taken together , malaria ( caused by plasmodium species ) , human african trypanosomiasis ( hat , caused by trypanosoma brucei ) , chagas disease ( caused by t. 
 cruzi ) , and leishmaniasis ( caused by leishmania species ) represent diseases with an estimated combined burden of 
 over 87 million disability - adjusted life years .
while progress has certainly been made toward the discovery 
 of new hits , much work remains to translate these hits into promising 
 chemical lead series that may be advanced for drug development .
target 
 repurposing  , wherein inhibitors of human homologues of essential 
 parasite proteins are assessed for efficacy against parasite cells .
we have recently initiated the repurposing of 
 a variety of kinase inhibitors for parasitic diseases and have also described the use of established human phosphodiesterase 
 inhibitors as starting points for lead discovery .
we have described the discovery of neu-617 ( 1 ) , a 
 derivative of the approved human cancer drug lapatinib ( 2 ) , which acts as a potent , orally bioavailable growth inhibitor of t. brucei that showed a modest effect in a mouse model of 
 bloodstream infection .
based on the close phylogenetic relationship 
 between the kinomes of the trypanosomatid parasites ( t. brucei , t. cruzi , and leishmania major ) , we hypothesized that all the pathogens 
 would be susceptible to these inhibitors .
we have therefore tested 1 , along with the other analogs synthesized during the course 
 of our hit - to - lead optimization program , against the two other kinetoplastid 
 parasites . based on our previous observation that related chemotypes 

show activity against plasmodium falciparum , we also screened this set of compounds against 
 cultures of drug - sensitive and drug - resistant strains of malaria . 
 in doing so , we noted differential structure  activity relationships 
 for these compounds growth inhibitory properties against each 
 of the parasites , thus launching a multiparasite optimization campaign 
 from the same lead series . in this paper
, we describe these 
 cross - pathogen assay results and 
 outline our evaluation of replacements for the quinazoline scaffold 
 of 1 for each of the parasites .
we posit that such a 
 cross - screening approach can be a highly fruitful method for identification 
 of new protozoan parasite growth inhibitors .
first , 
 in order to ascertain antiparasitic activities of our 66 
 previously reported analogs , we measured 
 their growth inhibitory activities against t. cruzi ( intracellular amastigotes ) , l. major ( promastigote 
 and intracellular amastigote life stages ) , and p. falciparum ( d6 , drug sensitive strain ) . the structures of the most potent compounds 
 for each parasite are shown in figure 1 and 
 table 1 , and the complete set of screening 
 data for these is tabulated in the supporting 
 information ( tables s1s7 ) . program progression from 2 to four
sem values within 50% . * % inh at 
 10 m . control compounds : t. brucei , suramin ; t. cruzi , benznidazole ; l. major , amphotericin b ; p. falciparum , chloroquine . from these 
 experiments
, we observed that 15 morpholinosulfonamide 
 compounds were identified with activity against l. major promastigotes : seven of these were submicromolar inhibitors and 
 two were also submicromolar against intracellular amastigotes ( the 
 most relevant life stage for human infections of leishmaniasis ) .
the 
 des - fluoro analog neu-551 ( 3 ) showed the highest activity 
 against promastigotes ( ec50 = 0.50 m ) .
we initially 
 tested compounds against t. cruzi at a single concentration 
 and found that 32 compounds inhibited proliferation > 65% at 10 
 m 
 concentrations ; of these 32 compounds , the homopiperazinyl sulfonamide - substituted 
 tail was preferred ( neu-628 ( 4 ) , ec50 = 0.51 
 m ) .
the active compounds against p. falciparum ( drug - sensitive d6 strain ) all contained a basic nitrogen at the 
 end of the tail group with neu-627 ( 5 ) being the most 
 potent with an ec50 of 27 nm . though we note that the number 
 of headgroup replacement analogs tested was far smaller and less diverse 
 than the tail variations , the lapatinib headgroup 3-chloro-4-((3-fluorobenzyl)oxy)aniline 
 showed optimal potency against all of the parasites , except for both leishmania life stages .
previous efforts focused on 
 the  head  ( 4-benzyloxyanilines ) 
 and  tail  ( denoted as r in figure 1 ) regions of lapatinib , while maintaining the central quinazoline 
 scaffold ( highlighted in blue in figure 1 ) . 

thus , we planned a broader evaluation of other bicyclic aromatic replacements 
 for the quinazoline scaffold that would test the important features 
 of the chemotype for activity .
these scaffold replacements were selected 
 for exploration of the requisite nitrogen atom positioning in the 
 heteroaromatic ring ( see the heterocycle precursors highlighted in 
 figure 2 , dihalides 69 ) .
in addition , the cyanoquinoline and thienopyrimidine scaffolds 
 ( dihalides 1012 ) were selected in 
 order to include other established tyrosine kinase inhibitor chemotypes . for a matched exploration of these scaffolds
, we elected to maintain 
 the four permutations of head / tail combinations that displayed the 
 most potency in each parasite ( shown in figure 1 ) in the new analogs that we prepared .
we first set out to synthesize 
 the requisite dihalogenated scaffolds 
 shown in figure 2 .
the syntheses of 6- and 
 7-bromo-4-chloroquinolines 6a and 6b were 
 carried out via the gould 
was devised to draw out essential interactions 
 with either nitrogen of the quinazoline scaffold .
the requisite cyanoquinoline template 12 was prepared 
 using established protocols similar to that of the 4-chloroquinolines . though few examples of cinnoline or phthalazine 
 based kinase inhibitors 
 exist in the literature , we opted to prepare analogues utilizing both heterocycles 
 to test the required positioning of the two nitrogen atoms on the 
 scaffold .
preparation of 6-bromo-4-chlorocinnoline 8a commenced with the bromination of o - aminoacetophenone 13 followed by diazotization of the amine and in situ cyclization to the 6-bromocinnolin-4(1h)-one 15 ( scheme 1 ) .
we hypothesized that this 
 side reaction occurred via chloride displacement under the acidic 
 conditions of the reaction ( scheme s1 , see supporting 
 information ) .
a 10:1 product ratio of 8a to 8b could be achieved through the use of thf as solvent and 
 3 equiv of pocl3 .
the regiomeric 7-bromo-4-chlorocinnoline 8c was prepared in a similar fashion starting instead with 
 the acylation of 3-bromoaniline 16 to 2-amino-4-bromoacetophenone 17 , followed by diazotization and chlorination .
reagents and conditions : ( a ) 
 nbs , ch2cl2 , 10 c  23 
 c , o.n . ;
( b ) nano2 , aq . hcl , h2o , 75 c , 
 o.n . ; ( c ) pocl3 , thf , reflux , 2 h ; ( d ) ( i ) bcl3 , ( ch2cl)2 , 0 c ; ( ii ) alcl3 , ch3cn , 80 c , o.n . ; ( iii ) aq . hcl , 80 c , 
 30 min ; ( b ) nano2 , aq . hcl , h2o , 75 c , 
 o.n . ; ( c ) pocl3 , thf , reflux , 2 h. the 7-bromo-1-chlorophthalazine template 9a was synthesized 
 as shown in scheme 2 .
aryl bromination of phthalide 19 was carried out in acidic medium with nbs to produce a 
 separable mixture of 4- and 6-bromophthalide 20 .
benzylic 
 bromination was achieved using a modification of an established procedure , and the resulting dibromides 21a , b were converted to the corresponding bromophthalazinone 22 upon treatment with hydrazine . as with 15 , 22a was converted to the dichlorinated side product 9b on treatment with neat pocl3 , though dilution 
 minimized this side reaction .
acetonitrile with 3 equiv of pocl3 provided a > 10:1 ratio of the desired chlorination product 9a .
the 6-bromo-1-chlorophthalazine scaffold 9c could be synthesized in an identical manner starting with the commercially 
 available 5-bromophthalide 20b .
reagents 
 and conditions : ( a ) 
 nbs , h2so4 , cf3co2h , 23 
 c , 40 h ; ( b ) nbs , aibn , chcl3 , reflux , 1 h ; ( c ) n2h4 , i - proh , reflux , 1.5 h ; ( d ) pocl3 , ch3cn , reflux , 3 h. amination 
 of the dihalogenated quinoline , isoquinoline , cyanoquinoline , 
 and thienopyrimidine scaffolds was carried out by applying methods 
 similar to those we previously reported ( scheme 3 ) .
however , low yields ( 20% ) 
 resulted when these conditions were applied to the cinnoline and phthalazine 
 templates .
switching the solvent to toluene and using 4 equiv of amine 
 improved yields to 5478% .
suzuki couplings using the requisite 
 boronates and 57 mol % pd(pph3)4 or 
 1 mol % pd(oac)2 provided the final analogs
. yields of 
 the cinnoline or phthalazine products were drastically improved by 
 switching to 2.5 mol % pdcl2(pph3)2 or 5 mol % pd(oac)2 with extended reaction times .
a higher 
 catalyst loading of pd(oac)2 was employed in lieu of pdcl2(pph3)2 in situations where the pph3o byproduct could not be separated from the products .
reagents and 
 conditions : ( a ) 1.1 equiv of amine , i - proh , reflux , o.n . ; ( b ) 4 equiv 
 of amine , toluene , reflux , 2.5 h ; ( c ) 4 equiv of amine , toluene , 50 
 c , o.n . ; ( d ) arbpin , et3n , pd(oac)2 , 1:1 
 h2o / etoh , mw , 120 c , 13 h ; ( e ) arbpin , et3n , pdcl2(pph3)2 , 1:1 h2o / etoh , mw , 120 c , 1 h ; ( f ) arbpin , aq .
na2co3 , pd(pph3)4 , 3:2 glyme / etoh , 
 n2 , 85 c , 712 h. with this set of new analogs that are matched to the previously 
 described antiparasitic agents , we set 
 out measuring these analogs activities against t. 
 brucei , t. cruzi , l. major , and p. falciparum , and counter - screened against 
 host cells ( nih 3t3 and hepg2 cell lines ) using assays that we previously 
 reported .
a 
 small number of compounds showed activity against nih 3t3 cells ; these 
 are summarized in the supporting information , table s8 .
all sem values 
 within 25% unless 
 noted otherwise . * % inh at 5 m .
compound 1 remained the most potent t. brucei growth inhibitor among this set of analogs .
a pair of quinoline - based 
 compounds , 50 and 52 , each with a basic 
 aliphatic amine on the tail group show double digit nanomolar potency 
 ( 79 and 87 nm , respectively ) .
the potency of these compounds seems 
 to be driven by the aliphatic amine in the tail region rather than 
 by the placement of nitrogen atoms in the scaffold , because the analogous 
 isoquinoline analogue 58 is approximately equipotent 
 ( 100 nm ) to 50 .
the quinoline analogs 50 , 51 , and 52 displayed submicromolar potency 
 against intracellular amastigotes 
 of t. cruzi .
most other analogs showed a complete 
 loss of activity , perhaps due to issues with penetration into both 
 the host cell and the parasite .
( with intracellular parasites , we 
 note that compensating effects from interactions with host cell targets 
 can not be ruled out . )
however , the 3-cyanoquinoline analogue 83 , shows a 5-fold improvement in potency over the matched 
 original quinazoline analog 4 . in the headgroup region
, 
 the 3-fluoro substituent affords a 10-fold increase in potency over 
 the matched des - fluoro analog ( cf .
the quinoline 51 displayed a slight drop in potency 
 compared with the quinazoline 4 , and the matched isoquinoline 59 is 10-fold less potent .
taken together with the cyanoquinoline 
 analog 83 , this data demonstrates the apparent importance 
 of two h - bond acceptor motifs in the scaffold . in the case of l. major
, 47 showed 
 a 2.5-fold increase in potency from the matched quinazoline analogue 3 ( 0.20 versus 0.50 m respectively ) against the promastigote 
 life stage of l. major .
the corresponding isoquinoline 
 compound 55 showed a complete loss in activity , reinforcing 
 the essentiality of the n1 atom of the quinazoline .
interestingly , 
 there was no activity observed against the amastigote life stage of 
 the parasite for 47 .
in contrast , the 7-substituted quinoline 52 displayed submicromolar potency against both life stages 
 ( 0.40 m against promastigotes and 0.89 m versus amastigotes ) . 

