it is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed . as used herein , the use of the singular includes the plural unless specifically stated otherwise . it will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers , such that the compounds may exist in enantiomeric as well as in diastereisoomeric forms . unless it is specifically noted otherwise , the scope of the present invention includes all enantiomers , diastereisomers and racemic mixtures . some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases , and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention . the present invention includes all pharmaceutically acceptable isotopically enriched compounds . any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium 2 h ( or d ) in place of protium 1 h ( or h ) or use of 13 c enriched material in place of 12 c and the like . similar substitutions can be employed for n , o and s . the use of isotopes may assist in analytical as well as therapeutic aspects of the invention . for example , use of deuterium may increase the in vivo half - life by altering the metabolism ( rate ) of the compounds of the invention . these compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents . as will be evident to those skilled in the art , individual isomeric forms can be obtained by separation of mixtures thereof in conventional manner . for example , in the case of diastereoisomeric isomers , chromatographic separation may be employed . the iupac names of the compounds mentioned in the examples were generated with acd version 8 and some intermediates &# 39 ; and reagents &# 39 ; names used in the examples were generated with software such as chem bio draw ultra version 12 . 0 or auto nom 2000 from mdl isis draw 2 . 5 sp1 . in general , characterization of the compounds is performed by nuclear magnetic resonance and / or mass spectrometry . nmr spectra , recorded on brukeravance 300 , 1 h - nmr ( 300 mhz ) in the indicated solvent at ambient temperature ; chemical shifts in ppm , coupling constants in hz . hplc - ms : hplc - system : agilent 1100 series , ms : thermo dionex surveyor msq plus . column gemininx c18 , 3 μm , 2 . 1 × 50 mm , gradient : 97 % a ( acidic : 0 . 1 % tfa in water ; basic : 1 mm nh 4 hco 3 in water ph 10 ) and 3 % b ( acidic : 0 . 085 % tfa in ch 3 cn ; basic : ch 3 cn ) for 0 . 1 min , then in 2 . 1 min to 3 % a and 97 % b , then 3 % a and 97 % b for 0 . 3 min ( flow : 0 . 8 ml / min ); or column ascentis express c18 , 2 . 7 μm , 3 × 50 mm , gradient : 97 % a ( acidic : 0 . 1 % tfa in water ; basic : 1 mm nh 4 ( co 3 ) 2 in water ph 10 ) and 3 % b ( acidic : 0 . 085 % tfa in ch 3 cn ; basic : ch 3 cn ) for 0 . 05 min , then in 2 . 9 min to 3 % a and 97 % b , then 3 % a and 97 % b for 0 . 2 min ( flow : 1 . 3 ml / min ); retention times t r in [ min ]; uv detection at 254 and 220 nm ; ionization method as indicated . all the reagents , solvents , catalysts for which the synthesis is not described are purchased from chemical vendors such as sigma aldrich , fluka , bio - blocks , combi - blocks , tci , vwr , lancaster , oakwood , trans world chemical , alfa , fisher , maybridge , frontier , matrix , ukrorgsynth , toronto , ryan scientific , silicycle , anaspec , syn chem , chem - impex , mic - scientific , ltd ; however some known intermediates , were prepared according to published procedures . solvents were purchased from commercial sources in appropriate quality and used as received . air and / or moisture - sensitive reactions were run under an argon or nitrogen atmosphere . flash chromatography : fluka silica gel 60 ( 0 . 04 - 0 . 063 mm ) and interchim puriflash ir 60 silica gel ( 0 . 04 - 0 . 063 mm ); ymc * gel silica sl06s50 ( 0 . 006 - 50 μm ), 60 × 200 mm , flow 175 ml / min , program 3 ( start with 7 % b , then in 12 min 100 % b , then 100 % b for 5 min ), program 7 ( start with 25 % b , then in 12 min 100 % b , then 100 % b for 5 . 