylate (4) was synthesized according to thereported procedure [12] Then treatment of intermediate 4with compound 2a or 2b in the presence of NaH affordedtert-butyl 4-(6-(34-dimethoxybenzylamino)-2-chloro-9H-purin-9-yl)piperidine-1-carboxylate (5a) or tert-butyl4-(6-(benzo[d][13]dioxol-5-ylmethylamino)-2-chloro-9H-purin-9-yl)piperidine-1-carboxylate (5b) respectively Thedeprotection of the tert-butoxycarbonyl (t-Boc) group of 5aand 5b was accomplished using trifluoroacetic acid (TFA) indichloromethane (DCM) to yield N-(34-dimethoxybenzyl)-2-chloro-9-(piperidin-4-yl)-9H-purin-6-amine (6a) and N-(benzo[d][13]dioxol-5-ylmethyl)-2-chloro-9-(piperidin-4-yl)-9H-purin-6-amine (6b) respectively in good yield (91and 87) In the last step the alkylation reaction of piperidineat NH position with various substituted benzyl chloride(bromine) afforded the target compounds The newlysynthesized compounds were characterized by physico-chemical and spectral means and the MS and NMR spectral


N

N NH

NN

N NH

N

N

OH

NBoc

Boc

Boc

O

NH

NH NH NH1

3 4

SO

O

N

N N

N

N

(i)

(ii)

(iii)2a2b

5a5b

6a6b

N

N N

N

NH

N

N N

N

N

(iv) (v)

Cl

Cl Cl Cl

Cl

Cl

Ar

Ar

Ar Ar Ar

R1

2a 5a 6a

2b 5b 6b

7a1ndasha13 Ar =

7b1ndashb13


Ar = benzo[d][

34-dimethoxyphenyl

NH2

13]dioxol-5-yl






3 Conclusion





3N


2O (100mL) the









HN

N N

NN

Cl

NAr

R1





NANA





2SO4 filtered and







3 The solution was





1= 1080Hz

J2= 512Hz) 374 (3H s OCH

3) 371 (3H s OCH

3) 308

(2H d J = 888Hz) 265 (2H dt J1= 1428Hz J

2= 352Hz)


19H23ClN6O2

(40216)


2O) 505 (1H s NH) 454 (2H d J = 492Hz)

435 (1H dt J1= 1048Hz J

2= 540Hz) 305 (2H d J =

1232Hz) 260 (2H dt J1= 1476Hz J

2= 360Hz) 196 (4H

dd J1= 1664Hz J



18H19ClN6O2

(38613)


2CO3(12 eq) fol-





1= 832Hz J

2

= 327Hz) 373 (3H s OCH3) 371 (3H s OCH

3) 354 (2H


26H28Cl2N6O2(52617)



2= 10Hz) 752 (1H dd J

1= 764Hz J

2= 152Hz)

740 (1H dt J1= 748Hz J

2= 10Hz) 723 (1H dt J

1= 776Hz

J2= 168Hz) 706 (1H s) 686 (2H d J = 826Hz) 507 (1H

s NH) 454 (2H d J = 544Hz) 434 (1H dt J1= 1172Hz

J2= 384Hz) 373 (3H s OCH

3) 371 (3H s OCH

3) 360


6O2(57011)


2= 326Hz) 507 (1H s NH) 454 (2H

d J = 520Hz) 432 (1H dt J1= 862Hz J

2= 356Hz) 374


3) 362 (2H s) 290 (2H

d J = 928Hz) 217 (4H dd J1= 1660 J

2= 888Hz) 195


27H28ClN7O2(51720)


1= 1132 J

2= 328Hz) 374 (3H s OCH

3) 371 (3H



26H28ClN7O4(53719)


2= 616Hz) 717 (2H dd J

1= 936Hz J

2


1= 1028Hz J

2

= 368Hz) 374 (3H s OCH3) 371 (3H s OCH

3) 355 (2H


26H28ClFN6O2(51019)



1=

456Hz J2= 136Hz) 830 (1H s) 735 (2H d J = 580Hz)


1= 728Hz J

2= 376Hz)

373 (3H s OCH3) 370 (3H s OCH

3) 357 (2H s) 292


25H28ClN7O2(49320)


2= 404Hz) 373 (3H s OCH

3) 370 (3H s



26H29ClN6O2(49220)


1= 837Hz J

2= 576Hz) 374 (3H s OCH

3)

371 (3H s OCH3) 349 (2H s) 291 (2H d J = 636Hz)


26H28BrClN

6O2(57011)


2= 760Hz) 768 (2H d J = 780Hz) 756


1= 1084 J

2

= 326Hz) 373 (3H s OCH3) 371 (3H s OCH

3) 359 (2H


27H28ClN7O2(51720)


1= 862Hz J

2= 364Hz) 374 (3H s

OCH3) 373 (3H s OCH

3) 370 (3H s) 344 (2H s) 292


27H31ClN6O3(52221)


1= 1722Hz J

2= 720Hz) 734 (1H dd J

1= 856Hz

J2= 748Hz) 706 (1H s) 686 (2H d J= 382Hz) 506 (1H

s NH) 455 (2H d J = 456Hz) 429 (1H dt J1= 1026 J

2=

432Hz) 374 (3H s OCH3) 372 (2H s) 370 (3H s OCH

3)

293 (2H d J = 1168Hz) 240 (2H dt J1= 992Hz J

2=


26H27Cl3N6O2(56013)


1= 1124Hz J

2= 548Hz)

373 (3H s OCH3) 370 (3H s OCH

3) 343 (2H s) 286


29H35ClN6O2(53425)


2= 180Hz) 734 (1H dt J

1= 548Hz J

2=


2= 740Hz) 373 (3H s OCH

3) 371 (3H s



26H28ClFN6O2(51019)



1= 838Hz J

2= 283Hz) 596


432 (1H dt J1= 924 J

2= 364Hz) 354 (2H s) 292 (2H d


25H24Cl2N6O2(51013)