compared with the quinazoline compound 4 , the analogous 
 cinnoline 68 displayed increased potency against amastigotes 
 ( 0.24 m ) albeit with a significant decrease in potency against 
 the promastigote form .
this lack of correlation of compounds between 
 promastigote and amastigote life stages of the parasite has been reported 
 by us and others recently .
other compounds displaying 
 modest potency include 76 and 91 , both containing 
 the n - methylhomopiperazinyl sulfonamide tail . in p. falciparum cultures , three isoquinoline 
 compounds with a basic amine at
the terminus of the tail region showed 
 modest potency highlighted by 57 being nearly equipotent 
 to the parent quinazoline 5 ( 40 vs 27 nm ) .
though the 
 matching quinoline 49 showed a complete loss in activity , 
 its regioisomer 50 was slightly more active than 5 ( ec50 = 19 nm ) .
the four quinoline analogs without 
 a basic amine on the tail group were within 2-fold of 5 with 48 being the most potent with an ec50 = 16 nm .
similarly , all four thienopyrimidine analogs with a basic 
 tail group amine ( 8992 ) were potent , 
 within 4-fold of 5 . among these compounds there was no 
 preference for either thienopyridine isomer ; the n - methylpiperazinyl tail group was 2.5- to 4-fold more potent than 
 the n - methylhomopiperazinyl tail on each scaffold . among the phthalazines , 74 and 76 , both 
 with a basic nitrogen on the tail and substituted at the 6-position 
 ( regiomeric to 5 ) were equipotent to 5 . 
 also requiring a basic amine on the tail region , the cinnoline analogs 
 with piperazinyl and homopiperazinyl moieties ( 6568 ) showed modest to high potency against p. falciparum d6 strain .
excitingly , the 7-substituted isomers ( 66 and 68 ) were highly potent antiplasmodial agents ( 14 
 and 3 nm , respectively ) . since we observed that the most potent 
 compounds against p. falciparum were 4-aminoquinolines 
 ( similar to the prototypical 
 antimalarial agent chloroquine ) , we tested them against drug resistant 
 parasite strains w2 and c235 .
we were gratified to observe that all 
 of the compounds tested are similarly active against drug resistant 
 strains of p. falciparum ( table s9 , supporting information ) , suggesting that despite the shared 
 scaffold , these analogs likely display a mechanism of action or mechanism 
 of resistance that differs from those of chloroquine .
our studies 
 demonstrate which of these scaffolds are the most promising 
 for further optimization on a parasite - by - parasite basis .
, it is clear that the quinoline scaffold 
 is significantly active across all four pathogens .
we note that cinnoline 
 ( c ) and quinoline ( a ) generally provide the most potent antiplasmodial 
 agents , and the 7-position substitutions are slightly favored in both 
 of these templates . for t. brucei ,
the 7-substituted 
 quinolines and 6-substituted isoquinolines appear optimal ( noting 
 that , despite the differential numbering of the scaffolds , these two 
 particular scaffolds present the same relative regiochemistry ) .
analogous 
 diagrams for the other pathogens are also provided in figure 3 ( and a diagram for leishmania promastigotes 
 is in the supporting information ( figure 
 s1 ) .
a summary of the preferred bicyclic scaffold for each parasite 
 is shown in figure 3e , noting that none appear 
 to be markedly better than the others against leishmania intracellular amastigotes .
bar chart showing range of potencies for each 
 scaffold ( as labeled 
 in tables 2 and 3 ) for 
 ( a ) malaria , ( b ) t. brucei , ( c ) l. major ( amastigotes ) , and ( d ) t. cruzi .
regiochemical 
 information is shown by the suffix number ( e.g. , scaffold a-7 is the 
 7-substituted quinoline scaffold ) .
quinolines are shown in blue , isoquinolines 
 in green , cinnolines in yellow , phthalazines in orange , cyanoquinolines 
 in red , thieno[3,2-d]pyrimidines in purple , thieno[2,3-d]pyrimidines in light gray , and quinazolines in dark gray . 

for all parasites except for t. brucei , we also 
 note a preference for tail substituents with a basic amine present . 

considering only the most  potent  compounds ( ec50  0.1 m for the extracellular parasites t. brucei and p. falciparum ; ec50  1 m for the intracellular parasites l. major and t. cruzi ) , we note that the n - methylpiperizine and n - methylhomopiperazine are 
 preferred among analogs that were tested , over the less - basic morpholine 
 or nonbasic morpholinosulfonamide substituents ( table 4 ) . at this point
, we can not discern whether this is an effect 
 that is mediated by the biological target(s ) involved in proliferation 
 inhibition , by parasite permeation , or by a combination of both ; this 
 will be a matter for further investigation .
 potent  compounds 
 are ec50  0.1 m .  potent  compounds 
 are ec50  1 m . we have previously observed that molecules bearing 
 these head and 
 tail combinations possess problematic physicochemical properties , 
 likely due to the molecular size and lipophilicity .
the intent of 
 the present work was to explore the central scaffold functionality , 
 rather than to address these shortcomings .
nonetheless , we selected 
 five representative compounds from among the most potent to be tested 
 for their physicochemical properties ( table 5 ) .
not unexpectedly , compounds tested were > 99% plasma protein 
 bound 
 with limited thermodynamic aqueous solubility ( < 1 m ) .
such 
 properties are undoubtedly a result of the high molecular weights 
 and clogp values ; these issues remain the focus of ongoing efforts , 
 which are now focused on specific scaffolds for each pathogen . in summary , through a cross - parasite 
 screening campaign of existing 
 quinazoline t. brucei proliferation inhibitors , we 
 uncovered new hits against three other protozoan parasites . encouraged 
 by that initial success , we focused on exploring the central heterocycle 
 scaffold , an exercise that has uncovered additional highly potent 
 compounds .
scaffold variations have revealed heteroatom positioning 
 essential for activity within this chemotype , while variations to 
 regiochemical attachment points have introduced a new set of regioisomers 
 with multiparasite potency .
thus , we have established a new lead series 
 for each of these protozoan parasites , which can be now advanced in 
 parallel for drug discovery against four different parasitic diseases . 
 with this in mind ,
further optimization of physicochemical properties 
 and cellular selectivity of each is ongoing , with a specific focus 
 on the  head  and  tail  regions .
( st . louis , mo ) , fisher scientific , 
 frontier scientific services , inc .
( newark , de ) , or matrix scientific 
 ( columbia , sc ) and used as received .
boronic acids and esters and 
 aniline reagents were purchased , except for those whose syntheses 
 are listed in the supporting information .
reaction solvents were dried by passage through alumina columns 
 on a purification system manufactured by innovative technology ( newburyport , 
 ma ) .
nmr spectra were obtained with varian nmr systems , operating 
 at 400 or 500 mhz for h acquisitions as noted .
lcms analysis 
 was performed using a waters alliance reverse - phase hplc , with single - wavelength 
 uv  visible detector and lct premier time - of - flight mass spectrometer 
 ( electrospray ionization ) .
all newly synthesized compounds that were 
 submitted for biological testing were deemed > 95% pure by lcms 
 analysis 
 ( uv and esi - ms detection ) prior to submission for biological testing . 

preparative lcms was performed on a waters fraction lynx system with 
 a waters micromass zq mass spectrometer ( electrospray ionization ) 
 and a single - wavelength uv 
yields reported 
 for products obtained by preparative hplc represent the amount of 
 pure material isolated ; impure fractions were not repurified . in a flame - dried 
 250 ml round - bottom flask
were added 6-bromocinnolin-4(1h)-one ( 1.00 g , 4.44 mmol ) , anhydrous tetrahydrofuran ( 45 ml ) , and 
 phosphorus oxychloride ( 1.25 ml , 13.41 mmol ) .
the mixture was refluxed 
 for 1 h at which point a deep green / blue solution had resulted .
the 
 solution was cooled to 0 c and was quenched by the dropwise 
 addition of sat .
the mixture was allowed 
 to warm to room temperature and stir for an additional 1 h. water 
 ( 50 ml ) was added , and the mixture was extracted with dichloromethane 
 ( 3  100 ml ) .
nahco3 ( 50 ml ) , washed with brine ( 50 ml ) , dried over 
 na2so4 , concentrated on to silica , and purified 
 by flash column chromatography using a gradient of 15% methanol 
 in dichloromethane to yield an inseparable 10:1 mixture of 8a and 8b as a brown solid in 85% yield .
h 
 nmr ( 500 mhz , cdcl3 )  9.36 ( s , 1 h ) , 8.43 ( d , j = 8.8 hz , 1 h ) , 8.36 ( d , j = 2.0 hz , 
 1 h ) , 7.98 ( dd , j = 9.3 , 2.0 hz , 1 h ) .
lcms found 
 242.9 [ m + h ] . in a flame - dried 
 25 ml round - bottom flask
were added 7-bromocinnolin-4(1h)-one ( 166 mg , 0.74 mmol ) , anhydrous tetrahydrofuran ( 7 ml ) , and 
 phosphorus oxychloride ( 0.2 ml , 2.15 mmol ) .
the mixture was refluxed 
 for 1 h at which point a deep green / blue solution had resulted .
the 
 solution was cooled to 0 c and was quenched by the dropwise 
 addition of sat .
. the mixture was allowed 
 to warm to room temperature and stir for an additional 1 h. water 
 ( 12 ml ) was added , and the mixture was extracted with dichloromethane 
 ( 3  25 ml ) .
nahco3 ( 20 ml ) , washed with brine ( 20 ml ) , and dried 
 over na2so4 to yield 8c as a dark 
 brown solid in 92% yield .
h nmr ( 500 mhz , cdcl3 )  9.39 ( s , 1 h ) , 8.76 ( d , j = 2.0 hz , 1 
 h ) , 8.09 ( d , j = 9.3 hz , 1 h ) , 7.95 ( dd , j = 9.0 , 1.7 hz , 1 h ) .
lcms found 242.9 [ m + h ] . in a 
 flame - dried 25 ml round - bottom flask were added 7-bromophthalazin-1(2h)-one ( 205 mg , 0.91 mmol ) , anhydrous acetonitrile ( 9 ml ) , 
 and phosphorus oxychloride ( 0.3 ml , 3.22 mmol ) .
the mixture was refluxed 
 for 2 h , then cooled to 0 c , diluted with dichloromethane ( 20 
 ml ) , and quenched with a dropwise addition of sat .
after 1 h , the layers were separated 
 and the aqueous was extracted with dichloromethane ( 2  30 ml ) . 
 the combined organic layers were washed with sat .
nahco3 ( 25 ml ) , washed with brine ( 20 ml ) , dried over na2so4 , and concentrated to yield 9a as an orange solid 
 in 91% yield .
h nmr ( 500 mhz , cdcl3 )  
 9.45 ( s , 1 h ) , 8.498.51 ( m , 1 h ) , 8.10 ( dd , j = 8.8 , 2.0 hz , 1 h ) , 7.91 ( d , j = 8.8 hz , 1 h ) . 

lcms found 242.9 [ m + h ] . in a 
 flame - dried 50 ml round - bottom flask were added 6-bromophthalazin-1(2h)-one ( 402 mg , 1.78 mmol ) , anhydrous acetonitrile ( 18 ml ) , 
 and phosphorus oxychloride ( 0.5 ml , 5.36 mmol ) .
the mixture was refluxed 
 for 2 h , then cooled to 0 c , diluted with dichloromethane ( 40 
 ml ) , and quenched with a dropwise addition of sat .
the biphasic mixture was stirred vigorously and allowed 
 to warm to room temperature . after 1 h , the layers were separated , 
 and the aqueous was extracted with dichloromethane ( 2  50 ml ) . 
 the combined organic layers were washed with sat .
nahco3 ( 40 ml ) , washed with brine ( 30 ml ) , dried over na2so4 , and concentrated to yield 29c as a yellow solid 
 in 94% yield .
h nmr ( 500 mhz , cdcl3 )  
 9.39 ( s , 1 h ) , 8.178.21 ( m , 2 h ) , 8.10 ( dd , j = 8.8 , 2.0 hz , 1 h ) .
in a 250 ml round - bottom 
 flask were added 1-(2-amino-5-bromophenyl)ethanone 
 ( 8.34 g , 39.0 mmol ) , water ( 30 ml ) , and conc .
the mixture was cooled to 0 c in an ice bath 
 and allowed to stir for 15 min until a suspension resulted .
aqueous 
 sodium nitrite ( 2 m , 20 ml , 40.0 mmol ) was then added dropwise with 
 an addition funnel .
the resulting solution was allowed to warm to 
 room temperature over 1.5 h and was stirred at room temperature overnight , 
 then refluxed for 6 h. the mixture was cooled to room temperature , 
 water ( 200 ml ) was added , and the mixture was extracted with ethyl 
 acetate ( 3  200 ml ) .
the combined organic layers were then washed 
 with brine ( 50 ml ) , dried over sodium sulfate , filtered , and concentrated 
 onto silica .
the crude product was then purified by flash column chromatography 
 using a gradient of 110% methanol in dichloromethane to yield 15 as a dark brown solid in 82% yield .
h nmr ( 500 
 mhz , dmso - d6 )  14.09 ( br .