5 min ); normal phase preparative hplc : macherey - nagel vp100 / 21 nucleosil 50 å - 10 μm , hexane / etoac / meoh gradient . reverse phase preparative hplc : waters xbridge c18 150 × 30 mm , 5 μm or phenomenex gemininx c18 axia pack 100 × 30 mm , 5 μm , water / ch 3 cn gradient with 0 . 1 % tfa or 10 mm nh 4 hco 3 ( ph 10 ). the following examples are for illustrative purposes only and are not intended , nor should they be construed as limiting the invention in any manner . those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention . method a is applied when r 5 does not contain a carboxylic acid group . to a solution of intermediate a ( 50 mg , 0 . 155 mmol ) in pyridine ( 1 ml ) was added sulfonyl chloride ( 1 . 5 eq .) at room temp . the screw cap tube containing the mixture was quickly transferred in a 100 ° c . hot heating block , the mixture was stirred at 100 ° c . for 30 min . if the reaction failed according to tlc analysis ( or hplc analysis in cases of doubts ), method c was applied . if tlc analysis ( or hplc analysis in cases of doubt ) showed the presence of major amount of starting material , additional sulfonyl chloride ( 1 . 5 eq .) was added and stirring at 100 ° c . was continued for another 30 min . half - saturated aq . nahco 3 solution was added at room temperature and extraction with ch 2 cl 2 followed . the organic layer was filtered through a pad of mgso 4 and silica gel , the pad was rinsed with ch 2 cl 2 / meoh 9 : 1 and the filtrate was concentrated . purification by preparative normal phase hplc ( oversized column : macherey - nagel vp 150 / 32 nucleosil 50 - 10 , hexane / etoac / meoh gradient ) afforded the compound of formula i . if further purification was required , a wash using et 2 o or additional purification by reverse phase preparative hplc , or depending on the nature of the material , a wash procedure using et 2 o / ch 2 cl 2 was performed . method b is applied when r 5 contains a carboxylic acid group . the reaction was performed as described in method a , the workup was modified : half - saturated aq . nahco 3 solution was added at room temperature and extraction with ch 2 cl 2 followed . the ph was adjusted to 2 by adding 4m aq . hcl solution to the aqueous layer . the mixture was extracted with ch 2 cl 2 the product is formed as immiscible oil . in this case , the aq . layer was removed , meoh was added in order to dissolve the oil into the organic layer , the organic layer was filtered through a pad of mgso 4 and silica gel , the pad was rinsed with ch 2 cl 2 / meoh 8 : 2 and the filtrate was concentrated . purification by preparative reverse phase hplc ( acidic mobile phase ) afforded the compound of formula i . if further purification was needed , a wash procedure using et 2 o ( ultrasound bath ) followed or additional purification was performed by reverse phase preparative hplc ( acidic mobile phase ). to a solution of intermediate a ( 80 mg , 0 . 248 mmol ) in pyridine ( 1 ml ) was added sulfonyl chloride ( 1 . 5 eq .) at room temperature ( screw cap tube ) the mixture was stirred at room temperature for 2 h . if the reaction failed according to tlc analysis ( or hplc analysis in cases of doubts ), method d was applied . if tlc analysis ( or hplc analysis in cases of doubt ) showed the presence of a major amount of starting material , additional sulfonyl chloride ( 1 . 5 eq .) was added and stirring at room temp . was continued for 1 h . the workup and purification were performed as described in method a . deprotonation of intermediate b with methyl lithium and subsequent reaction with aromatic sulfonyl chlorides afforded intermediate c type compounds , which were deprotected to give the compound of formula i using 4m hydrochloric acid / dioxane in the presence of ethanol . method e is applied when r 5 is an aliphatic group . reactions of intermediate b with aliphatic sulfonyl chlorides were performed in the presence of triethylamine and 4 - dimethylaminopyridine ( dmap ) in chloroform ( chcl 3 )/ acetone at 50 ° c . to afford intermediate c compounds , which were deprotected to give the compound of formula i using 4m hydrochloric acid / dioxane in the presence of ethanol . to an ice cold solution of 4 , 5 - dichloro - o - phenylenediamine ( cas rn : 5348 - 42 - 5 ), ( 15 . 