2= 428Hz) 597 (2H s OCH

2O) 504 (1H


2


1= 2184Hz J

2= 1172Hz) 196


25H24BrClN

6O2(55408)


1= 1088Hz J

2= 784Hz) 693 (1H s) 597 (2H s


(1H dt J1= 1088Hz J

2= 426Hz) 362 (2H s) 292 (2H d J


26H24ClN7O2(50117)


1= 708Hz J

2= 168Hz) 762 (2H d J =

868Hz) 692 (1H s) 683 (2H dd J1= 838Hz J

2= 283Hz)


520Hz) 432 (1H dt J1= 1140 J

2= 388Hz) 367 (2H s)


433 318 (2C) ESI-MS mz 5223 (M + 1) 5244 (M + 3)5444 (M + Na) C

25H24ClN7O4(52116)


1= 804Hz J

2= 648Hz) 717 (2H dt J

1=

796Hz J2= 212Hz) 708 (1H dt J

1= 864Hz J

2= 223Hz)



2= 426Hz) 355 (2H s) 293 (2H d J =


25H24ClFN6O2(49416)


1= 448Hz J

2= 144Hz) 831 (1H s) 735 (2H d

J = 584Hz) 692 (1H s) 683 (2H dd 1198691= 1012Hz J

2=


d J = 576Hz) 432 (1H dt J1= 1048Hz 119869

2= 362Hz) 357


24H24ClN7O2(47717)


1= 852Hz J

2= 428Hz) 692

(1H s) 683 (2H dd J1= 100Hz J

2= 780Hz) 596 (2H s


(1H dt J1= 781 J

2= 388Hz) 352 (2H s) 292 (2H d J =

636Hz) 213 (4H dt J1= 1136 J

2= 7 40Hz) 194 (2H s)


25H25ClN6O2(47617)


1= 726Hz J

2= 184Hz) 597 (2H s ndash


(1H dt J1= 728Hz J

2= 428Hz) 350 (2H s) 292 (2H d J =

66Hz) 220 (4H dt J1= 1236 J

2= 860Hz) 194 (2H s) 13C



1204 1189 1085 1012 614 529 525 (2C) 434 318 (2C)ESI-MS mz 5571 (M + 3) 5591 (M + 5) C

25H24BrClN

6O2

(55408)


1= 1084Hz J

2= 764Hz) 769 (2H d J =

784Hz) 657 (1H t J = 768Hz) 693 (1H s) 683 (2H ddJ1= 976 J


2Ondash) 504 (1H s

NH) 453 (2H d J = 540Hz) 431 (1H dt J1= 812 J

2=

384Hz) 360 (2H s) 293 (2H d J = 928Hz) 217 (4H dt J1

= 1204Hz J2= 968Hz) 194 (2H d J = 1104Hz) 13CNMR


26H24ClN7O2(50117)



2Ondash) 504

(1H s NH) 454 (2H d J = 592Hz) 428 (1H dt J1= 825 J

2


26H27ClN6O3

(50618)


1= 840Hz J

2= 076Hz) 734 (1H dd J

1=

754Hz J1= 862Hz) 692 (1H s) 683 (2H dd J

1= 1174


2Ondash) 504 (1H s NH) 454

(2H d J = 576Hz) 454 (2H d J = 604Hz) 432 (1H dt J1

= 782Hz J2= 426Hz) 374 (2H s) 295 (2H d J = 116Hz)

239 (2H t J = 16Hz) 199 (4H dt J1= 1151Hz J

2= 962Hz)




(1H dt J1= 1028Hz J

2= 480Hz) 344 (2H s) 286 (2H d



28H31ClN6O2(51822)


1= 80 J

2= 156Hz) 733 (1H dt J

1= 564 J

2

= 192Hz) 718 (2H dd J1= 142Hz J

2= 64Hz) 692 (1H


s NH) 454 (2H d J = 576Hz) 430 (1H dt J1= 1152Hz

J2= 416Hz) 359 (2H s) 295 (2H d J = 102Hz) 215 (4H

dt J1= 232Hz J

2= 1172Hz) 194 (2H t J = 1288Hz) 13C





Acknowledgments


References
























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

N NH

NN

N NH

N

N

OH

NBoc

Boc

Boc

O

NH

NH NH NH1

3 4

SO

O

N

N N

N

N

(i)

(ii)

(iii)2a2b

5a5b

6a6b

N

N N

N

NH

N

N N

N

N

(iv) (v)

Cl

Cl Cl Cl

Cl

Cl

Ar

Ar

Ar Ar Ar

R1

2a 5a 6a

2b 5b 6b

7a1ndasha13 Ar =

7b1ndashb13


Ar = benzo[d][

34-dimethoxyphenyl

NH2

13]dioxol-5-yl






3 Conclusion





3N


2O (100mL) the









HN

N N

NN

Cl

NAr

R1





NANA





2SO4 filtered and







3 The solution was





1= 1080Hz

J2= 512Hz) 374 (3H s OCH

3) 371 (3H s OCH

3) 308

(2H d J = 888Hz) 265 (2H dt J1= 1428Hz J

2= 352Hz)


19H23ClN6O2

(40216)


2O) 505 (1H s NH) 454 (2H d J = 492Hz)

435 (1H dt J1= 1048Hz J

2= 540Hz) 305 (2H d J =

1232Hz) 260 (2H dt J1= 1476Hz J

2= 360Hz) 196 (4H

dd J1= 1664Hz J



18H19ClN6O2

(38613)


2CO3(12 eq) fol-





1= 832Hz J

2

= 327Hz) 373 (3H s OCH3) 371 (3H s OCH

3) 354 (2H


26H28Cl2N6O2(52617)



2= 10Hz) 752 (1H dd J

1= 764Hz J

2= 152Hz)

740 (1H dt J1= 748Hz J

2= 10Hz) 723 (1H dt J

1= 776Hz

J2= 168Hz) 706 (1H s) 686 (2H d J = 826Hz) 507 (1H

s NH) 454 (2H d J = 544Hz) 434 (1H dt J1= 1172Hz

J2= 384Hz) 373 (3H s OCH

3) 371 (3H s OCH

3) 360


6O2(57011)