s. , 1 
 h ) , 8.09 ( d , j = 2.2 hz , 1 h ) , 7.92 ( dd , j = 8.8 , 2.2 hz , 1 h ) , 7.79 ( s , 1 h ) , 7.71 ( d , j = 9.1 hz , 1 h ) .
in a 50 ml round - bottom 
 flask were added 1-(2-amino-4-bromophenyl)ethanone 
 ( 712 mg , 3.33 mmol ) , water ( 3 ml ) , and conc .
the mixture was cooled to 0 c in an ice bath and 
 allowed to stir for 15 min until a suspension resulted .
aqueous sodium 
 nitrite ( 2 m , 1.84 ml , 3.68 mmol ) was then added dropwise with an 
 addition funnel .
the resulting solution was allowed to warm to room 
 temperature over 1.5 h and was stirred at room temperature overnight , 
 then refluxed for 6 h. the mixture was cooled to room temperature , 
 water ( 35 ml ) was added , and the mixture was extracted with ethyl 
 acetate ( 3  40 ml ) .
the combined organic layers were then washed 
 with brine ( 20 ml ) , dried over sodium sulfate , filtered , and concentrated 
 onto silica .
the crude product was then purified by flash column chromatography 
 using a gradient of 2050% ethyl acetate in hexanes , then ethyl 
 acetate to yield 18 as a light brown solid in 26% yield .
h nmr ( 500 mhz , dmso - d6 )  
 13.49 ( s , 1 h ) , 7.92 ( d , j = 8.8 hz , 1 h ) , 7.76 ( s , 
 1 h ) , 7.73 ( d , j = 2.0 hz , 1 h ) , 7.53 ( dd , j = 8.8 , 2.0 hz , 1 h ) .
in a 100 ml round - bottom flask was dissolved isobenzofuran-1(3h)-one ( 4.01 g , 29.9 mmol ) in trifluoroacetic acid ( 14 ml , 
 182 mmol ) and sulfuric acid ( 6.5 ml , 122 mmol ) .
n - bromosuccinimide ( 7.95 g , 1.49 mmol ) was added portionwise over 
 8 h , and the solution was stirred at room temperature for an additional 
 87 h. the solution was diluted with water ( 40 ml ) and ethyl acetate 
 ( 40 ml ) .
the organic layer was separated , 
 and the aqueous layer was extracted with ethyl acetate ( 3  50 
 ml ) .
the combined organic layers were washed with brine ( 25 ml ) , dried 
 over na2so4 , and concentrated onto silica .
the 
 crude product was then purified by flash column chromatography using 
 1020% ethyl acetate in hexanes to yield 20a as 
 white solid in 57% yield .
h nmr ( 500 mhz , cdcl3 )  7.98 ( d , j = 1.5 hz , 1 h ) , 7.77 ( dd , j = 8.3 , 1.5 hz , 1 h ) , 7.40 ( d , j = 8.3 
 hz , 1 h ) , 5.27 ( s , 2 h ) .
lcms found 212.9 [ m + h ] . in a 50 ml round - bottom 
 flask
n - bromosuccinimide 
 ( 958 mg , 5.38 mmol ) , 2,2-azobis(2-methylpropionitrile ) ( 75 
 mg , 0.46 mmol ) , and chloroform ( 23 ml ) . the mixture was refluxed for 
 2.5 h , then cooled to room temperature and quenched with sat .
the organic layer was removed , washed with 
 water ( 20 ml ) , washed with brine ( 15 ml ) , and concentrated onto silica . 

the crude product was purified by flash column chromatography using 
 a gradient of 510% ethyl acetate in hexanes to yield 21a as a white solid in 61% yield .
h nmr ( 500 
 mhz , cdcl3 )  8.06 ( d , j = 1.5 hz , 
 1 h ) , 7.90 ( dd , j = 8.1 , 1.7 hz , 1 h ) , 7.52 ( d , j = 8.3 hz , 1 h ) , 7.37 ( s , 1 h ) .
were 
 added 5-bromoisobenzofuran-1(3h)-one ( 499 mg , 2.34 
 mmol ) , n - bromosuccinimide 
 ( 421 mg , 2.37 mmol ) , 2,2-azobis(2-methylpropionitrile ) ( 38 
 mg , 0.23 mmol ) , and chloroform ( 10 ml ) .
the mixture was refluxed for 
 2.5 h , then cooled to room temperature and quenched with sat .
the organic layer was removed , washed with 
 water ( 10 ml ) , washed with brine ( 5 ml ) , and concentrated onto silica . 

the crude product was purified by flash column chromatography using 
 10% ethyl acetate in hexanes to yield 21b as a white 
 solid in 49% yield .
h nmr ( 500 mhz , cdcl3 ) 
  7.747.83 ( m , 3 h ) , 7.36 ( s , 1 h ) .
gcms found 289.8 
 [ m ] . in a 25 ml round - bottom flask
was dissolved 
 3,6-dibromoisobenzofuran-1(3h)-one ( 143 mg , 0.49 
 mmol ) in ethanol ( 5 ml ) .
hydrazine 
 monohydrate ( 0.12 ml , 2.48 mmol ) was then added via a syringe , and 
 the solution was refluxed for 1.5 h. the solution was cooled to room 
 temperature , and ice water ( 15 ml ) was added to the reaction mixture . 

the precipitate was vacuum filtered and dried under a vacuum overnight 
 to yield 22a as a white solid in 56% yield .
h nmr ( 500 mhz , dmso - d6 )  12.82 
 ( br .
s. , 1 h ) , 8.39 ( s , 1 h ) , 8.30 ( d , j = 2.0 hz , 
 1 h ) , 8.11 ( dd , j = 8.5 , 2.2 hz , 1 h ) , 7.90 ( d , j = 8.3 hz , 1 h ) .
in a 25 ml round - bottom flask was dissolved 3,5-dibromoisobenzofuran-1(3h)-one ( 302 mg , 1.04 mmol ) in ethanol ( 10 ml ) .
hydrazine 
 monohydrate ( 0.25 ml , 5.18 mmol ) was then added via a syringe , and 
 the solution was refluxed for 1.5 h. the solution was cooled to room 
 temperature , and ice water ( 30 ml ) was added to the reaction mixture . 

the precipitate was vacuum filtered and dried under a vacuum overnight 
 to yield 22b as a white solid in 73% yield .
h nmr ( 500 mhz , dmso - d6 )  12.78 
 ( br .
s. , 1 h ) , 8.33 ( s , 1 h ) , 8.23 ( d , j = 2.0 hz , 
 1 h ) , 8.12 ( d , j = 8.3 hz , 1 h ) , 8.00 ( dd , j = 8.3 , 2.0 hz , 1 h ) .
to a solution of the appropriate 
 aryl chloride ( 1 equiv ) in 2-propanol ( 0.15 m ) was added 3-chloro-4-((3-fluorobenzyl)oxy)aniline 
 or 4-(benzyloxy)-3-chloroaniline ( 1.1 equiv ) .
the formed precipitate was collected by vacuum 
 filtration to obtain the desired products . to a solution of the appropriate 
 aryl chloride ( 1 equiv ) in 2-propanol ( 0.15 m )
the combined organic layers were washed with water , washed with brine , 
 dried over na2so4 , and concentrated .
the crude 
 products were purified by flash column chromatography to obtain the 
 desired products .
a solution of the appropriate 4-chlorocinnoline 
 ( 1 equiv ) and 3-chloro-4-((3-fluorobenzyl)oxy)aniline 
 or 4-(benzyloxy)-3-chloroaniline ( 4 equiv ) in toluene ( 0.1 m ) was 
 refluxed for 2.5 h and cooled to room temperature .
triethylamine ( 4 
 equiv ) was added , and the mixture was returned to reflux for an additional 
 30 min .
the mixture was cooled back to room temperature , and the formed 
 yellow precipitate was vacuum filtered , washed with ethyl acetate , 
 concentrated onto silica , and purified by flash column chromatography .
a solution of the appropriate 1-chlorophthalazine ( 1 equiv ) and 
 3-chloro-4-((3-fluorobenzyl)oxy)aniline or 4-(benzyloxy)-3-chloroaniline 
 ( 4 equiv ) in anhydrous toluene ( 0.2 m ) was heated at 50 c overnight . 

the combined 
 organic layers were washed with brine , dried over na2so4 , concentrated onto silica , and purified by flash column chromatography . synthesized by general procedure b. flash 
 column chromatography : 2050% ethyl acetate in hexanes to yield 23 as a light brown solid in 90% yield .
h nmr 
 ( 500 mhz , dmso - d6 )  8.99 ( s , 1 
 h ) , 8.63 ( s , 1 h ) , 8.46 ( d , j = 5.4 hz , 1 h ) , 7.80 
 ( d , j = 1.5 hz , 2 h ) , 7.437.51 ( m , 2 h ) , 
 7.277.36 ( m , 4 h ) , 7.19 ( td , j = 8.7 , 2.2 
 hz , 1 h ) , 6.80 ( d , j = 5.4 hz , 1 h ) , 5.26 ( s , 2 h ) . 
 lcms found 456.8 [ m + h ] .
synthesized by general procedure b. flash 
 column chromatography : 2070% ethyl acetate in hexanes to yield 24 as a brown solid in 70% yield .
h nmr ( 500 mhz , 
 dmso - d6 )  8.98 ( s , 1 h ) , 8.63 ( s , 
 1 h ) , 8.45 ( d , j = 5.4 hz , 1 h ) , 7.80 ( s , 2 h ) , 7.50 
 ( d , j = 7.3 hz , 2 h ) , 7.397.46 ( m , 3 h ) , 
 7.35 ( t , j = 7.3 hz , 1 h ) , 7.30 ( s , 2 h ) , 6.79 ( d , j = 5.4 hz , 1 h ) , 5.23 ( s , 2 h ) .
synthesized by general procedure b. flash 
 column chromatography : 2050% ethyl acetate in hexanes to yield 25 as a tan colored solid in 82% yield .
h nmr 
 ( 399 mhz , dmso - d6 )  9.05 ( s , 1 
 h ) , 8.43 ( d , j = 5.1 hz , 1 h ) , 8.31 ( d , j = 8.8 hz , 1 h ) , 8.05 ( d , j = 2.2 hz , 1 h ) , 7.67 
 ( dd , j = 8.8 , 2.2 hz , 1 h ) , 7.417.52 ( m , 
 2 h ) , 7.257.37 ( m , 4 h ) , 7.18 ( td , j = 8.6 , 
 2.6 hz , 1 h ) , 6.76 ( d , j = 5.9 hz , 1 h ) , 5.25 ( s , 
 2 h ) .
synthesized by general procedure b. flash 
 column chromatography : 2050% ethyl acetate in hexanes to yield 26 as an off - white solid in 83% yield .
h nmr ( 500 
 mhz , dmso - d6 )  9.04 ( s , 1 h ) , 8.43 
 ( d , j = 4.9 hz , 1 h ) , 8.31 ( d , j = 9.3 hz , 1 h ) , 8.05 ( d , j = 2.0 hz , 1 h ) , 7.67 
 ( dd , j = 9.0 , 2.2 hz , 1 h ) , 7.49 ( d , j = 6.8 hz , 2 h ) , 7.397.46 ( m , 3 h ) , 7.35 ( t , j = 7.3 hz , 1 h ) , 7.30 ( s , 2 h ) , 6.75 ( d , j = 5.4 
 hz , 1 h ) , 5.23 ( s , 2 h ) .
synthesized by general procedure b. flash 
 column chromatography : 1030% ethyl acetate in hexanes to yield 27 as a pale red - brown solid in 97% yield .
h nmr 
 ( 500 mhz , dmso - d6 )  9.24 ( s , 1 
 h ) , 8.80 ( s , 1 h ) , 8.07 ( d , j = 2.4 hz , 1 h ) , 8.02 
 ( d , j = 5.9 hz , 1 h ) , 7.82 ( dd , j = 8.8 , 1.5 hz , 1 h ) , 7.727.79 ( m , 2 h ) , 7.417.49 
 ( m , 1 h ) , 7.277.35 ( m , 2 h ) , 7.137.23 ( m , 3 h ) , 5.21 
 ( s , 2 h ) .
synthesized by general procedure b. flash 
 column chromatography : 1030% ethyl acetate in hexanes to yield 28 as a light red solid in 93% yield .
h nmr ( 500 
 mhz , dmso - d6 )  9.22 ( s , 1 h ) , 8.80 
 ( s , 1 h ) , 8.07 ( d , j = 2.4 hz , 1 h ) , 8.02 ( d , j = 5.9 hz , 1 h ) , 7.81 ( dd , j = 8.8 , 1.5 
 hz , 1 h ) , 7.737.78 ( m , 2 h ) , 7.48 ( d , j = 
 7.3 hz , 2 h ) , 7.40 ( t , j = 7.6 hz , 2 h ) , 7.33 ( t , j = 7.3 hz , 1 h ) , 7.21 ( d , j = 8.8 hz , 
 1 h ) , 7.15 ( d , j = 5.9 hz , 1 h ) , 5.18 ( s , 2 h ) . lcms 
 found 439.2 [ m + h ] .