78 g , 89 . 14 mmol ) in ch 2 cl 2 ( 185 ml ) and pyridine ( 45 ml ) was added a solution of 2 - thiophenesulfonyl chloride ( 17 . 1 g , 93 . 62 mmol , 1 . 05 eq .) in ch 2 cl 2 ( 40 ml ). the mixture ( black solution ) was stirred and allowed to warm to room temperature overnight ( without removal of the cooling bath ), then added to etoac and washed with sat . aq . nahco 3 solution . the aq . layer was extracted 2 × with etoac , the combined organic layers were dried ( na 2 so 4 ) and concentrated . the crude product was combined with the crude product of an analogously performed 10 g scale attempt , chromatography on silica gel ( hexane / etoac 8 : 2 to 6 : 4 , chromatography was repeated with mixed fractions using the same eluent ) and afforded intermediate 1 ( 31 . 5 g , 67 %) as brown solid . c 10 h 8 cl 2 n 2 o 2 s 2 ( 323 . 22 ). ms ( esi +): 325 / 323 [ m + h ] + . 1 h - nmr ( dmso - d 6 ): δ ppm 9 . 8 - 9 . 5 ( br . signal , 1h ); 7 . 95 ( dd , j = 1 . 4 , 5 . 0 , 1h ); 7 . 50 ( dd , j = 1 . 4 , 3 . 7 , 1h ); 7 . 16 ( dd , j = 3 . 8 , 5 . 0 , 1h ); 6 . 87 , 6 . 85 ( 2s , 2 × 1h ); 5 . 5 - 5 . 25 ( br . s , 2h ). to an ice cold solution of intermediate 1 ( 3 . 24 g , 10 . 02 mmol ) in thf ( 90 ml ) and dmf ( 30 ml ) was added nah ( ca . 60 % in mineral oil , 0 . 6 g , ca . 15 mmol , 1 . 5 eq ., gas evolution , brown solution ). the mixture was stirred at 0 ° c . for 30 min ( dark colored after 5 min ), then a solution of 1 - chloromethyl ethyl ether ( 1 . 02 ml , ca . 1 . 04 g , 11 mmol , 1 . 1 eq .) was added dropwise at 0 ° c . the brown , light green mixture was stirred at 0 ° c . for 1 h , then sat . aq . nahco 3 solution ( ca . 10 ml ) was added at 0 ° c . the mixture was concentrated ( rotary evaporator ), water was added and extraction with etoac followed . the organic layer was washed with water ( 2 ×) and brine , dried ( na 2 so 4 ) and concentrated . the crude product was adsorbed on silica gel ( ch 2 cl 2 / meoh ), chromatography on silica gel ( hexane / acetone 90 : 10 to 88 : 12 to 86 : 14 to 84 : 16 to 82 : 18 to 80 : 20 ) afforded intermediate 2 ( 2 . 4 g , 63 %) as brown solid . c 13 h 14 cl 2 n 2 o 3 s 2 ( 381 . 30 ). ms ( esi +): 383 / 381 [ m + h ] + . 1 h - nmr ( dmso - d 6 ): δ ppm 8 . 05 ( dd , j = 0 . 5 , 4 . 9 , 1h ); 7 . 65 ( dd , j = 0 . 5 , 3 . 7 , 1h ); 7 . 24 ( dd , j = 3 . 8 , 5 . 0 , 1h ); 6 . 92 , 6 . 72 ( 2s , 2 × 1h ); 5 . 60 ( br . s , 2h , exchanged upon treatment with d 2 o ); 5 . 20 - 5 . 05 ( br . signal , 1h ); 4 . 78 - 4 . 62 ( br . signal , 1h ); 3 . 54 ( q , j = 7 . 0 , 2h ); 1 . 09 ( t , j = 7 . 0 , 3h ). sulfonamide formation according to method d : to an ice cold solution of intermediate 2 ( 70 mg , 0 . 184 mmol ) in thf ( 1 ml ) was added dropwise meli ( 1 . 6m in et 2 o , 0 . 25 ml , ca . 0 . 4 mmol , 2 . 2 eq .). the dark green mixture was stirred at 0 ° c . for 15 min , then a solution of an aromatic sulfonyl chloride for example : 3 - chloro - 4 - fluorobenzenesulfonyl chloride ( 63 . 1 mg , 0 . 275 mmol , 1 . 5 eq .) in thf ( 1 ml ) was added dropwise at 0 ° c . the orange solution was stirred at 0 ° c . for 40 min and at room temp . overnight . meoh was added at room temp . and the mixture was concentrated . purification by reverse phase preparative hplc ( acidic mobile phase ) afforded intermediate 3 ( 37 mg , 35 %) as light yellow solid . 1 h - nmr ( dmso - d 6 ): δ ppm 10 . 6 - 10 . 35 ( br . signal , 1h ); 8 . 14 ( dd , j = 2 . 1 , 6 . 7 , 1h ); 8 . 08 ( dd , j = 1 . 3 , 5 . 0 , 1h ); 7 . 94 - 7 . 89 ( m , 1h ); 7 . 67 ( t , j = 8 . 9 , 1h ); 7 . 60 ( s , 1h ); 7 . 56 ( dd , j = 1 . 3 , 3 . 8 , 1h ); 7 . 23 ( dd , j = 3 . 9 , 4 . 9 , 1h ); 6 . 86 ( s , 1h ); 5 . 4 - 5 . 0 ( br . signal , 1h ); 4 . 5 - 4 . 