2= 326Hz) 507 (1H s NH) 454 (2H

d J = 520Hz) 432 (1H dt J1= 862Hz J

2= 356Hz) 374


3) 362 (2H s) 290 (2H

d J = 928Hz) 217 (4H dd J1= 1660 J

2= 888Hz) 195


27H28ClN7O2(51720)


1= 1132 J

2= 328Hz) 374 (3H s OCH

3) 371 (3H



26H28ClN7O4(53719)


2= 616Hz) 717 (2H dd J

1= 936Hz J

2


1= 1028Hz J

2

= 368Hz) 374 (3H s OCH3) 371 (3H s OCH

3) 355 (2H


26H28ClFN6O2(51019)



1=

456Hz J2= 136Hz) 830 (1H s) 735 (2H d J = 580Hz)


1= 728Hz J

2= 376Hz)

373 (3H s OCH3) 370 (3H s OCH

3) 357 (2H s) 292


25H28ClN7O2(49320)


2= 404Hz) 373 (3H s OCH

3) 370 (3H s



26H29ClN6O2(49220)


1= 837Hz J

2= 576Hz) 374 (3H s OCH

3)

371 (3H s OCH3) 349 (2H s) 291 (2H d J = 636Hz)


26H28BrClN

6O2(57011)


2= 760Hz) 768 (2H d J = 780Hz) 756


1= 1084 J

2

= 326Hz) 373 (3H s OCH3) 371 (3H s OCH

3) 359 (2H


27H28ClN7O2(51720)


1= 862Hz J

2= 364Hz) 374 (3H s

OCH3) 373 (3H s OCH

3) 370 (3H s) 344 (2H s) 292


27H31ClN6O3(52221)


1= 1722Hz J

2= 720Hz) 734 (1H dd J

1= 856Hz

J2= 748Hz) 706 (1H s) 686 (2H d J= 382Hz) 506 (1H

s NH) 455 (2H d J = 456Hz) 429 (1H dt J1= 1026 J

2=

432Hz) 374 (3H s OCH3) 372 (2H s) 370 (3H s OCH

3)

293 (2H d J = 1168Hz) 240 (2H dt J1= 992Hz J

2=


26H27Cl3N6O2(56013)


1= 1124Hz J

2= 548Hz)

373 (3H s OCH3) 370 (3H s OCH

3) 343 (2H s) 286


29H35ClN6O2(53425)


2= 180Hz) 734 (1H dt J

1= 548Hz J

2=


2= 740Hz) 373 (3H s OCH

3) 371 (3H s



26H28ClFN6O2(51019)



1= 838Hz J

2= 283Hz) 596


432 (1H dt J1= 924 J

2= 364Hz) 354 (2H s) 292 (2H d


25H24Cl2N6O2(51013)


2= 428Hz) 597 (2H s OCH

2O) 504 (1H


2


1= 2184Hz J

2= 1172Hz) 196


25H24BrClN

6O2(55408)


1= 1088Hz J

2= 784Hz) 693 (1H s) 597 (2H s


(1H dt J1= 1088Hz J

2= 426Hz) 362 (2H s) 292 (2H d J


26H24ClN7O2(50117)


1= 708Hz J

2= 168Hz) 762 (2H d J =

868Hz) 692 (1H s) 683 (2H dd J1= 838Hz J

2= 283Hz)


520Hz) 432 (1H dt J1= 1140 J

2= 388Hz) 367 (2H s)


433 318 (2C) ESI-MS mz 5223 (M + 1) 5244 (M + 3)5444 (M + Na) C

25H24ClN7O4(52116)


1= 804Hz J

2= 648Hz) 717 (2H dt J

1=

796Hz J2= 212Hz) 708 (1H dt J

1= 864Hz J

2= 223Hz)



2= 426Hz) 355 (2H s) 293 (2H d J =


25H24ClFN6O2(49416)


1= 448Hz J

2= 144Hz) 831 (1H s) 735 (2H d

J = 584Hz) 692 (1H s) 683 (2H dd 1198691= 1012Hz J

2=


d J = 576Hz) 432 (1H dt J1= 1048Hz 119869

2= 362Hz) 357


24H24ClN7O2(47717)


1= 852Hz J

2= 428Hz) 692

(1H s) 683 (2H dd J1= 100Hz J

2= 780Hz) 596 (2H s


(1H dt J1= 781 J

2= 388Hz) 352 (2H s) 292 (2H d J =

636Hz) 213 (4H dt J1= 1136 J

2= 7 40Hz) 194 (2H s)


25H25ClN6O2(47617)


1= 726Hz J

2= 184Hz) 597 (2H s ndash


(1H dt J1= 728Hz J

2= 428Hz) 350 (2H s) 292 (2H d J =

66Hz) 220 (4H dt J1= 1236 J

2= 860Hz) 194 (2H s) 13C



1204 1189 1085 1012 614 529 525 (2C) 434 318 (2C)ESI-MS mz 5571 (M + 3) 5591 (M + 5) C

25H24BrClN

6O2

(55408)


1= 1084Hz J

2= 764Hz) 769 (2H d J =

784Hz) 657 (1H t J = 768Hz) 693 (1H s) 683 (2H ddJ1= 976 J


2Ondash) 504 (1H s

NH) 453 (2H d J = 540Hz) 431 (1H dt J1= 812 J

2=

384Hz) 360 (2H s) 293 (2H d J = 928Hz) 217 (4H dt J1

= 1204Hz J2= 968Hz) 194 (2H d J = 1104Hz) 13CNMR


26H24ClN7O2(50117)



2Ondash) 504

(1H s NH) 454 (2H d J = 592Hz) 428 (1H dt J1= 825 J

2


26H27ClN6O3

(50618)