synthesized by general procedure b. flash 
 column chromatography : 1030% ethyl acetate in hexanes to yield 29 as a salmon colored solid in 91% yield .
h nmr 
 ( 500 mhz , dmso - d6 )  9.27 ( s , 1 
 h ) , 8.45 ( d , j = 8.8 hz , 1 h ) , 8.08 ( dd , j = 12.0 , 2.2 hz , 2 h ) , 8.01 ( d , j = 5.4 
 hz , 1 h ) , 7.75 ( ddd , j = 13.8 , 9.2 , 2.4 hz , 2 h ) , 
 7.46 ( m , j = 5.9 hz , 1 h ) , 7.277.35 ( m , 2 
 h ) , 7.107.23 ( m , 3 h ) , 5.22 ( s , 2 h ) .
synthesized by general procedure b. flash 
 column chromatography : 1030% ethyl acetate in hexanes to yield 30 as a burnt orange solid in 81% yield .
h nmr 
 ( 500 mhz , dmso - d6 )  9.24 ( s , 1 
 h ) , 8.45 ( d , j = 8.8 hz , 1 h ) , 8.10 ( d , j = 2.0 hz , 1 h ) , 8.05 ( d , j = 2.4 hz , 1 h ) , 8.01 
 ( d , j = 5.9 hz , 1 h ) , 7.76 ( dd , j = 9.0 , 2.2 hz , 1 h ) , 7.72 ( dd , j = 8.8 , 2.4 hz , 
 1 h ) , 7.48 ( d , j = 6.8 hz , 2 h ) , 7.41 ( t , j = 7.3 hz , 2 h ) , 7.34 ( t , j = 7.8 hz , 
 1 h ) , 7.21 ( d , j = 9.3 hz , 1 h ) , 7.13 ( d , j = 5.9 hz , 1 h ) , 5.19 ( s , 2 h ) .
synthesized by general procedure c. flash 
 column chromatography : 5% methanol in dichloromethane to yield an 
 inseparable 10:1 mixture of 31 and dichloro side product 
 as a vibrant yellow solid in 54% yield .
h nmr ( 500 mhz , 
 dmso - d6 )  9.33 ( s , 1 h ) , 8.78 ( s , 
 1 h ) , 8.70 ( d , j = 1.5 hz , 1 h ) , 8.14 ( d , j = 8.8 hz , 1 h ) , 7.97 ( dd , j = 9.3 , 1.5 
 hz , 1 h ) , 7.54 ( d , j = 2.0 hz , 1 h ) , 7.48 ( td , j = 8.3 , 6.3 hz , 1 h ) , 7.40 ( dd , j = 8.8 , 
 2.4 hz , 1 h ) , 7.307.37 ( m , 3 h ) , 7.20 ( td , j = 9.3 , 2.0 hz , 1 h ) , 5.29 ( s , 2 h ) .
synthesized by general procedure c. flash 
 column chromatography : 5% methanol in dichloromethane to yield an 
 inseparable 10:1 mixture of 32 and dichloro side product 
 as a yellow solid in 68% yield .
h nmr ( 500 mhz , dmso - d6 )  9.32 ( s , 1 h ) , 8.78 ( s , 1 h ) , 8.71 
 ( d , j = 2.0 hz , 1 h ) , 8.14 ( d , j = 9.3 hz , 1 h ) , 7.97 ( dd , j = 9.0 , 1.7 hz , 1 h ) , 
 7.477.55 ( m , 3 h ) , 7.44 ( t , j = 7.6 hz , 2 
 h ) , 7.337.41 ( m , 3 h ) , 5.26 ( s , 2 h ) .
synthesized by general procedure c. flash 
 column chromatography : 5% methanol in dichloromethane to yield 33 as a brown solid in 55% yield with 84% purity .
h nmr ( 500 mhz , dmso - d6 )  9.43 
 ( s , 1 h ) , 8.76 ( s , 1 h ) , 8.41 ( d , j = 2.0 hz , 1 h ) , 
 8.35 ( d , j = 9.3 hz , 1 h ) , 7.90 ( dd , j = 9.0 , 2.2 hz , 1 h ) , 7.55 ( d , j = 2.4 hz , 1 h ) , 
 7.49 ( m , j = 6.3 hz , 1 h ) , 7.41 ( dd , j = 8.8 , 2.4 hz , 1 h ) , 7.317.37 ( m , 3 h ) , 7.20 ( td , j = 8.4 , 2.7 hz , 1 h ) , 5.29 ( s , 2 h ) .
synthesized by general procedure c. flash 
 column chromatography : 5% methanol in dichloromethane to yield 34 as a metallic bronze colored solid in 57% yield with 85% 
 purity .
h nmr ( 500 mhz , dmso - d6 )  9.42 ( s , 1 h ) , 8.75 ( s , 1 h ) , 8.41 ( d , j = 2.0 hz , 1 h ) , 8.35 ( d , j = 8.8 hz , 1 h ) , 7.90 
 ( dd , j = 9.0 , 2.2 hz , 1 h ) , 7.54 ( d , j = 2.4 hz , 1 h ) , 7.51 ( d , j = 7.3 hz , 2 h ) , 7.43 
 ( t , j = 7.6 hz , 2 h ) , 7.40 ( dd , j = 8.8 , 2.4 hz , 1 h ) , 7.337.38 ( m , 2 h ) , 5.26 ( s , 2 h ) .
synthesized by general procedure d. flash 
 column chromatography : 520% ethyl acetate in dichloromethane 
 to yield 35 as a yellow solid in 69% yield .
h nmr ( 500 mhz , dmso - d6 )  9.21 
 ( s , 1 h ) , 9.13 ( s , 1 h ) , 8.87 ( s , 1 h ) , 8.16 ( d , j = 2.4 hz , 1 h ) , 8.11 ( dd , j = 8.8 , 1.5 hz , 1 h ) , 
 7.99 ( d , j = 8.8 hz , 1 h ) , 7.81 ( dd , j = 8.8 , 2.4 hz , 1 h ) , 7.47 ( td , j = 7.9 , 6.1 hz , 
 1 h ) , 7.297.36 ( m , 2 h ) , 7.25 ( d , j = 9.3 
 hz , 1 h ) , 7.17 ( td , j = 8.7 , 2.2 hz , 1 h ) , 5.24 ( s , 
 2 h ) .
synthesized by general procedure d. flash 
 column chromatography : 520% ethyl acetate in dichloromethane 
 to yield 36 as a light greenish brown solid in 78% yield .
h nmr ( 500 mhz , dmso - d6 )  
 9.20 ( s , 1 h ) , 9.14 ( s , 1 h ) , 8.88 ( s , 1 h ) , 8.15 ( d , j = 2.4 hz , 1 h ) , 8.13 ( dd , j = 8.5 , 1.7 hz , 1 h ) , 
 8.00 ( d , j = 8.8 hz , 1 h ) , 7.80 ( dd , j = 9.0 , 2.7 hz , 1 h ) , 7.50 ( d , j = 7.3 hz , 2 h ) , 
 7.42 ( t , j = 7.6 hz , 2 h ) , 7.35 ( t , j = 7.3 hz , 1 h ) , 7.27 ( d , j = 8.8 hz , 1 h ) , 5.21 
 ( s , 2 h ) .
synthesized by general procedure d. flash 
 column chromatography : 520% ethyl acetate in dichloromethane 
 to yield 37 as a light brown solid in 64% yield .
h nmr ( 500 mhz , dmso - d6 )  
 9.42 ( s , 1 h ) , 9.09 ( s , 1 h ) , 8.62 ( d , j = 9.3 hz , 
 1 h ) , 8.33 ( d , j = 2.0 hz , 1 h ) , 8.19 ( d , j = 2.4 hz , 1 h ) , 8.16 ( dd , j = 9.0 , 2.2 
 hz , 1 h ) , 7.83 ( dd , j = 8.8 , 2.4 hz , 1 h ) , 7.47 ( td , j = 7.8 , 5.9 hz , 1 h ) , 7.32 ( m , j = 7.3 
 hz , 2 h ) , 7.25 ( d , j = 9.3 hz , 1 h ) , 7.17 ( td , j = 8.5 , 2.0 hz , 1 h ) , 5.24 ( s , 2 h ) .
synthesized by general procedure d. flash 
 column chromatography : 530% ethyl acetate in dichloromethane 
 to yield 38 as a green - gray colored solid in 75% yield .
h nmr ( 500 mhz , dmso - d6 )  
 9.25 ( s , 1 h ) , 9.09 ( s , 1 h ) , 8.51 ( d , j = 8.8 hz , 
 1 h ) , 8.33 ( d , j = 2.0 hz , 1 h ) , 8.17 ( dd , j = 8.8 , 2.0 hz , 1 h ) , 8.14 ( d , j = 2.9 
 hz , 1 h ) , 7.78 ( dd , j = 9.0 , 2.7 hz , 1 h ) , 7.49 ( d , j = 6.8 hz , 2 h ) , 7.42 ( t , j = 7.6 hz , 
 2 h ) , 7.35 ( t , j = 7.3 hz , 1 h ) , 7.26 ( d , j = 8.8 hz , 1 h ) , 5.21 ( s , 2 h ) .
synthesized by general procedure a , collected 
 as a yellow solid in 80% yield .
h nmr ( 400 mhz , dmso - d6 )  9.03 ( s , 1h ) , 8.85 ( br , s , 1h ) , 8.23 
 ( d , j = 8.8 hz , 1h ) , 7.73 ( d , j = 
 8.8 , 1h ) , 7.59 ( d , j = 2.4 , 1h ) , 7.457.50 
 ( m , 1h ) , 7.307.39 ( m , 4h ) , 7.187.22 ( m , 1h ) , 5.30 
 ( s , 2h ) .
synthesized by general procedure a , collected 
 as a yellow solid in 52% yield .
h nmr ( 500 mhz , dmso - d6 )  ppm 9.02 ( s , 1h ) , 8.82 ( br , s , 1h ) , 
 8.22 ( d , j = 9.0 hz , 1h ) , 7.72 ( d , j = 8.5 hz , 1h ) , 7.57 ( s , 1h ) , 7.5 ( d , j = 7.0 hz , 
 2h ) , 7.43 ( t , j = 7.5 hz , 2h ) , 7.35 ( m , 3h ) , 5.26 
 ( s , 2h ) .
h nmr ( 400 mhz , dmso - d6 )  ppm 
 10.64 ( s , 1 h ) , 8.71 ( s , 1 h ) , 7.87 ( d , j = 2.9 hz , 
 1 h ) , 7.74 ( s , 1 h ) , 7.57 ( dd , j = 8.8 , 2.2 hz , 1 
 h ) , 7.47 ( m , 1 h ) , 7.31 ( m , 3 h ) , 7.19 ( td , j = 8.1 , 
 2.2 hz , 1 h ) , 5.28 ( s , 2 h ) .
h nmr ( 500 mhz , dmso - d6 )  ppm 
 9.7 1 ( s , 1 h ) , 8.54 ( s , 1 h ) , 7.89 ( d , j = 2.0 hz , 
 1 h ) , 7.68 ( s , 1 h ) , 7.58 ( dd , j = 8.8 , 2.9 hz , 1 
 h ) , 7.49 ( d , j = 7.8 hz , 2 h ) , 7.42 ( t , j = 7.6 hz , 2 h ) , 7.35 ( t , j = 7.3 hz , 1 h ) , 7.26 
 ( d , j = 8.8 hz , 1 h ) , 5.23 ( s , 2 h ) .
h nmr ( 500 mhz , dmso - d6 )  9.80 ( s , 1h ) , 8.49 ( s , 1h ) , 8.12 
 ( s , 1h ) , 8.02 ( d , j = 2.4 hz , 1h ) , 7.67 ( dd , j = 2.7 , 9.03 hz , 1h ) , 7.437.49 ( m , 1h ) , 7.247.35 
 ( m , 3h ) , 7.18 ( dt , j = 2.4 , 8.6 hz , 1h ) , 5.24 ( s , 
 2h ) .
h nmr ( 500 mhz , dmso - d6 )  ppm 
 9.94 ( s , 1 h ) , 8.49 ( s , 1 h ) , 8.19 ( s , 1 h ) , 8.02 ( d , j = 2.4 hz , 1 h ) , 7.68 ( dd , j = 8.8 , 2.4 hz , 1 h ) , 
 7.49 ( m , 2 h ) , 7.41 ( m , 2 h ) , 7.34 ( m , 1 h ) , 7.27 ( d , j = 9.3 hz , 1 h ) , 5.21 ( s , 2 h ) .
lcms found 445.9 [ m + h ] . in a 25 
 ml microwave vial equipped with a stir bar
were added aryl bromide 
 ( 1 equiv ) , boronic ester ( 1.3 equiv ) , 1:1 water / ethanol ( 0.04 m ) , 
 triethylamine ( 3 equiv ) , and palladium(ii ) acetate ( 0.01 m in acetone , 
 1 mol % ) .
the vial was sealed with a septum , and the contents were 
 irradiated to and held at 120 c with stirring for 1 h. the reaction 
 mixture was cooled to room temperature , diluted with water ( 8 ml ) , 
 and extracted with dichloromethane ( 3  8 ml ) .
naoh ( 1 m , 2  5 ml ) , water ( 5 ml ) , 
 and brine ( 5 ml ) .
the crude product was 
 purified by flash column chromatography . in a 25 
 ml microwave vial equipped with a stir bar
were added aryl bromide 
 ( 1 equiv ) , boronic ester ( 1.3 equiv ) , 1:1 water / ethanol ( 0.04 m ) , 
 triethylamine ( 3 equiv ) , and bis(triphenylphosphine)palladium(ii ) 
 chloride ( 2.5 mol % ) .
the vial was sealed with a septum , and the contents 
 were irradiated to and held at 120 c with stirring for 1 h. 
 the reaction mixture was cooled to room temperature , diluted with 
 water ( 8 ml ) , and extracted with dichloromethane ( 3  8 ml ) . 