1 ( br . signal , 1h ); 3 . 41 ( partially hidden , partially resolved q , j = 7 . 0 , 2h ); 1 . 04 ( t , j = 7 . 0 , 3h ). to a − 10 ° c . cold yellow solution of 5 - chloro - 2 - nitroaniline ( 8 . 00 g , 46 . 36 mmol ) in dry dmf ( 130 ml ) was added sodium hydride 60 % ( 9 . 27 g , 231 . 79 mmol ) under ar . the resulting red suspension was stirred at − 10 ° c . for 10 minutes . a solution of 1 - benzofuran - 2 - sulfonyl chloride ( 12 . 05 g , 55 . 63 mmol ) in dry dmf ( 50 ml ) was added dropwise with a dropping funnel at − 10 ° c . ( 10 minutes of addition , exothermic reaction , maximum temperature of addition was 0 ° c ., 5 ml of dmf to rinse the funnel ). the resulting orange suspension was stirred at − 10 ° c . for 30 minutes ( color changed to brown ). the reaction mixture was quenched with half saturated nahco 3 solution ( 400 ml ) and the product was extracted five times with etoac ( 1 × 650 ml and 4 × 300 ml ). the combined organic layers were dried over na 2 so 4 , filtered and the filtrate evaporated to dryness . the crude product was combined with the crude product of an analogously performed 8 g scale attempt to give 61 . 82 g of an orange oil which was purified by mplc ( crude was dissolved in ch 2 cl 2 / meoh , preabsorption on silica gel , column d , program 3 , 5 runs ) to afford intermediate 4 ( 28 . 91 g , 88 % yield based on combined starting material ) as yellow solid . c 14 h 9 cln 2 o 5 s ( 352 . 75 ). hplc - ms ( basic mobile phase , esi − ): t r = 1 . 31 min , 350 . 7 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): 7 . 70 ( ddd , j = 0 . 6 , 1 . 3 , 7 . 8 , 1h ); 7 . 60 ( dd , j = 0 . 8 , 8 . 3 , 1h ); 7 . 52 - 7 . 47 ( m , 2h ); 7 . 39 ( m , 1h ); 7 . 28 ( m , 1h ); 7 . 18 ( s , 1h ); 6 . 75 ( d , j = 8 . 3 , 1h ). to an orange solution of intermediate 4 ( 14 . 41 g , 40 . 85 mmol ) in thf ( 55 ml ) and meoh ( 285 ml ) was added saturated aqueous nh 4 cl solution ( 285 ml , precipitation of starting material ) and then zinc ( 20 . 03 g , 306 . 38 mmol ) in a cold water bath ( 20 ° c .). the resulting suspension was stirred at room temperature for 20 minutes ( color changed from brown to dark green ). etoac ( 400 ml ) and saturated aqueous nh 4 cl solution ( 400 ml ) were added . the solid in suspension was filtered through a pad of celite and washed with etoac ( 3 × 250 ml ) and saturated aqueous nh 4 cl solution ( 3 × 200 ml ). the filtrate was shaken and the organic layer was collected , dried over na 2 so 4 , filtered and evaporated to dryness . the residue was dissolved in ch 2 cl 2 , filtered through a pad of silica , washed three times with ch 2 cl 2 / meoh 9 / 1 and evaporated to dryness . the crude product was combined with the crude product of an analogously performed 14 . 41 g scale attempt to leave 27 . 23 g of red foam . the crude foam was dissolved in ch 2 cl 2 / meoh 99 / 1 whereupon a solid precipitates . the mixture was evaporated to dryness and re - dissolved in a mixture of etoac / meoh . the remaining solid was filtered off . the filtrate was preabsorbed on silica gel and purified by flash chromatography over silica gel eluted with ch 2 cl 2 / meoh from 99 / 1 to 97 / 3 to give 20 . 25 g of impure brown solid . this product was repurified by mplc ( crude was dissolved in ch 2 cl 2 / meoh , preabsorption on silica gel , column d , program 7 , 5 runs ) to afford intermediate 5 ( 18 . 18 g , 69 % yield based on combined starting material ) as beige solid . c 14 h 11 cln 2 o 3 s ( 322 . 76 ). hplc - ms ( acidic mobile phase , esi +): t r = 1 . 93 min , 323 / 325 [ m + h ] + . 1 h - nmr ( dmso - d 6 ): 10 . 7 - 9 . 3 ( br . signal , ca . 1h ); 7 . 75 ( m , 2h ); 7 . 60 - 7 . 50 ( m , 2h ); 7 . 39 ( m , 1h ); 6 . 96 ( dd , j = 2 . 5 , 8 . 7 , 1h ); 6 . 81 ( d , j = 2 . 5 , 1h ); 6 . 62 ( d , j = 8 . 7 , 1h ), 6 . 9 - 5 . 4 ( br . signal , ca . 2h ). to a solution of 4 - chloro - 2 - nitroaniline ( cas rn : 89 - 63 - 4 ) ( 0 . 52 g , 3 . 0 mmol ) in pyridine ( 3 . 