1= 840Hz J

2= 076Hz) 734 (1H dd J

1=

754Hz J1= 862Hz) 692 (1H s) 683 (2H dd J

1= 1174


2Ondash) 504 (1H s NH) 454

(2H d J = 576Hz) 454 (2H d J = 604Hz) 432 (1H dt J1

= 782Hz J2= 426Hz) 374 (2H s) 295 (2H d J = 116Hz)

239 (2H t J = 16Hz) 199 (4H dt J1= 1151Hz J

2= 962Hz)




(1H dt J1= 1028Hz J

2= 480Hz) 344 (2H s) 286 (2H d



28H31ClN6O2(51822)


1= 80 J

2= 156Hz) 733 (1H dt J

1= 564 J

2

= 192Hz) 718 (2H dd J1= 142Hz J

2= 64Hz) 692 (1H


s NH) 454 (2H d J = 576Hz) 430 (1H dt J1= 1152Hz

J2= 416Hz) 359 (2H s) 295 (2H d J = 102Hz) 215 (4H

dt J1= 232Hz J

2= 1172Hz) 194 (2H t J = 1288Hz) 13C





Acknowledgments


References
























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



HN

N N

NN

Cl

NAr

R1





NANA





2SO4 filtered and







3 The solution was





1= 1080Hz

J2= 512Hz) 374 (3H s OCH

3) 371 (3H s OCH

3) 308

(2H d J = 888Hz) 265 (2H dt J1= 1428Hz J

2= 352Hz)


19H23ClN6O2

(40216)


2O) 505 (1H s NH) 454 (2H d J = 492Hz)

435 (1H dt J1= 1048Hz J

2= 540Hz) 305 (2H d J =

1232Hz) 260 (2H dt J1= 1476Hz J

2= 360Hz) 196 (4H

dd J1= 1664Hz J



18H19ClN6O2

(38613)


2CO3(12 eq) fol-





1= 832Hz J

2

= 327Hz) 373 (3H s OCH3) 371 (3H s OCH

3) 354 (2H


26H28Cl2N6O2(52617)



2= 10Hz) 752 (1H dd J

1= 764Hz J

2= 152Hz)

740 (1H dt J1= 748Hz J

2= 10Hz) 723 (1H dt J

1= 776Hz

J2= 168Hz) 706 (1H s) 686 (2H d J = 826Hz) 507 (1H

s NH) 454 (2H d J = 544Hz) 434 (1H dt J1= 1172Hz

J2= 384Hz) 373 (3H s OCH

3) 371 (3H s OCH

3) 360


6O2(57011)


2= 326Hz) 507 (1H s NH) 454 (2H

d J = 520Hz) 432 (1H dt J1= 862Hz J

2= 356Hz) 374


3) 362 (2H s) 290 (2H

d J = 928Hz) 217 (4H dd J1= 1660 J

2= 888Hz) 195


27H28ClN7O2(51720)


1= 1132 J

2= 328Hz) 374 (3H s OCH

3) 371 (3H



26H28ClN7O4(53719)


2= 616Hz) 717 (2H dd J

1= 936Hz J

2


1= 1028Hz J

2

= 368Hz) 374 (3H s OCH3) 371 (3H s OCH

3) 355 (2H


26H28ClFN6O2(51019)



1=

456Hz J2= 136Hz) 830 (1H s) 735 (2H d J = 580Hz)


1= 728Hz J

2= 376Hz)

373 (3H s OCH3) 370 (3H s OCH

3) 357 (2H s) 292


25H28ClN7O2(49320)


2= 404Hz) 373 (3H s OCH

3) 370 (3H s



26H29ClN6O2(49220)


1= 837Hz J

2= 576Hz) 374 (3H s OCH

3)

371 (3H s OCH3) 349 (2H s) 291 (2H d J = 636Hz)


26H28BrClN

6O2(57011)


2= 760Hz) 768 (2H d J = 780Hz) 756


1= 1084 J

2

= 326Hz) 373 (3H s OCH3) 371 (3H s OCH

3) 359 (2H


27H28ClN7O2(51720)


1= 862Hz J

2= 364Hz) 374 (3H s

OCH3) 373 (3H s OCH

3) 370 (3H s) 344 (2H s) 292


27H31ClN6O3(52221)


1= 1722Hz J

2= 720Hz) 734 (1H dd J

1= 856Hz

J2= 748Hz) 706 (1H s) 686 (2H d J= 382Hz) 506 (1H

s NH) 455 (2H d J = 456Hz) 429 (1H dt J1= 1026 J

2=

432Hz) 374 (3H s OCH3) 372 (2H s) 370 (3H s OCH

3)

293 (2H d J = 1168Hz) 240 (2H dt J1= 992Hz J

2=


26H27Cl3N6O2(56013)


1= 1124Hz J

2= 548Hz)

373 (3H s OCH3) 370 (3H s OCH

3) 343 (2H s) 286


29H35ClN6O2(53425)


2= 180Hz) 734 (1H dt J

1= 548Hz J

2=


2= 740Hz) 373 (3H s OCH

3) 371 (3H s



26H28ClFN6O2(51019)



1= 838Hz J

2= 283Hz) 596


432 (1H dt J1= 924 J

2= 364Hz) 354 (2H s) 292 (2H d


25H24Cl2N6O2(51013)


2= 428Hz) 597 (2H s OCH

2O) 504 (1H


2


1= 2184Hz J

2= 1172Hz) 196


25H24BrClN

6O2(55408)


1= 1088Hz J

2= 784Hz) 693 (1H s) 597 (2H s


(1H dt J1= 1088Hz J

2= 426Hz) 362 (2H s) 292 (2H d J


26H24ClN7O2(50117)


1= 708Hz J

2= 168Hz) 762 (2H d J =

868Hz) 692 (1H s) 683 (2H dd J1= 838Hz J

2= 283Hz)


520Hz) 432 (1H dt J1= 1140 J

2= 388Hz) 367 (2H s)


433 318 (2C) ESI-MS mz 5223 (M + 1) 5244 (M + 3)5444 (M + Na) C

25H24ClN7O4(52116)