naoh ( 1 m , 2  
 5 ml ) , water ( 5 ml ) , and brine ( 5 ml ) .
the organic layer was then 
 dried over na2so4 and concentrated on to silica . 

the crude product was purified by flash column chromatography . in a 25 
 ml microwave vial equipped with a stir bar
were added aryl bromide 
 ( 1 equiv ) , boronic ester ( 1.3 equiv ) , 1:1 water / ethanol ( 0.04 m ) , 
 triethylamine ( 3 equiv ) , and palladium(ii ) acetate ( 5 mol % ) .
the 
 vial was sealed with a septum , and the contents were irradiated to 
 and held at 120 c with stirring for 3 h. the reaction mixture 
 was cooled to room temperature , diluted with water ( 8 ml ) , and extracted 
 with dichloromethane ( 3  8 ml ) .
naoh ( 1 m , 2  5 ml ) , water ( 5 ml ) , and 
 brine ( 5 ml ) .
the crude product was 
 purified by flash column chromatography . to a solution 
 of the appropriate aryl iodide ( 1 equiv ) in 3:2 dimethoxyethane / ethanol 
 ( 0.05 m )
2 m na2co3 ( 6 equiv ) , and pd(pph3)4 ( 5 mol % ) .
the mixture was purged with nitrogen and 
 heated at 85 c for 7 h. the mixture was cooled to room temperature 
 and filtered , and the filtrate was concentrated .
the residue was dissolved 
 in ethyl acetate , washed with water , washed with brine , dried over 
 na2so4 , and purified by flash column chromatography . to a solution 
 of the appropriate aryl bromide ( 1 equiv ) in 3:2 dimethoxyethane / ethanol 
 ( 0.05 m )
2 m na2co3 ( 6 equiv ) , and pd(pph3)4 ( 7 mol % ) .
the mixture was heated at 85 c for 
 12 h , then cooled to room temperature , and the solvents were removed 
 under reduced pressure .
the residue was purified by silica column 
 chromatography ( hexanes / ethyl acetate ) and then by reverse phase chromatography 
 ( water / acetonitrile ) unless otherwise mentioned . synthesized by general procedure a. flash 
 column chromatography : 25% methanol in dichloromethane , isolated 
 as a yellow solid in 27% yield .
h nmr ( 500 mhz , dmso - d6 )  ppm 9.10 ( br .
s. , 1 h ) , 8.61 ( d , j = 2.0 hz , 1 h ) , 8.43 ( d , j = 5.4 hz , 
 1 h ) , 8.04 ( dd , j = 8.8 , 2.0 hz , 1 h ) , 7.92 ( d , j = 8.8 hz , 1 h ) , 7.457.52 ( m , 2 h ) , 7.39 ( t , j = 7.8 hz , 1 h ) , 7.297.37 ( m , 6 h ) , 7.20 ( td , j = 8.8 , 2.0 hz , 1 h ) , 7.00 ( dd , j = 8.1 , 
 1.7 hz , 1 h ) , 6.77 ( d , j = 5.4 hz , 1 h ) , 5.28 ( s , 
 2 h ) , 3.753.81 ( m , 4 h ) , 3.193.26 ( m , 4 h ) . lcms found 
 540.1 [ m + h ] . synthesized by general procedure a. flash 
 column chromatography : 25% methanol in dichloromethane , isolated 
 as a yellow solid in 24% yield .
h nmr ( 500 mhz , dmso - d6 )  ppm 8.99 ( br .
s. , 1 h ) , 8.47 ( d , j = 5.4 hz , 1 h ) , 8.41 ( d , j = 8.8 hz , 
 1 h ) , 8.12 ( d , j = 2.0 hz , 1 h ) , 7.88 ( dd , j = 8.8 , 1.5 hz , 1 h ) , 7.457.51 ( m , 2 h ) , 7.267.40 
 ( m , 7 h ) , 7.20 ( td , j = 8.8 , 2.4 hz , 1 h ) , 7.02 ( dd , j = 8.3 , 2.0 hz , 1 h ) , 6.76 ( d , j = 5.4 
 hz , 1 h ) , 5.27 ( s , 2 h ) , 3.743.82 ( m , 4 h ) , 3.203.27 
 ( m , 4 h ) .
synthesized by general procedure a. flash 
 column chromatography : 05% methanol in dichloromethane , isolated 
 as a tan colored solid in 65% yield .
h nmr ( 500 mhz , dmso - d6 )  ppm 9.14 ( s , 1 h ) , 8.78 ( d , j = 2.0 hz , 1 h ) , 8.47 ( d , j = 5.4 hz , 
 1 h ) , 8.17 ( d , j = 8.8 hz , 2 h ) , 8.11 ( dd , j = 8.8 , 2.0 hz , 1 h ) , 7.98 ( d , j = 8.8 
 hz , 1 h ) , 7.88 ( d , j = 8.3 hz , 2 h ) , 7.51 ( d , j = 7.3 hz , 2 h ) , 7.48 ( d , j = 1.5 hz , 
 1 h ) , 7.43 ( t , j = 7.6 hz , 2 h ) , 7.327.39 
 ( m , 3 h ) , 6.80 ( d , j = 5.4 hz , 1 h ) , 5.25 ( s , 2 h ) , 
 3.613.70 ( m , 4 h ) , 2.882.97 ( m , 4 h ) .
synthesized by general procedure a. flash 
 column chromatography : 25% methanol in dichloromethane , isolated 
 as a tan colored solid in 63% yield .
h nmr ( 500 mhz , dmso - d6 )  ppm 9.02 ( s , 1 h ) , 8.50 ( m , j = 5.4 hz , 2 h ) , 8.25 ( d , j = 1.5 hz , 
 1 h ) , 8.18 ( d , j = 8.8 hz , 2 h ) , 7.97 ( dd , j = 8.8 , 1.5 hz , 1 h ) , 7.87 ( d , j = 8.3 
 hz , 2 h ) , 7.51 ( d , j = 7.3 hz , 2 h ) , 7.47 ( d , j = 2.0 hz , 1 h ) , 7.44 ( t , j = 7.6 hz , 
 2 h ) , 7.36 ( m , j = 6.8 hz , 1 h ) , 7.307.34 
 ( m , 2 h ) , 6.79 ( d , j = 5.4 hz , 1 h ) , 5.24 ( s , 2 h ) , 
 3.623.70 ( m , 4 h ) , 2.902.97 ( m , 4 h ) .
synthesized by general procedure a. flash 
 column chromatography : 510% methanol in dichloromethane , isolated 
 as a yellow solid in 40% yield .
h nmr ( 500 mhz , dmso - d6 )  ppm 9.19 ( br .
s. , 1 h ) , 8.78 ( d , j = 2.0 hz , 1 h ) , 8.47 ( d , j = 5.4 hz , 
 1 h ) , 8.16 ( d , j = 8.8 hz , 2 h ) , 8.12 ( dd , j = 8.8 , 2.0 hz , 1 h ) , 7.98 ( d , j = 8.8 
 hz , 1 h ) , 7.87 ( d , j = 8.8 hz , 2 h ) , 7.457.52 
 ( m , 2 h ) , 7.307.38 ( m , 4 h ) , 7.20 ( td , j = 
 8.7 , 2.7 hz , 1 h ) , 6.81 ( d , j = 5.4 hz , 1 h ) , 5.28 
 ( s , 2 h ) , 2.95 ( br . s. , 4 h ) , 2.352.43 ( m , 4 h ) , 2.15 ( s , 
 3 h ) .
synthesized by general procedure a. flash 
 column chromatography : 510% methanol in dichloromethane , isolated 
 as a yellow solid in 33% yield .
h nmr ( 500 mhz , dmso - d6 )  ppm 9.10 ( br .
s. , 1 h ) , 8.50 ( d , j = 8.3 hz , 2 h ) , 8.25 ( d , j = 2.0 hz , 
 1 h ) , 8.16 ( d , j = 8.3 hz , 2 h ) , 7.97 ( dd , j = 8.8 , 2.0 hz , 1 h ) , 7.87 ( d , j = 8.3 
 hz , 2 h ) , 7.457.52 ( m , 2 h ) , 7.297.38 ( m , 4 h ) , 7.20 
 ( td , j = 8.5 , 2.0 hz , 1 h ) , 6.80 ( d , j = 5.4 hz , 1 h ) , 5.28 ( s , 2 h ) , 2.96 ( br . s. , 4 h ) , 2.40 ( br .
then 
 prep hplc : 595% acetonitrile in water , isolated as a yellow 
 solid in 10% yield .
h nmr ( 500 mhz , dmso - d6 )  ppm 8.77 ( d , j = 2.0 hz , 1 
 h ) , 8.46 ( d , j = 5.4 hz , 1 h ) , 8.27 ( s , 1 h ) , 8.078.15 
 ( m , 3 h ) , 7.97 ( d , j = 8.8 hz , 1 h ) , 7.92 ( d , j = 8.3 hz , 2 h ) , 7.457.52 ( m , 2 h ) , 7.307.38 
 ( m , 4 h ) , 7.20 ( td , j = 8.5 , 2.4 hz , 1 h ) , 6.80 ( d , j = 5.4 hz , 1 h ) , 5.28 ( s , 2 h ) , 3.36 ( m , j = 5.2 , 2.5 , 2.5 hz , 2 h ) , 3.33 ( t , j = 6.3 hz , 
 2 h ) , 2.532.57 ( m , 2 h ) , 2.47 ( m , j = 5.9 
 hz , 2 h ) , 2.22 ( s , 3 h ) , 1.74 ( quin , j = 5.9 hz , 
 2 h ) .
synthesized by general procedure a. flash 
 column chromatography : 520% methanol in dichloromethane , isolated 
 as a brown solid in 32% yield .
h nmr ( 500 mhz , dmso - d6 )  ppm 9.06 ( s , 1 h ) , 8.478.52 
 ( m , 2 h ) , 8.23 ( d , j = 2.0 hz , 1 h ) , 8.12 ( d , j = 8.3 hz , 2 h ) , 7.96 ( dd , j = 8.8 , 2.0 
 hz , 1 h ) , 7.91 ( d , j = 8.3 hz , 2 h ) , 7.457.52 
 ( m , 2 h ) , 7.297.37 ( m , 4 h ) , 7.20 ( td , j = 
 8.5 , 2.4 hz , 1 h ) , 6.79 ( d , j = 4.9 hz , 1 h ) , 5.27 
 ( s , 2 h ) , 3.39 ( m , j = 3.4 hz , 2 h ) , 3.313.35 
 ( m , 2 h ) , 2.63 ( br . s. , 2 h ) , 2.58 ( br . s. , 2 h ) , 2.29 ( br . s. , 3 
 h ) , 1.741.83 ( m , 2 h ) .
synthesized by general procedure a. flash 
 column chromatography : 3050% ethyl acetate in hexanes , isolated 
 as a biege solid in 59% yield .