0 ml ) was added benzofuran - 2 - sulfonyl chloride ( 0 . 65 g , 3 . 0 mmol ) and the mixture was stirred at room temperature for 64 h . more benzofuran - 2 - sulfonyl chloride ( 0 . 65 g , 3 . 0 mmol ) and pyridine ( 3 . 0 ml ) were added and the reaction was heated to 100 ° c . for 4 h , cooled to room temperature , poured onto a mixture of ice and 6m hcl ( 20 ml ). the resulting suspension was filtered , rinsed with h 2 o , and the cake was dissolved in etoac , washed with brine , dried over na 2 so 4 , and concentrated to give 1 . 28 g brown solid . the solid was dissolved in meoh / thf ( 40 ml / 10 ml ), treated with 4 m naoh ( 4 ml ) at 100 ° c . for 15 min , and concentrated in vacuo . the residue was quenched with cold 1m hcl , extracted with etoac (× 2 ). the combined organic layer was washed with brine , dried over na 2 so 4 and concentrated . re - crystallization from hot etoh yielded 0 . 68 g ( 64 %) of intermediate 6 . 1 h - nmr ( 600 mhz , cdcl 3 ) δ ppm 10 . 00 ( s , 1h ), 8 . 13 ( d , j = 2 . 3 hz , 1h ), 7 . 93 ( d , j = 9 . 1 hz , 1h ), 7 . 64 - 7 . 68 ( m , 1h ), 7 . 58 ( dd , j = 9 . 0 , 2 . 5 hz , 1h ), 7 . 45 - 7 . 53 ( m , 3h ), 7 . 34 ( ddd , j = 7 . 9 , 6 . 9 , 1 . 0 hz , 1h ). to a suspension of intermediate 6 ( 217 mg , 0 . 61 mmol ) in meoh ( 25 ml ) and saturated aqueous nh 4 cl ( 25 ml ) was added zinc dust ( 1 . 0 g , 15 . 4 mmol ). the reaction was stirred at room temperature for 45 min . hoac ( 1 . 0 ml ) and zinc dust ( 1 . 0 g , 15 . 4 mmol ) were added and the reaction was stirred for another 45 min and was filtered . the filtrate was extracted with etoac (× 2 ). the combined organic layer was washed with brine , dried over na 2 so 4 , and concentrated . the crude product was purified by flash column chromatography on silica gel ( 25 % etoac - hexane ) to yield 158 mg ( 79 %) of intermediate 7 . 1 h - nmr ( 600 mhz , cdcl 3 ) δ ppm 7 . 65 ( dt , j = 7 . 4 , 0 . 8 hz , 1h ), 7 . 57 - 7 . 61 ( m , 1h ), 7 . 50 ( ddd , j = 8 . 4 , 7 . 1 , 1 . 2 hz , 1h ), 7 . 35 ( ddd , j = 8 . 0 , 7 . 3 , 0 . 9 hz , 1h ), 7 . 30 ( d , j = 0 . 9 hz , 1h ), 6 . 70 ( d , j = 2 . 3 hz , 1h ), 6 . 59 ( d , j = 8 . 5 hz , 1h ), 6 . 45 - 6 . 48 ( m , 1h ), 6 . 32 ( s , 1h ), 4 . 17 ( br . s ., 2h ). to a solution of 2 - chloro - 3 - nitro - pyridine ( cas rn : 5470 - 18 - 8 , 0 . 64 g , 4 . 0 mmol ) in dmso ( 4 ml ) was added thiophene - 2 - sulfonic acid amide ( cas rn : 6339 - 87 - 3 , 0 . 33 g , 2 . 0 mmol ) and k 2 co 3 ( 0 . 55 g , 4 . 0 mmol ). the mixture was stirred at 60 ° c . for 24 h , diluted with etoac , extracted with 1m hcl , brine , dried over na 2 so 4 , and concentrated in vacuo . the crude product was purified by flash column chromatography on silica gel ( 25 %- 40 % etoac in hexanes ) to yield intermediate 8 ( 0 . 50 g , 87 %) as yellow powder . 1 h nmr ( chloroform - d ) δ ppm : 10 . 27 ( br . s , 1h ), 8 . 63 ( dd , j = 4 . 5 , 1 . 6 hz , 1h ), 8 . 53 ( dd , j = 8 . 2 , 1 . 8 hz , 1h ), 8 . 00 ( dd , j = 3 . 8 , 1 . 5 hz , 1h ), 7 . 67 ( dd , j = 5 . 0 , 1 . 5 hz , 1h ), 7 . 13 - 7 . 19 ( m , 1h ), 7 . 08 - 7 . 12 ( m , 1h ). to a solution of 2 - bromo - 5 - chloro - 3 - nitro - pyridine ( cas rn : 75806 - 86 - 9 , 360 mg , 1 . 5 mmol ) in dmso ( 2 ml ) was added thiophene - 2 - sulfonic acid amide ( cas rn : 6339 - 87 - 3 , 165 mg , 1 . 0 mmol ) and k 2 co 3 ( 276 mg , 2 . 0 mmol ). the mixture was stirred at 60 ° c . for 24 h , diluted with etoac , extracted with 1m hcl , brine , dried over na 2 so 4 , and concentrated in vacuo . the crude product was purified by flash column chromatography on silica gel ( 0 %- 100 % etoac in hexanes ) to yield intermediate 9 ( 245 mg , 77 %) as light brown solid . 1 h nmr ( methanol - d 4 ) δ : 8 . 57 - 8 . 63 ( m , 2h ), 7 . 95 ( dd , j = 4 . 0 , 1 . 3 hz , 1h ), 7 . 86 ( dd , j = 5 . 0 , 1 . 5 hz , 1h ), 7 . 14 ( dd , j = 5 . 1 , 4 . 0 hz , 1h ). to a solution of intermediate 8 ( 175 mg , 0 . 61 mmol ) in meoh ( 30 ml ) and 1m hcl ( 2 ml ) was added pd — c ( 10 %, 65 mg , 0 . 