1= 804Hz J

2= 648Hz) 717 (2H dt J

1=

796Hz J2= 212Hz) 708 (1H dt J

1= 864Hz J

2= 223Hz)



2= 426Hz) 355 (2H s) 293 (2H d J =


25H24ClFN6O2(49416)


1= 448Hz J

2= 144Hz) 831 (1H s) 735 (2H d

J = 584Hz) 692 (1H s) 683 (2H dd 1198691= 1012Hz J

2=


d J = 576Hz) 432 (1H dt J1= 1048Hz 119869

2= 362Hz) 357


24H24ClN7O2(47717)


1= 852Hz J

2= 428Hz) 692

(1H s) 683 (2H dd J1= 100Hz J

2= 780Hz) 596 (2H s


(1H dt J1= 781 J

2= 388Hz) 352 (2H s) 292 (2H d J =

636Hz) 213 (4H dt J1= 1136 J

2= 7 40Hz) 194 (2H s)


25H25ClN6O2(47617)


1= 726Hz J

2= 184Hz) 597 (2H s ndash


(1H dt J1= 728Hz J

2= 428Hz) 350 (2H s) 292 (2H d J =

66Hz) 220 (4H dt J1= 1236 J

2= 860Hz) 194 (2H s) 13C



1204 1189 1085 1012 614 529 525 (2C) 434 318 (2C)ESI-MS mz 5571 (M + 3) 5591 (M + 5) C

25H24BrClN

6O2

(55408)


1= 1084Hz J

2= 764Hz) 769 (2H d J =

784Hz) 657 (1H t J = 768Hz) 693 (1H s) 683 (2H ddJ1= 976 J


2Ondash) 504 (1H s

NH) 453 (2H d J = 540Hz) 431 (1H dt J1= 812 J

2=

384Hz) 360 (2H s) 293 (2H d J = 928Hz) 217 (4H dt J1

= 1204Hz J2= 968Hz) 194 (2H d J = 1104Hz) 13CNMR


26H24ClN7O2(50117)



2Ondash) 504

(1H s NH) 454 (2H d J = 592Hz) 428 (1H dt J1= 825 J

2


26H27ClN6O3

(50618)


1= 840Hz J

2= 076Hz) 734 (1H dd J

1=

754Hz J1= 862Hz) 692 (1H s) 683 (2H dd J

1= 1174


2Ondash) 504 (1H s NH) 454

(2H d J = 576Hz) 454 (2H d J = 604Hz) 432 (1H dt J1

= 782Hz J2= 426Hz) 374 (2H s) 295 (2H d J = 116Hz)

239 (2H t J = 16Hz) 199 (4H dt J1= 1151Hz J

2= 962Hz)




(1H dt J1= 1028Hz J

2= 480Hz) 344 (2H s) 286 (2H d



28H31ClN6O2(51822)


1= 80 J

2= 156Hz) 733 (1H dt J

1= 564 J

2

= 192Hz) 718 (2H dd J1= 142Hz J

2= 64Hz) 692 (1H


s NH) 454 (2H d J = 576Hz) 430 (1H dt J1= 1152Hz

J2= 416Hz) 359 (2H s) 295 (2H d J = 102Hz) 215 (4H

dt J1= 232Hz J

2= 1172Hz) 194 (2H t J = 1288Hz) 13C





Acknowledgments


References
























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of





1= 1080Hz

J2= 512Hz) 374 (3H s OCH

3) 371 (3H s OCH

3) 308

(2H d J = 888Hz) 265 (2H dt J1= 1428Hz J

2= 352Hz)


19H23ClN6O2

(40216)


2O) 505 (1H s NH) 454 (2H d J = 492Hz)

435 (1H dt J1= 1048Hz J

2= 540Hz) 305 (2H d J =

1232Hz) 260 (2H dt J1= 1476Hz J

2= 360Hz) 196 (4H

dd J1= 1664Hz J



18H19ClN6O2

(38613)


2CO3(12 eq) fol-





1= 832Hz J

2

= 327Hz) 373 (3H s OCH3) 371 (3H s OCH

3) 354 (2H


26H28Cl2N6O2(52617)



2= 10Hz) 752 (1H dd J

1= 764Hz J

2= 152Hz)

740 (1H dt J1= 748Hz J

2= 10Hz) 723 (1H dt J

1= 776Hz

J2= 168Hz) 706 (1H s) 686 (2H d J = 826Hz) 507 (1H

s NH) 454 (2H d J = 544Hz) 434 (1H dt J1= 1172Hz

J2= 384Hz) 373 (3H s OCH

3) 371 (3H s OCH

3) 360


6O2(57011)


2= 326Hz) 507 (1H s NH) 454 (2H

d J = 520Hz) 432 (1H dt J1= 862Hz J

2= 356Hz) 374


3) 362 (2H s) 290 (2H

d J = 928Hz) 217 (4H dd J1= 1660 J

2= 888Hz) 195


27H28ClN7O2(51720)


1= 1132 J

2= 328Hz) 374 (3H s OCH

3) 371 (3H



26H28ClN7O4(53719)


2= 616Hz) 717 (2H dd J

1= 936Hz J

2


1= 1028Hz J

2

= 368Hz) 374 (3H s OCH3) 371 (3H s OCH

3) 355 (2H


26H28ClFN6O2(51019)



1=

456Hz J2= 136Hz) 830 (1H s) 735 (2H d J = 580Hz)


1= 728Hz J

2= 376Hz)

373 (3H s OCH3) 370 (3H s OCH

3) 357 (2H s) 292


25H28ClN7O2(49320)


2= 404Hz) 373 (3H s OCH

3) 370 (3H s



26H29ClN6O2(49220)


1= 837Hz J

2= 576Hz) 374 (3H s OCH

3)

371 (3H s OCH3) 349 (2H s) 291 (2H d J = 636Hz)


26H28BrClN

6O2(57011)


2= 760Hz) 768 (2H d J = 780Hz) 756


1= 1084 J

2

= 326Hz) 373 (3H s OCH3) 371 (3H s OCH

3) 359 (2H


27H28ClN7O2(51720)