h nmr ( 500 mhz , dmso - d6 )  ppm 9.27 ( s , 1 h ) , 8.71 ( s , 1 h ) , 
 8.06 ( d , j = 2.4 hz , 1 h ) , 8.03 ( dd , j = 8.3 , 1.5 hz , 1 h ) , 7.98 ( d , j = 5.4 hz , 1 h ) , 
 7.88 ( d , j = 8.8 hz , 1 h ) , 7.76 ( dd , j = 8.8 , 2.4 hz , 1 h ) , 7.47 ( td , j = 8.1 , 6.3 hz , 
 1 h ) , 7.40 ( t , j = 7.8 hz , 1 h ) , 7.297.36 
 ( m , 4 h ) , 7.23 ( d , j = 9.3 hz , 1 h ) , 7.157.21 
 ( m , 2 h ) , 7.02 ( dd , j = 8.3 , 2.0 hz , 1 h ) , 5.23 ( s , 
 2 h ) , 3.753.82 ( m , 4 h ) , 3.203.26 ( m , 4 h ) .
synthesized by general procedure a. flash 
 column chromatography : 3050% ethyl acetate in hexanes , isolated 
 as an orange solid in 81% yield .
h nmr ( 500 mhz , dmso - d6 )  ppm 9.21 ( s , 1 h ) , 8.56 ( d , j = 8.8 hz , 1 h ) , 8.13 ( d , j = 2.4 hz , 
 1 h ) , 8.11 ( d , j = 2.0 hz , 1 h ) , 8.00 ( d , j = 5.4 hz , 1 h ) , 7.94 ( dd , j = 8.8 , 1.5 
 hz , 1 h ) , 7.78 ( dd , j = 8.8 , 2.4 hz , 1 h ) , 7.47 ( td , j = 8.0 , 6.3 hz , 1 h ) , 7.357.41 ( m , 2 h ) , 7.307.35 
 ( m , 2 h ) , 7.28 ( d , j = 7.8 hz , 1 h ) , 7.207.25 
 ( m , 2 h ) , 7.18 ( td , j = 8.8 , 2.4 hz , 1 h ) , 7.03 ( dd , j = 8.1 , 2.2 hz , 1 h ) , 5.23 ( s , 2 h ) , 3.763.81 ( m , 
 4 h ) , 3.213.25 ( m , 4 h ) . lcms found 540.2 [ m + h ] . synthesized by general procedure a. flash 
 column chromatography : 2050% ethyl acetate in hexanes , isolated 
 as an orange solid in 55% yield .
h nmr ( 500 mhz , dmso - d6 )  ppm 9.35 ( s , 1 h ) , 8.86 ( s , 1 h ) , 
 8.18 ( d , j = 8.8 hz , 2 h ) , 8.12 ( dd , j = 8.8 , 1.5 hz , 1 h ) , 8.04 ( d , j = 2.4 hz , 1 h ) , 
 8.03 ( d , j = 5.9 hz , 1 h ) , 7.96 ( d , j = 8.3 hz , 1 h ) , 7.90 ( d , j = 8.3 hz , 2 h ) , 7.76 
 ( dd , j = 9.3 , 2.9 hz , 1 h ) , 7.50 ( d , j = 6.8 hz , 2 h ) , 7.42 ( t , j = 7.3 hz , 2 h ) , 7.35 
 ( t , j = 7.3 hz , 1 h ) , 7.25 ( d , j = 9.3 hz , 1 h ) , 7.22 ( d , j = 5.9 hz , 1 h ) , 5.21 
 ( s , 2 h ) , 3.633.70 ( m , 4 h ) , 2.902.96 ( m , 4 h ) .
synthesized by general procedure a. flash 
 column chromatography : 3050% ethyl acetate in hexanes , isolated 
 as an orange solid in 81% yield .
h nmr ( 500 mhz , dmso - d6 )  ppm 9.26 ( s , 1 h ) , 8.65 ( d , j = 9.3 hz , 1 h ) , 8.25 ( d , j = 1.5 hz , 
 1 h ) , 8.16 ( d , j = 8.8 hz , 2 h ) , 8.12 ( d , j = 2.9 hz , 1 h ) , 8.018.07 ( m , 2 h ) , 7.88 ( d , j = 8.3 hz , 2 h ) , 7.78 ( dd , j = 9.0 , 2.7 
 hz , 1 h ) , 7.50 ( d , j = 6.8 hz , 2 h ) , 7.42 ( t , j = 7.3 hz , 2 h ) , 7.35 ( t , j = 7.3 hz , 
 1 h ) , 7.27 ( d , j = 5.9 hz , 1 h ) , 7.23 ( d , j = 9.3 hz , 1 h ) , 5.20 ( s , 1 h ) , 3.623.69 ( m , 4 
 h ) , 2.892.97 ( m , 4 h ) .
synthesized by general procedure a. flash 
 column chromatography : ethyl acetate , isolated as a cream colored 
 solid in 53% yield .
h nmr ( 500 mhz , cdcl3 ) 
  ppm 8.118.14 ( m , 2 h ) , 7.797.89 ( m , 7 h ) , 
 7.54 ( dd , j = 8.8 , 2.4 hz , 1 h ) , 7.36 ( td , j = 7.8 , 5.9 hz , 1 h ) , 7.28 ( s , 1 h ) , 7.217.27 ( m , 
 2 h ) , 7.18 ( d , j = 5.9 hz , 1 h ) , 7.03 ( td , j = 8.3 , 2.4 hz , 1 h ) , 6.97 ( d , j = 8.8 
 hz , 1 h ) , 5.15 ( s , 2 h ) , 3.08 ( br . s. , 4 h ) , 2.49 ( t , j = 4.6 hz , 4 h ) , 2.28 ( s , 3 h ) .
synthesized by general procedure a. flash 
 column chromatography : ethyl acetate , isolated as a pale orange solid 
 in 52% yield .
h nmr ( 500 mhz , cdcl3 )  
 ppm 8.14 ( d , j = 5.9 hz , 1 h ) , 8.02 ( d , j = 8.8 hz , 1 h ) , 7.95 ( d , j = 2.0 hz , 1 h ) , 7.837.91 
 ( m , 5 h ) , 7.76 ( dd , j = 8.5 , 1.7 hz , 1 h ) , 7.50 ( dd , j = 8.8 , 2.4 hz , 1 h ) , 7.37 ( td , j = 7.8 , 
 5.9 hz , 1 h ) , 7.227.27 ( m , 2 h ) , 7.21 ( d , j = 5.9 hz , 1 h ) , 7.007.07 ( m , 2 h ) , 6.98 ( d , j = 8.8 hz , 1 h ) , 5.16 ( s , 2 h ) , 3.11 ( br . s. , 4 h ) , 2.52 ( t , j = 4.6 hz , 4 h ) , 2.29 ( s , 3 h ) .
synthesized by general procedure a. flash 
 column chromatography : 5% methanol in dichloromethane , isolated as 
 an orange solid in 73% yield .
h nmr ( 500 mhz , dmso - d6 )  ppm 9.36 ( s , 1 h ) , 8.85 ( s , 1 h ) , 
 8.098.14 ( m , 3 h ) , 8.05 ( d , j = 2.4 hz , 1 
 h ) , 8.02 ( d , j = 5.9 hz , 1 h ) , 7.917.97 ( m , 
 3 h ) , 7.77 ( dd , j = 8.8 , 2.9 hz , 1 h ) , 7.47 ( td , j = 8.1 , 6.3 hz , 1 h ) , 7.297.36 ( m , 2 h ) , 7.24 ( d , j = 9.3 hz , 1 h ) , 7.22 ( d , j = 5.4 hz , 
 1 h ) , 7.18 ( td , j = 9.3 , 2.0 hz , 1 h ) , 5.24 ( s , 2 
 h ) , 3.353.38 ( m , 2 h ) , 3.313.35 ( m , 2 h ) , 2.542.58 
 ( m , 2 h ) , 2.472.49 ( m , 2 h ) , 2.23 ( s , 3 h ) , 1.75 ( quin , j = 5.8 hz , 2 h ) .
synthesized by general procedure a. flash 
 column chromatography : 5% methanol in dichloromethane , isolated as 
 a pale yellow solid in 68% yield .
h nmr ( 500 mhz , dmso - d6 )  ppm 9.26 ( s , 1 h ) , 8.64 ( d , j = 8.8 hz , 1 h ) , 8.23 ( d , j = 1.5 hz , 
 1 h ) , 8.13 ( d , j = 2.4 hz , 1 h ) , 8.10 ( d , j = 8.3 hz , 2 h ) , 8.008.06 ( m , 2 h ) , 7.92 ( d , j = 8.3 hz , 2 h ) , 7.79 ( dd , j = 9.0 , 2.7 
 hz , 1 h ) , 7.47 ( td , j = 8.3 , 6.3 hz , 1 h ) , 7.297.35 
 ( m , 2 h ) , 7.27 ( d , j = 5.9 hz , 1 h ) , 7.22 ( d , j = 9.3 hz , 1 h ) , 7.18 ( td , j = 8.7 , 2.7 
 hz , 1 h ) , 5.23 ( s , 2 h ) , 3.36 ( m , j = 4.9 , 2.4 , 2.4 
 hz , 2 h ) , 3.313.35 ( m , 2 h ) , 2.532.58 ( m , 2 h ) , 2.462.49 
 ( m , 2 h ) , 2.23 ( s , 3 h ) , 1.75 ( quin , j = 5.8 hz , 
 2 h ) .
synthesized by general procedure b. flash 
 column chromatography : 210% methanol in dichloromethane , isolated 
 as a yellow solid in 67% yield .
s. , 1 h ) , 8.30 ( s , 1 h ) , 8.26 ( d , j = 4.9 hz , 1 h ) , 7.95 ( dd , j = 9.0 , 1.2 
 hz , 1 h ) , 7.487.59 ( m , 1 h ) , 7.327.41 ( m , 2 h ) , 7.29 
 ( t , j = 7.8 hz , 1 h ) , 7.177.24 ( m , 2 h ) , 
 7.087.17 ( m , 3 h ) , 7.02 ( td , j = 8.4 , 2.2 
 hz , 1 h ) , 6.876.94 ( m , 2 h ) , 5.13 ( s , 2 h ) , 3.763.82 
 ( m , 4 h ) , 3.093.16 ( m , 4 h ) .
synthesized by general procedure b. flash 
 column chromatography : 28% methanol in dichloromethane , then 
 50100% ethyl acetate in hexanes , isolated as a yellow solid 
 in 38% yield .
s. , 1 h ) , 8.31 ( d , j = 8.8 hz , 1 h ) , 7.96 ( d , j = 8.8 hz , 
 1 h ) , 7.387.50 ( m , 3 h ) , 7.237.35 ( m , 5 h ) , 7.15 ( d , j = 8.8 hz , 1 h ) , 7.06 ( m , j = 8.3 , 2.0 
 hz , 2 h ) , 5.24 ( s , 2 h ) , 3.903.96 ( m , 4 h ) , 3.273.32 
 ( m , 4 h ) .
synthesized by general procedure a. flash 
 column chromatography : 2% methanol and 18% acetone in dichloromethane , 
 then 1% methanol in ethyl acetate , isolated as a yellow solid in 8% 
 yield .
s. , 2 h ) , 8.098.40 
 ( m , 4 h ) , 7.91 ( d , j = 7.8 hz , 2 h ) , 7.487.60 
 ( m , 3 h ) , 7.44 ( t , j = 7.6 hz , 3 h ) , 7.37 ( t , j = 7.3 hz , 2 h ) , 5.26 ( s , 2 h ) , 3.613.70 ( m , 4 
 h ) , 2.872.99 ( m , 4 h ) .
synthesized by general procedure b. flash 
 column chromatography : 28% methanol in dichloromethane , then 
 10100% ethyl acetate in dichloromethane , isolated as a yellow 
 solid in 71% yield .
s. , 1 h ) , 8.40 
 ( d , j = 8.8 hz , 1 h ) , 8.05 ( d , j = 8.3 hz , 2 h ) , 8.01 ( d , j = 8.8 hz , 1 h ) , 7.95 
 ( d , j = 8.3 hz , 2 h ) , 7.52 ( d , j = 7.3 hz , 2 h ) , 7.48 ( br .
s. , 1 h ) , 7.43 ( t , j = 
 7.6 hz , 2 h ) , 7.36 ( t , j = 7.3 hz , 1 h ) , 7.30 ( d , j = 8.8 hz , 1 h ) , 7.17 ( d , j = 8.8 hz , 
 1 h ) , 5.25 ( s , 2 h ) , 3.773.82 ( m , 4 h ) , 3.073.12 ( m , 
 4 h ) .
synthesized by general procedure a. flash 
 column chromatography : 510% methanol in dichloromethane , then 
 1030% methanol in ethyl acetate , isolated as a yellow solid 
 in 15% yield .