061 mmol ). the reaction was pressurized under 45 psi h 2 for 3 h using parr apparatus , filtered , and the filtrate was concentrated in vacuo . the crude product was purified by flash column chromatography on silica gel ( 50 %- 100 % etoac in hexanes , then 2 : 98 et 3 n : etoac , then 2 : 20 : 80 et 3 n : meoh : ch 2 cl 2 ) to yield intermediate 10 ( 157 mg , 84 %) as off - white solid . 1 h nmr ( chloroform - d ) δ : 7 . 61 ( dd , j = 3 . 7 , 1 . 3 hz , 1h ), 7 . 44 ( dd , j = 5 . 0 , 1 . 2 hz , 1h ), 6 . 96 - 7 . 03 ( m , 2h ), 6 . 83 ( dd , j = 7 . 6 , 1 . 5 hz , 1h ), 6 . 56 ( dd , j = 7 . 6 , 6 . 2 hz , 1h ). to a solution of intermediate 9 ( 111 mg , 0 . 35 mmol ) in meoh ( 15 ml ) was added aqueous nh 4 cl ( 15 ml ) and zinc dust ( 0 . 56 g , 8 . 7 mmol ). the mixture was stirred at room temperature for 2 h , filtered and extracted with etoac . the organic layer was washed with brine , dried over na 2 so 4 , and concentrated in vacuo . the crude product was purified by flash column chromatography on silica gel ( 30 %- 100 % etoac in hexanes , then 10 % meoh in ch 2 cl 2 ) to yield intermediate 11 ( 75 mg , 75 %). c 9 h 8 cln 3 o 2 s 2 ( 289 . 8 ). ms ( esi − ): 288 / 290 /[ m − h ] − . sulfonamide formation : to a solution of intermediate 2 ( 80 mg , 0 . 21 mmol ) and dmap ( 5 . 1 mg , 0 . 042 mmol , 0 . 2 eq .) in chcl 3 ( 0 . 8 ml ) and acetone ( 0 . 8 ml ) was added isobutanesulfonyl chloride ( 32 . 9 μl , ca . 39 mg , 0 . 25 mmol , 1 . 2 eq .) at room temp . followed by et 3 n ( 87 . 2 μl , ca . 63 mg , 0 . 62 mmol , 3 eq .). the orange - brown solution was stirred at 50 ° c . overnight . water and etoac were added at room temp . and extraction with etoac followed . the organic layer was dried ( na 2 so 4 ), filtered and concentrated . chromatography on silica gel ( hexane / ch 2 cl 2 / et 2 o 5 : 5 : 0 . 5 to 5 : 5 : 1 ) afforded the corresponding type intermediate 12 product ( 43 mg , 41 %) as light yellow oil . 1 h - nmr ( cdcl 3 ): δ ppm 7 . 85 ( s , 1h ); ca . 7 . 85 - 7 . 84 ( partially hidden signal , 1h ); 7 . 74 ( dd , j = 1 . 3 , 5 . 0 , 1h ); 7 . 54 ( dd , j = 1 . 3 , 3 . 8 , 1h ); 7 . 15 ( dd , j = 3 . 8 , 5 . 0 , 1h ); 7 . 00 ( s , 1h ); 5 . 05 - 4 . 88 ( br . signal , 2h ); 3 . 75 - 3 . 60 ( br . signal , 2h ); 3 . 04 ( d , j = 6 . 6 , 2h ); 2 . 43 - 2 . 30 ( heptet , 1h ); 1 . 28 ( t , j = 7 . 0 , 3h ); 1 . 14 ( d , j = 6 . 7 , 6h ). to intermediate 3 ( 47 mg , 0 . 082 mmol ) and etoh ( 0 . 2 ml ) was added 4m hcl / dioxane ( 1 ml ) at room temp . the solution was stirred for 42 h at room temp . and then concentrated . chromatography on silica gel ( ch 2 cl 2 / meoh 9 : 1 ) afforded compound 1 ( 24 . 9 mg , 59 %) as off - white solid . c 16 h 10 cl 3 fn 2 o 4 s 3 ( 515 . 81 ). hplc - ms ( acidic mobile phase , esi − ): t r = 2 . 14 min , 517 / 515 / 513 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm ca . 10 . 5 - ca . 9 ( br . signal , ca . 1h ); 7 . 99 - 7 . 95 ( m , 2h ); 7 . 74 - 7 . 69 ( m , 1h ); 7 . 63 ( d , j = 8 . 9 , 1h ); 7 . 58 - 7 . 55 ( m , 1h ); 7 . 30 ( s , 1h ); 7 . 17 ( dd , j = 3 . 8 , 5 . 0 , 1h ); 7 . 15 ( s , 1h ). to intermediate 12 ( 42 mg , 0 . 084 mmol ) in etoh ( 0 . 2 ml ) was added 4m hcl / dioxane ( 2 ml ) at room temp . the solution was stirred for 72 h at room temp . and then concentrated . chromatography on silica gel ( ch 2 cl 2 / meoh 95 : 5 to 9 : 1 ) afforded compound 2 ( 29 . 8 mg , 80 %) as white solid . c 14 h 16 cl 2 n 2 o 4 s 3 ( 443 . 39 ). hplc - ms ( basic mobile phase , esi − ): t r = 1 . 66 min , 443 / 441 [ m − h ] − . 1 h - nmr ( cdcl 3 ): δ ppm 7 . 71 ( dd , j = 1 . 3 , 5 . 0 , 1h ); 7 . 65 ( s , 1h ); 7 . 55 ( dd , j = 1 . 3 , 3 . 8 , 1h ); 7 . 14 ( dd , j = 3 . 8 , 5 . 0 , 1h ); 7 . 05 ( s , 1h ); 6 . 97 , 6 . 96 ( 2 partially separated s , 2 × 1h ); 3 . 02 ( d , j = 6 . 6 , 2h ); 2 . 42 - 2 . 28 ( heptet , 1h ); 1 . 14 ( d , j = 6 . 6 , 6h ). preparation according to method c ( 18 % yield ) from intermediate 1 . c 16 h 10 cl 2 f 2 n 2 o 4 s 3 ( 499 . 