1= 862Hz J

2= 364Hz) 374 (3H s

OCH3) 373 (3H s OCH

3) 370 (3H s) 344 (2H s) 292


27H31ClN6O3(52221)


1= 1722Hz J

2= 720Hz) 734 (1H dd J

1= 856Hz

J2= 748Hz) 706 (1H s) 686 (2H d J= 382Hz) 506 (1H

s NH) 455 (2H d J = 456Hz) 429 (1H dt J1= 1026 J

2=

432Hz) 374 (3H s OCH3) 372 (2H s) 370 (3H s OCH

3)

293 (2H d J = 1168Hz) 240 (2H dt J1= 992Hz J

2=


26H27Cl3N6O2(56013)


1= 1124Hz J

2= 548Hz)

373 (3H s OCH3) 370 (3H s OCH

3) 343 (2H s) 286


29H35ClN6O2(53425)


2= 180Hz) 734 (1H dt J

1= 548Hz J

2=


2= 740Hz) 373 (3H s OCH

3) 371 (3H s



26H28ClFN6O2(51019)



1= 838Hz J

2= 283Hz) 596


432 (1H dt J1= 924 J

2= 364Hz) 354 (2H s) 292 (2H d


25H24Cl2N6O2(51013)


2= 428Hz) 597 (2H s OCH

2O) 504 (1H


2


1= 2184Hz J

2= 1172Hz) 196


25H24BrClN

6O2(55408)


1= 1088Hz J

2= 784Hz) 693 (1H s) 597 (2H s


(1H dt J1= 1088Hz J

2= 426Hz) 362 (2H s) 292 (2H d J


26H24ClN7O2(50117)


1= 708Hz J

2= 168Hz) 762 (2H d J =

868Hz) 692 (1H s) 683 (2H dd J1= 838Hz J

2= 283Hz)


520Hz) 432 (1H dt J1= 1140 J

2= 388Hz) 367 (2H s)


433 318 (2C) ESI-MS mz 5223 (M + 1) 5244 (M + 3)5444 (M + Na) C

25H24ClN7O4(52116)


1= 804Hz J

2= 648Hz) 717 (2H dt J

1=

796Hz J2= 212Hz) 708 (1H dt J

1= 864Hz J

2= 223Hz)



2= 426Hz) 355 (2H s) 293 (2H d J =


25H24ClFN6O2(49416)


1= 448Hz J

2= 144Hz) 831 (1H s) 735 (2H d

J = 584Hz) 692 (1H s) 683 (2H dd 1198691= 1012Hz J

2=


d J = 576Hz) 432 (1H dt J1= 1048Hz 119869

2= 362Hz) 357


24H24ClN7O2(47717)


1= 852Hz J

2= 428Hz) 692

(1H s) 683 (2H dd J1= 100Hz J

2= 780Hz) 596 (2H s


(1H dt J1= 781 J

2= 388Hz) 352 (2H s) 292 (2H d J =

636Hz) 213 (4H dt J1= 1136 J

2= 7 40Hz) 194 (2H s)


25H25ClN6O2(47617)


1= 726Hz J

2= 184Hz) 597 (2H s ndash


(1H dt J1= 728Hz J

2= 428Hz) 350 (2H s) 292 (2H d J =

66Hz) 220 (4H dt J1= 1236 J

2= 860Hz) 194 (2H s) 13C



1204 1189 1085 1012 614 529 525 (2C) 434 318 (2C)ESI-MS mz 5571 (M + 3) 5591 (M + 5) C

25H24BrClN

6O2

(55408)


1= 1084Hz J

2= 764Hz) 769 (2H d J =

784Hz) 657 (1H t J = 768Hz) 693 (1H s) 683 (2H ddJ1= 976 J


2Ondash) 504 (1H s

NH) 453 (2H d J = 540Hz) 431 (1H dt J1= 812 J

2=

384Hz) 360 (2H s) 293 (2H d J = 928Hz) 217 (4H dt J1

= 1204Hz J2= 968Hz) 194 (2H d J = 1104Hz) 13CNMR


26H24ClN7O2(50117)



2Ondash) 504

(1H s NH) 454 (2H d J = 592Hz) 428 (1H dt J1= 825 J

2


26H27ClN6O3

(50618)


1= 840Hz J

2= 076Hz) 734 (1H dd J

1=

754Hz J1= 862Hz) 692 (1H s) 683 (2H dd J

1= 1174


2Ondash) 504 (1H s NH) 454

(2H d J = 576Hz) 454 (2H d J = 604Hz) 432 (1H dt J1

= 782Hz J2= 426Hz) 374 (2H s) 295 (2H d J = 116Hz)

239 (2H t J = 16Hz) 199 (4H dt J1= 1151Hz J

2= 962Hz)




(1H dt J1= 1028Hz J

2= 480Hz) 344 (2H s) 286 (2H d



28H31ClN6O2(51822)


1= 80 J

2= 156Hz) 733 (1H dt J

1= 564 J

2

= 192Hz) 718 (2H dd J1= 142Hz J

2= 64Hz) 692 (1H


s NH) 454 (2H d J = 576Hz) 430 (1H dt J1= 1152Hz

J2= 416Hz) 359 (2H s) 295 (2H d J = 102Hz) 215 (4H

dt J1= 232Hz J

2= 1172Hz) 194 (2H t J = 1288Hz) 13C





Acknowledgments


References
























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



1=

456Hz J2= 136Hz) 830 (1H s) 735 (2H d J = 580Hz)


1= 728Hz J

2= 376Hz)

373 (3H s OCH3) 370 (3H s OCH

3) 357 (2H s) 292


25H28ClN7O2(49320)


2= 404Hz) 373 (3H s OCH

3) 370 (3H s



26H29ClN6O2(49220)


1= 837Hz J

2= 576Hz) 374 (3H s OCH

3)

371 (3H s OCH3) 349 (2H s) 291 (2H d J = 636Hz)


26H28BrClN

6O2(57011)