h nmr ( 500 mhz , dmso - d6 )  9.81 ( s , 1 h ) , 9.01 ( s , 1 h ) , 8.82 ( s , 1 h ) , 8.218.34 
 ( m , 4 h ) , 7.88 ( d , j = 8.3 hz , 2 h ) , 7.61 ( d , j = 2.0 hz , 1 h ) , 7.437.53 ( m , 2 h ) , 7.297.40 
 ( m , 3 h ) , 7.20 ( t , j = 8.8 hz , 1 h ) , 5.29 ( s , 2 h ) , 
 2.95 ( br .
synthesized by general procedure b. flash 
 column chromatography : 510% methanol in dichloromethane , isolated 
 as a yellow solid in 50% yield .
s. , 
 1 h ) , 8.39 ( d , j = 8.8 hz , 1 h ) , 7.938.04 
 ( m , 5 h ) , 7.48 ( br . s. , 1 h ) , 7.42 ( td , j = 8.1 , 
 5.9 hz , 1 h ) , 7.31 ( d , j = 7.8 hz , 2 h ) , 7.26 ( d , j = 9.8 hz , 1 h ) , 7.16 ( d , j = 8.8 hz , 
 1 h ) , 7.06 ( td , j = 8.5 , 2.0 hz , 1 h ) , 5.25 ( s , 2 
 h ) , 3.483.52 ( m , 2 h ) , 3.46 ( t , j = 6.3 hz , 
 2 h ) , 2.732.77 ( m , 2 h ) , 2.692.73 ( m , 2 h ) , 2.40 ( s , 
 3 h ) , 1.95 ( dt , j = 11.4 , 5.8 hz , 2 h ) . lcms found 
 618.1 [ m + h ] . synthesized by general procedure b. flash 
 column chromatography : 210% methanol in dichloromethane , isolated 
 as a yellow solid in 61% yield
s. , 1 h ) , 8.62 ( s , 1 
 h ) , 8.31 ( br .
s. , 1 h ) , 8.14 ( d , j = 8.8 hz , 1 h ) , 
 8.02 ( d , j = 8.3 hz , 2 h ) , 7.94 ( d , j = 8.8 hz , 2 h ) , 7.48 ( br .
s. , 1 h ) , 7.387.45 ( m , 2 h ) , 7.237.33 
 ( m , 3 h ) , 7.16 ( d , j = 8.8 hz , 1 h ) , 7.06 ( td , j = 8.4 , 2.2 hz , 1 h ) , 5.25 ( s , 2 h ) , 3.473.50 ( m , 
 2 h ) , 3.45 ( t , j = 6.6 hz , 2 h ) , 2.702.74 
 ( m , 2 h ) , 2.662.70 ( m , 2 h ) , 2.38 ( s , 3 h ) , 1.891.96 
 ( m , 2 h ) .
synthesized by general procedure b. flash 
 column chromatography : 515% methanol in dichloromethane , isolated 
 as a yellow solid in 52% yield .
s. , 
 1 h ) , 8.39 ( d , j = 8.8 hz , 1 h ) , 7.938.04 
 ( m , 5 h ) , 7.48 ( br . s. , 1 h ) , 7.42 ( td , j = 8.1 , 
 5.9 hz , 1 h ) , 7.31 ( d , j = 7.8 hz , 2 h ) , 7.26 ( d , j = 9.8 hz , 1 h ) , 7.16 ( d , j = 8.8 hz , 
 1 h ) , 7.06 ( td , j = 8.5 , 2.0 hz , 1 h ) , 5.25 ( s , 2 
 h ) , 3.483.52 ( m , 2 h ) , 3.46 ( t , j = 6.3 hz , 
 2 h ) , 2.732.77 ( m , 2 h ) , 2.692.73 ( m , 2 h ) , 2.40 ( s , 
 3 h ) , 1.95 ( dt , j = 11.4 , 5.8 hz , 2 h ) . lcms found 
 632.1 [ m + h ] .
synthesized by general procedure c. flash 
 column chromatography : 4080% ethyl acetate in hexanes , then 
 prep hplc 3050% acetonitrile in water , isolated as a yellow 
 solid in 9% yield .
h nmr ( 500 mhz , dmso - d6 )  9.27 ( s , 1 h ) , 9.14 ( s , 1 h ) , 8.78 ( s , 1 h ) , 
 8.27 ( dd , j = 8.3 , 1.5 hz , 1 h ) , 8.16 ( d , j = 2.4 hz , 1 h ) , 8.09 ( d , j = 8.3 hz , 
 1 h ) , 7.82 ( dd , j = 9.0 , 2.7 hz , 1 h ) , 7.407.50 
 ( m , 2 h ) , 7.39 ( s , 1 h ) , 7.307.36 ( m , 3 h ) , 7.27 ( d , j = 8.8 hz , 1 h ) , 7.18 ( td , j = 8.7 , 2.2 
 hz , 1 h ) , 7.07 ( dd , j = 8.3 , 2.0 hz , 1 h ) , 5.25 ( s , 
 2 h ) , 3.763.82 ( m , 4 h ) , 3.223.27 ( m , 4 h ) .
synthesized by general procedure c. flash 
 column chromatography : 4080% ethyl acetate in hexanes , then 
 prep hplc 3050% acetonitrile in water , isolated as a pale 
 yellow solid in 14% yield .
h nmr ( 500 mhz , dmso - d6 )  9.24 ( s , 1 h ) , 9.16 ( s , 1 h ) , 8.62 
 ( d , j = 8.3 hz , 1 h ) , 8.308.36 ( m , 2 h ) , 
 8.21 ( d , j = 2.4 hz , 1 h ) , 7.84 ( dd , j = 9.0 , 2.7 hz , 1 h ) , 7.47 ( td , j = 7.8 , 5.9 hz , 
 1 h ) , 7.387.43 ( m , 2 h ) , 7.297.36 ( m , 3 h ) , 7.26 ( d , j = 9.3 hz , 1 h ) , 7.18 ( td , j = 8.7 , 2.2 
 hz , 1 h ) , 7.06 ( dd , j = 8.3 , 2.0 hz , 1 h ) , 5.25 ( s , 
 2 h ) , 3.753.83 ( m , 4 h ) , 3.213.28 ( m , 4 h ) .
synthesized by general procedure c. flash 
 column chromatography : 50100% ethyl acetate in hexanes , then 
 prep hplc 3050% acetonitrile in water , isolated as a yellow 
 solid in 9% yield .
h nmr ( 500 mhz , dmso - d6 )  9.36 ( s , 1 h ) , 9.18 ( s , 1 h ) , 8.93 ( s , 1 h ) , 
 8.36 ( dd , j = 8.3 , 1.5 hz , 1 h ) , 8.20 ( d , j = 8.3 hz , 2 h ) , 8.17 ( d , j = 8.3 hz , 
 1 h ) , 8.15 ( d , j = 2.9 hz , 1 h ) , 7.94 ( d , j = 8.3 hz , 2 h ) , 7.82 ( dd , j = 9.0 , 2.7 
 hz , 1 h ) , 7.50 ( d , j = 7.3 hz , 2 h ) , 7.42 ( t , j = 7.6 hz , 2 h ) , 7.35 ( t , j = 7.3 hz , 
 1 h ) , 7.30 ( d , j = 9.3 hz , 1 h ) , 5.22 ( s , 2 h ) , 3.633.69 
 ( m , 4 h ) , 2.902.98 ( m , 4 h ) .
synthesized by general procedure c. flash 
 column chromatography : 5100% ethyl acetate in hexanes , then 
 prep hplc 3050% acetonitrile in water , isolated as a yellow 
 solid in 23% yield .
h nmr ( 500 mhz , dmso - d6 )  9.28 ( s , 1 h ) , 9.19 ( s , 1 h ) , 8.70 ( d , j = 8.8 hz , 1 h ) , 8.45 ( d , j = 2.0 hz , 
 1 h ) , 8.41 ( dd , j = 8.5 , 1.7 hz , 1 h ) , 8.20 ( d , j = 2.4 hz , 1 h ) , 8.18 ( d , j = 8.3 hz , 
 2 h ) , 7.91 ( d , j = 8.3 hz , 2 h ) , 7.83 ( dd , j = 8.8 , 2.4 hz , 1 h ) , 7.50 ( d , j = 6.8 
 hz , 2 h ) , 7.42 ( t , j = 7.3 hz , 2 h ) , 7.35 ( t , j = 6.8 hz , 1 h ) , 7.27 ( d , j = 8.8 hz , 
 1 h ) , 5.21 ( s , 2 h ) , 3.633.69 ( m , 4 h ) , 2.912.97 ( m , 
 4 h ) .
synthesized by general procedure 
 b. flash column chromatography : 37% methanol in dichloromethane , 
 then prep hplc 595% acetonitrile in water , isolated as an 
 orange solid in 39% yield .
s. , 1 h ) , 9.18 ( s , 1 h ) , 
 8.91 ( s , 1 h ) , 8.35 ( d , j = 7.3 hz , 1 h ) , 8.128.21 
 ( m , 6 h ) , 7.93 ( d , j = 8.3 hz , 2 h ) , 7.83 ( d , j = 6.8 hz , 1 h ) , 7.47 ( td , j = 8.3 , 6.3 
 hz , 1 h ) , 7.307.36 ( m , 2 h ) , 7.28 ( d , j = 
 8.8 hz , 1 h ) , 7.18 ( td , j = 8.7 , 2.2 hz , 1 h ) , 5.25 
 ( s , 2 h ) , 2.96 ( br . s. , 4 h ) , 2.352.43 ( m , 4 h ) , 2.15 ( s , 
 3 h ) .
synthesized by general procedure 
 b. flash column chromatography : 310% methanol in dichloromethane , 
 then prep hplc 595% acetonitrile in water , isolated as a dull 
 yellow solid in 28% yield .
h nmr ( 500 mhz , dmso - d6 )  9.28 ( s , 1 h ) , 9.20 ( s , 1 h ) , 8.70 
 ( d , j = 8.3 hz , 1 h ) , 8.47 ( d , j = 2.0 hz , 1 h ) , 8.42 ( dd , j = 8.5 , 1.7 hz , 1 h ) , 
 8.21 ( d , j = 2.9 hz , 1 h ) , 8.168.20 ( m , 3 
 h ) , 7.91 ( d , j = 8.3 hz , 2 h ) , 7.84 ( dd , j = 9.0 , 2.7 hz , 1 h ) , 7.48 ( td , j = 8.3 , 
 6.3 hz , 1 h ) , 7.307.36 ( m , 2 h ) , 7.27 ( d , j = 9.3 hz , 1 h ) , 7.18 ( td , j = 8.7 , 2.7 hz , 1 h ) , 
 5.25 ( s , 2 h ) , 2.96 ( br . s. , 4 h ) , 2.39 ( t , j = 4.6 
 hz , 4 h ) , 2.15 ( s , 3 h ) .
synthesized by general procedure 
 b. flash column chromatography : 510% methanol in dichloromethane , 
 then prep hplc 595% acetonitrile in water , isolated as an 
 orange solid in 29% yield .
h nmr ( 500 mhz , meoh - d4 )  8.94 ( s , 1 h ) , 8.73 ( s , 1 h ) , 8.25 
 ( s , 2 h ) , 8.20 ( dd , j = 8.5 , 1.2 hz , 1 h ) , 8.008.06 
 ( m , 3 h ) , 7.95 ( d , j = 8.3 hz , 2 h ) , 7.88 ( d , j = 2.4 hz , 1 h ) , 7.59 ( dd , j = 8.8 , 2.4 
 hz , 1 h ) , 7.38 ( td , j = 8.1 , 5.9 hz , 1 h ) , 7.28 ( d , j = 7.8 hz , 1 h ) , 7.23 ( d , j = 9.8 hz , 
 1 h ) , 6.997.06 ( m , 2 h ) , 5.18 ( s , 2 h ) , 3.603.66 ( m , 
 2 h ) , 3.47 ( t , j = 6.6 hz , 2 h ) , 3.223.28 
 ( m , 4 h ) , 2.77 ( s , 3 h ) , 2.142.21 ( m , 2 h ) .
synthesized by general procedure 
 b. flash column chromatography : 515% methanol in dichloromethane , 
 then prep hplc 595% acetonitrile in water , isolated as a light 
 yellow solid in 29% yield .
h nmr ( 500 mhz , meoh - d4 )  8.99 ( s , 1 h ) , 8.51 ( d , j = 8.3 hz , 1 h ) , 8.25 ( s , 1 h ) , 8.178.22 ( m , 2 h ) , 7.97 ( s , 
 4 h ) , 7.91 ( d , j = 2.9 hz , 1 h ) , 7.587.63 
 ( m , 1 h ) , 7.39 ( td , j = 7.8 , 5.9 hz , 1 h ) , 7.29 ( d , j = 7.8 hz , 1 h ) , 7.24 ( d , j = 9.3 hz , 
 1 h ) , 7.007.08 ( m , 2 h ) , 5.20 ( s , 2 h ) , 3.543.59 ( m , 
 2 h ) , 3.47 ( t , j = 6.6 hz , 2 h ) , 2.973.04 
 ( m , 4 h ) , 2.60 ( s , 3 h ) , 2.06 ( quin , j = 6.3 hz , 
 2 h ) .