36 ). hplc - ms ( acidic mobile phase , esi − ): t r = 2 . 16 min , 499 / 497 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm ca . 10 . 4 - ca . 9 . 3 ( br . signal , ca . 2h ); 8 . 00 ( dd , j = 1 . 3 , 5 . 0 , 1h ); 7 . 68 ( tt , j = 2 . 3 , 9 . 2 , 1h ); 7 . 59 ( dd , j = 1 . 3 , 3 . 8 , 1h ); 7 . 54 - 7 . 43 ( m , 2h ); 7 . 31 ( s , 1h ); 7 . 18 ( dd , j = 3 . 8 , 5 . 0 , 1h ); 7 . 13 ( s , 1h ). preparation according to method a ( 10 % yield ) from intermediate 1 . c 15 h 13 cl 2 n 3 o 4 s 4 ( 498 . 45 ). hplc - ms ( acidic mobile phase , esi − ): t r = 1 . 98 min , 498 / 496 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm 10 . 3 - 9 . 3 ( br . signal , ca . 2h ); 7 . 99 ( dd , j = 1 . 3 , 5 . 0 , 1h ); 7 . 60 ( dd , j = 1 . 3 , 3 . 8 , 1h ); 7 . 31 , 7 . 27 ( 2s , 2 × 1h ); 7 . 18 ( dd , j = 3 . 8 , 5 . 0 , 1h ); 2 . 62 , 2 . 33 ( 2s , 2 × 3h ). preparation according to method a ( 18 % yield ) from intermediate 1 . c 15 h 13 cl 2 n 3 o 5 s 3 ( 482 . 38 ). hplc - ms ( acidic mobile phase , esi − ): t r = 2 . 01 min , 482 / 480 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm ca . 10 . 3 - ca . 9 . 5 ( br . signal , ca . 2h ); 8 . 00 ( dd , j = 1 . 2 , 4 . 9 , 1h ); 7 . 61 ( dd , j = 1 . 3 , 3 . 8 , 1h ); 7 . 31 , 7 . 21 ( 2s , 2 × 1h ); 7 . 19 ( dd , j = 3 . 9 , 5 . 0 , 1h ); 2 . 40 , 2 . 19 ( 2s , 2 × 3h ). preparation according to method a ( 24 % yield ) from intermediate 1 . c 18 h 13 cl 2 n 3 o 5 s 3 ( 518 . 41 ). hplc - ms ( acidic mobile phase , esi − ): t r = 1 . 88 min , 518 / 516 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm 10 . 84 ( s , 1h ); ca . 10 . 1 - ca . 10 . 65 ( br . signal , ca . 1h ); ca . 10 . 65 - ca . 9 . 3 ( br . signal , ca . 1h ); 7 . 99 ( signal appears as d , “ j ”= 4 . 9 , 1h ); 7 . 60 - 7 . 55 ( m , 3h ); 7 . 28 , 7 . 19 ( 2s , 2 × 1h ); 7 . 17 ( dd , j = 3 . 8 , 4 . 9 , 1h ); 6 . 93 ( d , j = 8 . 7 , 1h ); 3 . 55 ( s , 2h ). preparation according to method a ( 31 % yield ) from intermediate 1 . c 17 h 11 cl 2 n 3 o 6 s 3 ( 520 . 39 ). hplc - ms ( basic mobile phase , esi − ): t r = 1 . 21 min , 520 / 518 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm ca . 12 . 4 - ca . 11 . 95 ( br . signal , 1h ); ca . 10 . 1 - ca . 9 . 3 ( br . signal , 2h ); 7 . 98 ( dd , j = 1 . 3 , 5 . 0 , 1h ); 7 . 65 ( d , j = 1 . 6 , 1h ); 7 . 56 - 7 . 52 ( m , 2h ); 7 . 31 ( s , 1h ); 7 . 23 ( d , j = 8 . 3 , 1h ); 7 . 16 ( dd , j = 3 . 7 , 4 . 9 , 1h ); 7 . 15 ( s , 1h ). preparation according to method a ( 26 % yield ) from intermediate 1 . c 17 h 12 cl 2 n 2 o 6 s 3 ( 507 . 39 ). hplc - ms ( acidic mobile phase , esi − ): t r = 1 . 78 min , 507 / 505 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm 10 . 3 - 10 . 05 ( br . signal , 1h ); 9 . 58 ( s , 1h ); 8 . 06 ( s , 1h ); 7 . 88 ( partially resolved dd , j = 0 . 9 , 5 . 0 , 1h ); 7 . 75 ( s , 4h ); 7 . 46 - 7 . 45 ( m , 2h ); 7 . 06 - 7 . 03 ( t - like signal , 1h ). preparation according to method b ( 31 % yield ) from intermediate 1 . c 18 h 14 cl 2 n 2 o 7 s 3 ( 537 . 41 ). hplc - ms ( basic mobile phase , esi − ): t r = 1 . 16 min , 537 / 535 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm 10 . 80 ( s , 1h ); 10 . 4 - 10 . 15 ( br . signal , 1h ); 8 . 73 ( s , 1h ); 8 . 30 ( d , j = 2 . 3 , 1h ); 8 . 05 ( dd , j = 1 . 4 , 5 . 0 , 1h ); 7 . 81 ( dd , j = 2 . 3 , 8 . 6 , 1h ); 7 . 55 ( dd , j = 1 . 4 , 3 . 8 , 1h ); 7 . 26 - 7 . 21 ( m , 2h ); 6 . 71 ( s , 1h ); 4 . 14 ( s , 3h ). preparation according to method a ( 40 % yield ) from intermediate 1 . c 18 h 16 cl 2 n 2 o 6 s 3 ( 523 . 43 ). hplc - ms ( basic mobile phase , esi − ): t r = 1 . 58 min , 523 / 521 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm ca . 10 . 1 - ca . 9 . 7 ( br . signal , ca . 1h ); 9 . 16 ( br . s , 1h ); 7 . 99 ( signal appears as partially resolved d , “ j ”= 4 . 2 , 1h ); 7 . 62 ( d , j = 8 . 8 , 1h ); 7 . 54 ( signal appears as partially resolved d , “ j ”= 2 . 5 , 1h ); 7 . 39 ( s , 1h ); 7 . 17 ( t - like signal , “ j ”= 4 . 