2= 760Hz) 768 (2H d J = 780Hz) 756


1= 1084 J

2

= 326Hz) 373 (3H s OCH3) 371 (3H s OCH

3) 359 (2H


27H28ClN7O2(51720)


1= 862Hz J

2= 364Hz) 374 (3H s

OCH3) 373 (3H s OCH

3) 370 (3H s) 344 (2H s) 292


27H31ClN6O3(52221)


1= 1722Hz J

2= 720Hz) 734 (1H dd J

1= 856Hz

J2= 748Hz) 706 (1H s) 686 (2H d J= 382Hz) 506 (1H

s NH) 455 (2H d J = 456Hz) 429 (1H dt J1= 1026 J

2=

432Hz) 374 (3H s OCH3) 372 (2H s) 370 (3H s OCH

3)

293 (2H d J = 1168Hz) 240 (2H dt J1= 992Hz J

2=


26H27Cl3N6O2(56013)


1= 1124Hz J

2= 548Hz)

373 (3H s OCH3) 370 (3H s OCH

3) 343 (2H s) 286


29H35ClN6O2(53425)


2= 180Hz) 734 (1H dt J

1= 548Hz J

2=


2= 740Hz) 373 (3H s OCH

3) 371 (3H s



26H28ClFN6O2(51019)



1= 838Hz J

2= 283Hz) 596


432 (1H dt J1= 924 J

2= 364Hz) 354 (2H s) 292 (2H d


25H24Cl2N6O2(51013)


2= 428Hz) 597 (2H s OCH

2O) 504 (1H


2


1= 2184Hz J

2= 1172Hz) 196


25H24BrClN

6O2(55408)


1= 1088Hz J

2= 784Hz) 693 (1H s) 597 (2H s


(1H dt J1= 1088Hz J

2= 426Hz) 362 (2H s) 292 (2H d J


26H24ClN7O2(50117)


1= 708Hz J

2= 168Hz) 762 (2H d J =

868Hz) 692 (1H s) 683 (2H dd J1= 838Hz J

2= 283Hz)


520Hz) 432 (1H dt J1= 1140 J

2= 388Hz) 367 (2H s)


433 318 (2C) ESI-MS mz 5223 (M + 1) 5244 (M + 3)5444 (M + Na) C

25H24ClN7O4(52116)


1= 804Hz J

2= 648Hz) 717 (2H dt J

1=

796Hz J2= 212Hz) 708 (1H dt J

1= 864Hz J

2= 223Hz)



2= 426Hz) 355 (2H s) 293 (2H d J =


25H24ClFN6O2(49416)


1= 448Hz J

2= 144Hz) 831 (1H s) 735 (2H d

J = 584Hz) 692 (1H s) 683 (2H dd 1198691= 1012Hz J

2=


d J = 576Hz) 432 (1H dt J1= 1048Hz 119869

2= 362Hz) 357


24H24ClN7O2(47717)


1= 852Hz J

2= 428Hz) 692

(1H s) 683 (2H dd J1= 100Hz J

2= 780Hz) 596 (2H s


(1H dt J1= 781 J

2= 388Hz) 352 (2H s) 292 (2H d J =

636Hz) 213 (4H dt J1= 1136 J

2= 7 40Hz) 194 (2H s)


25H25ClN6O2(47617)


1= 726Hz J

2= 184Hz) 597 (2H s ndash


(1H dt J1= 728Hz J

2= 428Hz) 350 (2H s) 292 (2H d J =

66Hz) 220 (4H dt J1= 1236 J

2= 860Hz) 194 (2H s) 13C



1204 1189 1085 1012 614 529 525 (2C) 434 318 (2C)ESI-MS mz 5571 (M + 3) 5591 (M + 5) C

25H24BrClN

6O2

(55408)


1= 1084Hz J

2= 764Hz) 769 (2H d J =

784Hz) 657 (1H t J = 768Hz) 693 (1H s) 683 (2H ddJ1= 976 J


2Ondash) 504 (1H s

NH) 453 (2H d J = 540Hz) 431 (1H dt J1= 812 J

2=

384Hz) 360 (2H s) 293 (2H d J = 928Hz) 217 (4H dt J1

= 1204Hz J2= 968Hz) 194 (2H d J = 1104Hz) 13CNMR


26H24ClN7O2(50117)



2Ondash) 504

(1H s NH) 454 (2H d J = 592Hz) 428 (1H dt J1= 825 J

2


26H27ClN6O3

(50618)


1= 840Hz J

2= 076Hz) 734 (1H dd J

1=

754Hz J1= 862Hz) 692 (1H s) 683 (2H dd J

1= 1174


2Ondash) 504 (1H s NH) 454

(2H d J = 576Hz) 454 (2H d J = 604Hz) 432 (1H dt J1

= 782Hz J2= 426Hz) 374 (2H s) 295 (2H d J = 116Hz)

239 (2H t J = 16Hz) 199 (4H dt J1= 1151Hz J

2= 962Hz)




(1H dt J1= 1028Hz J

2= 480Hz) 344 (2H s) 286 (2H d



28H31ClN6O2(51822)


1= 80 J

2= 156Hz) 733 (1H dt J

1= 564 J

2

= 192Hz) 718 (2H dd J1= 142Hz J

2= 64Hz) 692 (1H


s NH) 454 (2H d J = 576Hz) 430 (1H dt J1= 1152Hz

J2= 416Hz) 359 (2H s) 295 (2H d J = 102Hz) 215 (4H

dt J1= 232Hz J

2= 1172Hz) 194 (2H t J = 1288Hz) 13C





Acknowledgments


References
























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



1= 838Hz J

2= 283Hz) 596


432 (1H dt J1= 924 J

2= 364Hz) 354 (2H s) 292 (2H d


25H24Cl2N6O2(51013)


2= 428Hz) 597 (2H s OCH

2O) 504 (1H


2


1= 2184Hz J

2= 1172Hz) 196


25H24BrClN

6O2(55408)