synthesized by general procedure d. flash 
 column chromatography : 030% methanol in dichloromethane , isolated 
 as a yellow solid in 20% yield .
h nmr ( 400 mhz , dmso - d6 )  9.91 ( br , s , 1h ) , 8.73 ( s , 1h ) , 8.55 
 ( s , 1h ) , 8.18 ( d , j = 8.8 hz , 1h ) , 7.98 ( d , j = 8.8 hz , 1h ) , 7.55 ( d , j = 2.4 hz , 1h ) , 
 7.457.50 ( m , 1h ) , 7.377.41 ( m , 1h ) , 7.307.35 
 ( m , 6h ) , 7.177.22 ( m , 1h ) , 7.02 ( d , j = 8.0 
 hz , 1h ) , 5.29 ( s , 2h ) , 3.763.79 ( m , 4h ) , 3.203.23 
 ( m , 4h ) . lcms found 565.0 [ m + h ] . synthesized by general procedure d. flash 
 column chromatography : 020% ethyl acetate in hexanes , isolated 
 as a yellow solid in 50% yield .
h nmr ( 400 mhz , dmso - d6 )  9.99 ( s , 1h ) , 8.87 ( s , 1h ) , 8.55 
 ( s , 1h ) , 8.24 ( d , j = 8.8 hz , 1h ) , 8.14 ( d , j = 8.0 hz , 2h ) , 8.01 ( d , j = 8.8 , 1h ) , 
 7.85 ( d , j = 8.4 hz , 2h ) , 7.467.51 ( m , 3h ) , 
 7.39 ( t , j = 7.2 hz , 2h ) , 7.297.34 ( m , 3h ) , 
 5.22 ( s , 2h ) , 3.603.63 ( m , 4h ) , 2.872.89 ( m , 4h ) . 
 lcms found 611.1 [ m + h ] . synthesized by general procedure d. flash 
 column chromatography : 030% methanol in dichloromethane , isolated 
 as a yellow solid in 16% yield .
h nmr ( 400 mhz , dmso - d6 )  10.01 ( br , s , 1h ) , 8.89 ( s , 1h ) , 
 8.59 ( s , 1h ) , 8.27 ( d , j = 8.8 hz , 1h ) , 8.16 ( d , j = 8.0 hz , 2h ) , 8.05 ( d , j = 8.8 hz , 1h ) , 
 7.88 ( d , j = 8.0 hz , 2h ) , 7.55 ( br , s , 1h ) , 7.457.70 
 ( m , 1h ) , 7.317.35 ( m 4h ) , 7.177.21 ( m , 1h ) , 5.30 ( s , 
 2h ) , 2.95 ( br , s , 4h ) , 2.38 ( br , 4h ) , 2.14 ( s , 3h ) .
synthesized by general procedure d. flash 
 column chromatography : 030% methanol in dichloromethane , isolated 
 as a yellow solid in 32% yield .
h nmr ( 400 mhz , cdcl3 )  8.71 ( s , 1h ) , 8.14 ( d , j = 8.8 
 hz , 1h ) , 8.08 ( d , j = 2.4 hz , 1h ) , 7.99 ( dd , j = 8.8 , 2.2 hz , 1h ) , 7.807.82 ( m , 2h ) , 7.66 ( d , j = 8.8 hz , 2h ) , 7.47 ( s , 1h ) , 7.41 ( d , j = 2 hz , 1h ) , 7.367.39 ( m , 1h ) , 7.23 ( s , 1h ) , 7.197.20 
 ( m , 1h ) , 7.17 ( d , j = 2 hz , 1h ) , 7.05 ( dd , j = 8.0,2.4 hz , 1h ) , 7.01 ( d , j = 8.8 hz , 
 1h ) , 5.19 ( s , 2h ) , 3.363.40 ( m , 4h ) , 2.562.62 ( m , 
 4h ) , 2.33 ( s , 3h ) , 1.811.85 ( m , 2h ) .
synthesized 
 by general procedure e , isolated as a yellow solid in 12% yield .
h nmr ( 500 mhz , dmso - d6 )  
 ppm 9.68 ( s , 1 h ) , 8.59 ( s , 1 h ) , 8.01 ( d , j = 2.4 
 hz , 1 h ) , 7.94 ( s , 1 h ) , 7.67 ( dd , j = 8.8 , 2.4 hz , 
 1 h ) , 7.47 ( m , 1 h ) , 7.40 ( m , 1 h ) , 7.37 ( d , j = 
 7.8 hz , 1 h ) , 7.32 ( m , 2 h ) , 7.25 ( m , 2 h ) , 7.18 ( td , j = 9.3 , 2.4 hz , 1 h ) , 7.08 ( dd , j = 7.8 , 2.4 hz , 
 1 h ) , 5.25 ( s , 2 h ) , 3.78 ( m , 4 h ) , 3.23 ( m , 4 h ) , lcms found 547.0 , 
 [ m + h ] .
h nmr ( 500 mhz , dmso - d6 )  9.64 ( s , 1h ) , 8.49 ( s , 1h ) , 8.18 
 ( s , 1h ) , 8.05 ( d , j = 2.93 hz , 1h ) , 7.71 ( dd , j = 2.44 , 8.79 hz , 1h ) , 7.447.50 ( m , 1h ) , 7.137.41 
 ( m , 7h ) , 7.04 ( dd , j = 1.95 , 8.30 hz , 1h ) , 5.25 ( s , 
 2h ) , 3.78 ( t , j = 4.7 hz , 4h ) , 3.21 ( t , j = 4.7 hz , 4h ) .
synthesized 
 by general procedure e , isolated as a yellow solid in 8% yield .
h nmr ( 400 mhz , dmso - d6 )  
 ppm 8.61 ( s , 1 h ) , 9.83 ( s , 1 h ) , 8.15 ( m , 3 h ) , 7.98 ( s , 1 h ) , 7.88 
 ( d , j = 8.8 hz , 2 h ) , 7.65 ( m , 1 h ) , 7.49 ( m , 2 h ) , 
 7.42 ( t , j = 7.3 hz , 2 h ) , 7.35 ( m , 1 h ) , 7.27 ( d , j = 8.8 hz , 1 h ) , 5.23 ( s , 2 h ) , 3.65 ( m , 4 h ) , 2.94 ( m , 
 4 h ) .
synthesized 
 by general procedure e , isolated as a yellow solid in 40% yield .
h nmr ( 500 mhz , dmso - d6 )  
 ppm 9.79 ( s , 1 h ) , 8.52 ( s , 1 h ) , 8.41 ( s , 1 h ) , 8.03 ( d , j = 2.0 hz , 1 h ) , 7.97 ( d , j = 8.3 hz , 
 2 h ) , 7.88 ( d , j = 8.3 hz , 2 h ) , 7.68 ( dd , j = 8.8 , 2.4 hz , 1 h ) , 7.49 ( d , j = 7.8 
 hz , 2 h ) , 7.42 ( t , j = 7.6 hz , 2 h ) , 7.35 ( t , j = 7.3 hz , 1 h ) , 7.29 ( d , j = 9.3 hz , 
 1 h ) , 5.22 ( s , 2 h ) , 3.65 ( m , 4 h ) , 2.94 ( m , 4 h ) .
synthesized 
 by general procedure e , isolated as a yellow solid in 36% yield .
h nmr ( 400 mhz , dmso - d6 )  
 ppm 9.84 ( s , 1 h ) , 8.62 ( s , 1 h ) , 8.14 ( m , 3 h ) , 7.99 ( d , j = 2.2 hz , 1 h ) , 7.87 ( d , j = 8.8 hz , 
 2 h ) , 7.66 ( dd , j = 9.2 , 2.6 hz , 1 h ) , 7.47 ( m , 1 
 h ) , 7.32 ( m , 2 h ) , 7.26 ( d , j = 8.8 hz , 1 h ) , 7.19 
 ( td , j = 8.8 , 2.2 hz , 1 h ) , 5.26 ( s , 2 h ) , 2.95 ( m , 
 4 h ) , 2.38 ( m , 4 h ) , 2.14 ( s , 3 h ) .
synthesized 
 by general procedure e , isolated as a yellow solid in 25% yield .
h nmr ( 500 mhz , dmso - d6 )  
 ppm 9.79 ( s , 1 h ) , 8.52 ( s , 1 h ) , 8.41 ( s , 1 h ) , 8.05 ( d , j = 2.4 hz , 1 h ) , 7.95 ( d , j = 8.3 hz , 
 2 h ) , 7.87 ( d , j = 8.3 hz , 2 h ) , 7.69 ( dd , j = 8.8 , 2.4 hz , 1 h ) , 7.47 ( m , 1 h ) , 7.32 ( m , 2 h ) , 7.28 
 ( d , j = 8.8 hz , 1 h ) , 7.18 ( td , j = 8.5 , 2.4 hz , 1 h ) , 5.24 ( s , 2 h ) , 2.95 ( m , 4 h ) , 2.37 ( m , 4 h ) , 
 2.14 ( s , 3 h ) .
synthesized by general procedure e , isolated as a pale yellow solid 
 in 4% yield .
the product was separated by silica column chromatography 
 ( dichloromethane / methanol ) and purified by hplc to obtain the formic 
 acid salt .
h nmr ( 500 mhz , dmso - d6 )  ppm 9.82 ( s , 1 h ) , 8.61 ( s , 1 h ) , 8.22 ( s , 1 h ) , 
 8.068.13 ( m , 3 h ) , 7.99 ( d , j = 2.4 hz , 1 
 h ) , 7.91 ( d , j = 8.8 hz , 2 h ) , 7.66 ( dd , j = 9.0 , 2.7 hz , 1 h ) , 7.47 ( td , j = 8.3 , 
 6.3 hz , 1 h ) , 7.297.36 ( m , 2 h ) , 7.26 ( d , j = 8.8 hz , 1 h ) , 7.18 ( td , j = 8.7 , 2.2 hz , 1 h ) , 
 5.26 ( s , 2 h ) , 3.35 ( dt , j = 5.1 , 2.3 hz , 2 h ) , 3.32 
 ( t , j = 6.1 hz , 2 h ) , 2.532.58 ( m , 2 h ) , 
 2.48 ( d , j = 5.9 hz , 2 h ) , 2.23 ( s , 3 h ) , 1.74 ( quin , j = 5.9 hz , 2 h ) .
synthesized by general procedure e , isolated as a pale yellow solid 
 in 10% yield .
the product was separated by silica column chromatography 
 ( dichloromethane / methanol ) and purified by hplc to obtain the formic 
 acid salt .
h nmr ( 500 mhz , cdcl3/cd3od )  ppm 8.46 ( s , 1 h ) , 8.10 ( s , 1 h ) , 7.89 ( m , 5 h ) , 7.60 
 ( m , 1 h ) , 7.39 ( m , 1 h ) , 7.28 ( d , j = 7.8 hz , 1 h ) , 
 7.24 ( d , j = 9.3 hz , 1 h ) , 7.04 ( m , 2 h ) , 5.20 ( s , 
 2 h ) , 3.57 ( m , 2 h ) , 3.45 ( t , j = 6.6 hz , 2 h ) , 3.05 
 ( m , 4 h ) , 2.63 ( s , 3 h ) , 2.08 ( m , 2 h ) .
 tropical protozoal infections are 
 a significant cause of morbidity 
 and mortality worldwide ; four in particular ( human african trypanosomiasis 
 ( hat ) , chagas disease , cutaneous leishmaniasis , and malaria ) have 
 an estimated combined burden of over 87 million disability - adjusted 
 life years . 
 new drugs are needed for each of these diseases . 
 building 
 on the previous identification of neu-617 ( 1 ) as a potent 
 and nontoxic inhibitor of proliferation for the hat pathogen ( trypanosoma brucei ) , we have now tested this class of analogs 
 against other protozoal species : t. cruzi ( chagas 
 disease ) , leishmania major ( cutaneous leishmaniasis ) , 
 and plasmodium falciparum ( malaria ) . 
 based on hits 
 identified in this screening campaign , we describe the preparation 
 of several replacements for the quinazoline scaffold and report these 
 inhibitors biological activities against these parasites . 
 in doing this , we have identified several potent proliferation inhibitors 
 for each pathogen , such as 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile 
 ( neu-924 , 83 ) for t. cruzi and n-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)cinnolin-4-amine 
 ( neu-1017 , 68 ) for l. major and p. falciparum . 
Introduction
Results
Discussion and Conclusions
Experimental
Section