1= 1088Hz J

2= 784Hz) 693 (1H s) 597 (2H s


(1H dt J1= 1088Hz J

2= 426Hz) 362 (2H s) 292 (2H d J


26H24ClN7O2(50117)


1= 708Hz J

2= 168Hz) 762 (2H d J =

868Hz) 692 (1H s) 683 (2H dd J1= 838Hz J

2= 283Hz)


520Hz) 432 (1H dt J1= 1140 J

2= 388Hz) 367 (2H s)


433 318 (2C) ESI-MS mz 5223 (M + 1) 5244 (M + 3)5444 (M + Na) C

25H24ClN7O4(52116)


1= 804Hz J

2= 648Hz) 717 (2H dt J

1=

796Hz J2= 212Hz) 708 (1H dt J

1= 864Hz J

2= 223Hz)



2= 426Hz) 355 (2H s) 293 (2H d J =


25H24ClFN6O2(49416)


1= 448Hz J

2= 144Hz) 831 (1H s) 735 (2H d

J = 584Hz) 692 (1H s) 683 (2H dd 1198691= 1012Hz J

2=


d J = 576Hz) 432 (1H dt J1= 1048Hz 119869

2= 362Hz) 357


24H24ClN7O2(47717)


1= 852Hz J

2= 428Hz) 692

(1H s) 683 (2H dd J1= 100Hz J

2= 780Hz) 596 (2H s


(1H dt J1= 781 J

2= 388Hz) 352 (2H s) 292 (2H d J =

636Hz) 213 (4H dt J1= 1136 J

2= 7 40Hz) 194 (2H s)


25H25ClN6O2(47617)


1= 726Hz J

2= 184Hz) 597 (2H s ndash


(1H dt J1= 728Hz J

2= 428Hz) 350 (2H s) 292 (2H d J =

66Hz) 220 (4H dt J1= 1236 J

2= 860Hz) 194 (2H s) 13C



1204 1189 1085 1012 614 529 525 (2C) 434 318 (2C)ESI-MS mz 5571 (M + 3) 5591 (M + 5) C

25H24BrClN

6O2

(55408)


1= 1084Hz J

2= 764Hz) 769 (2H d J =

784Hz) 657 (1H t J = 768Hz) 693 (1H s) 683 (2H ddJ1= 976 J


2Ondash) 504 (1H s

NH) 453 (2H d J = 540Hz) 431 (1H dt J1= 812 J

2=

384Hz) 360 (2H s) 293 (2H d J = 928Hz) 217 (4H dt J1

= 1204Hz J2= 968Hz) 194 (2H d J = 1104Hz) 13CNMR


26H24ClN7O2(50117)



2Ondash) 504

(1H s NH) 454 (2H d J = 592Hz) 428 (1H dt J1= 825 J

2


26H27ClN6O3

(50618)


1= 840Hz J

2= 076Hz) 734 (1H dd J

1=

754Hz J1= 862Hz) 692 (1H s) 683 (2H dd J

1= 1174


2Ondash) 504 (1H s NH) 454

(2H d J = 576Hz) 454 (2H d J = 604Hz) 432 (1H dt J1

= 782Hz J2= 426Hz) 374 (2H s) 295 (2H d J = 116Hz)

239 (2H t J = 16Hz) 199 (4H dt J1= 1151Hz J

2= 962Hz)




(1H dt J1= 1028Hz J

2= 480Hz) 344 (2H s) 286 (2H d



28H31ClN6O2(51822)


1= 80 J

2= 156Hz) 733 (1H dt J

1= 564 J

2

= 192Hz) 718 (2H dd J1= 142Hz J

2= 64Hz) 692 (1H


s NH) 454 (2H d J = 576Hz) 430 (1H dt J1= 1152Hz

J2= 416Hz) 359 (2H s) 295 (2H d J = 102Hz) 215 (4H

dt J1= 232Hz J

2= 1172Hz) 194 (2H t J = 1288Hz) 13C





Acknowledgments


References
























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


1204 1189 1085 1012 614 529 525 (2C) 434 318 (2C)ESI-MS mz 5571 (M + 3) 5591 (M + 5) C

25H24BrClN

6O2

(55408)


1= 1084Hz J

2= 764Hz) 769 (2H d J =

784Hz) 657 (1H t J = 768Hz) 693 (1H s) 683 (2H ddJ1= 976 J


2Ondash) 504 (1H s

NH) 453 (2H d J = 540Hz) 431 (1H dt J1= 812 J

2=

384Hz) 360 (2H s) 293 (2H d J = 928Hz) 217 (4H dt J1

= 1204Hz J2= 968Hz) 194 (2H d J = 1104Hz) 13CNMR


26H24ClN7O2(50117)



2Ondash) 504

(1H s NH) 454 (2H d J = 592Hz) 428 (1H dt J1= 825 J

2


26H27ClN6O3

(50618)


1= 840Hz J

2= 076Hz) 734 (1H dd J

1=

754Hz J1= 862Hz) 692 (1H s) 683 (2H dd J

1= 1174


2Ondash) 504 (1H s NH) 454

(2H d J = 576Hz) 454 (2H d J = 604Hz) 432 (1H dt J1

= 782Hz J2= 426Hz) 374 (2H s) 295 (2H d J = 116Hz)

239 (2H t J = 16Hz) 199 (4H dt J1= 1151Hz J

2= 962Hz)




(1H dt J1= 1028Hz J

2= 480Hz) 344 (2H s) 286 (2H d



28H31ClN6O2(51822)


1= 80 J

2= 156Hz) 733 (1H dt J

1= 564 J

2

= 192Hz) 718 (2H dd J1= 142Hz J

2= 64Hz) 692 (1H


s NH) 454 (2H d J = 576Hz) 430 (1H dt J1= 1152Hz

J2= 416Hz) 359 (2H s) 295 (2H d J = 102Hz) 215 (4H

dt J1= 232Hz J

2= 1172Hz) 194 (2H t J = 1288Hz) 13C





Acknowledgments


References
























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

Documents

Research Article Design, Synthesis, and