3 , 1h ); 7 . 04 ( s , 1h ); 6 . 73 ( d , j = 2 . 3 , 1h ); 6 . 61 ( dd , j = 2 . 3 , 8 . 8 , 1h ); 3 . 91 , 3 . 83 ( 2s , 2 × 3h ). preparation : dipea ( 3 eq . ), ch 2 cl 2 , rt ( 76 % yield ) from intermediate 1 . c 17 h 14 cl 2 n 2 o 6 s 4 ( 541 . 47 ). hplc - ms ( acidic mobile phase , esi − ): t r = 1 . 99 min , 541 / 539 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm ca . 10 . 1 - ca . 9 ( 2 br . signals , ca . 2h ); 8 . 27 ( partially resolved dd , j = 1 . 2 , 7 . 9 , 1h ); 8 . 02 - 7 . 94 ( m , 3h ); 7 . 89 - 7 . 84 ( m , 1h ); 7 . 63 ( s , 1h ); 7 . 44 ( dd , j = 1 . 4 , 3 . 8 , 1h ); 7 . 16 ( dd , j = 3 . 8 , 5 . 0 , 1h ); 6 . 68 ( br . s , 1h ); 3 . 51 ( s , 3h ). preparation according to method a ( 33 % yield ) from intermediate 1 . c 18 h 14 cl 2 n 2 o 6 s 3 ( 521 . 42 ). hplc - ms ( basic mobile phase , esi − ): t r = 1 . 58 min , 521 / 519 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm ca . 10 . 2 - ca . 9 . 5 ( br . signal , ca . 2h ); 8 . 12 ( d , j = 8 . 6 , 2h ); 7 . 98 ( dd , j = 1 . 3 , 5 . 0 , 1h ); 7 . 87 ( d , j = 8 . 7 , 2h ); 7 . 55 ( dd , j = 1 . 4 , 3 . 8 , 1h ); 7 . 24 , 7 . 20 ( 2s , 2 × 1h ); 7 . 16 ( dd , j = 3 . 8 , 5 . 0 , 1h ); 3 . 90 ( s , 3h ). preparation according to method a ( 51 % yield ) from intermediate 1 . c 19 h 12 cl 2 n 2 o 6 s 3 ( 531 . 41 ). hplc - ms ( acidic mobile phase , esi − ): t r = 2 . 04 min , 531 / 529 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm 10 . 1 - 9 . 5 ( br . signal , 2h ); 8 . 21 ( d , j = 2 . 3 , 1h ); 8 . 18 ( d , j = 9 . 7 , 1h ); 7 . 98 ( dd , j = 1 . 3 , 5 . 0 , 1h ); 7 . 89 ( dd , j = 2 . 3 , 8 . 8 , 1h ); 7 . 59 - 7 . 55 ( m , 2h ); 7 . 33 ( s , 1h ); 7 . 16 ( dd , j = 3 . 8 , 5 . 0 , 1h ); 7 . 15 ( s , 1h ); 6 . 64 ( d , j = 9 . 6 , 1h ). preparation according to method c ( 8 % yield ) from intermediate 1 . c 15 h 9 cl 3 n 4 o 4 s 4 ( 543 . 88 ). hplc - ms ( acidic mobile phase , esi − ): t r = 1 . 99 min , 545 / 543 / 541 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm ca . 10 . 4 - ca . 9 . 3 ( br . signal , ca . 1h ); 7 . 98 ( dd , j = 1 . 2 , 5 . 0 , 1h ); 7 . 91 , 7 . 63 ( 2d , j = 4 . 5 , 2 × 1h ); 7 . 56 ( dd , j = 1 . 3 , 3 . 8 , 1h ); 7 . 31 ( s , 1h ); 7 . 16 ( dd , j = 3 . 9 , 4 . 9 , 1h ); 7 . 12 ( s , 1h ). preparation according to method a ( 40 % yield ) from intermediate 1 . c 16 h 14 cl 2 n 2 o 5 s 3 ( 481 . 39 ). hplc - ms ( acidic mobile phase , esi − ): t r = 2 . 15 min , 481 / 479 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm ca . 10 . 1 - ca . 9 . 7 ( br . signal , ca . 1h ); ca . 9 . 7 - ca . 9 . 4 ( br . signal , 1h ); 8 . 01 ( dd , j = 1 . 4 , 5 . 0 , 1h ); 7 . 59 ( dd , j = 1 . 4 , 3 . 8 , 1h ); 7 . 30 , 7 . 28 ( 2s , 2 × 1h ); 7 . 18 ( dd , j = 3 . 8 , 5 . 0 , 1h ); 6 . 15 ( signal appears as partially resolved d , “ j ”= 1 . 0 , 1h ); 2 . 28 , 2 . 21 ( 2s , 2 × 3h ). preparation according to method a ( 51 % yield ) from intermediate 1 . c 21 h 18 cl 2 n 4 o 4 s 3 ( 557 . 49 ). hplc - ms ( basic mobile phase , esi − ): t r = 1 . 61 min , 557 / 555 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm ca . 10 - ca . 9 . 5 ( br . signal , 2h ); 7 . 97 ( dd , j = 1 . 3 , 5 . 0 , 1h ); 7 . 81 , 7 . 75 ( 2d , j = 9 . 0 , 2 × 2h ); 7 . 56 ( dd , j = 1 . 3 , 3 . 8 , 1h ); 7 . 27 , 7 . 22 ( 2s , 2 × 1h ); 7 . 16 ( dd , j = 3 . 8 , 5 . 0 , 1h ); 6 . 15 ( s , 1h ); 2 . 38 , 2 . 19 ( 2s , 2 × 3h ). preparation according to method a ( 57 % yield ) from intermediate 1 . c 14 h 12 cl 2 n 4 o 4 s 3 ( 467 . 37 ). hplc - ms ( basic mobile phase , esi − ): t r = 1 . 41 min , 467 / 465 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm 10 - 9 . 6 ( br . signal , 2h ); 7 . 99 ( dd , j = 1 . 3 , 5 . 0 , 1h ); 7 . 91 ( d , j = 2 . 3 , 1h ); 7 . 60 ( dd , j = 1 . 3 , 3 . 8 , 1h ); 7 . 47 , 7 . 32 ( 2s , 2 × 1h ); 7 . 17 ( dd , j = 3 . 8 , 5 . 0 , 1h ); 6 . 64 ( d , j = 2 . 3 , 1h ); 3 . 93 ( s , 3h ). preparation according to method a , 15 min ( 45 % yield ) from intermediate 1 . c 19 h 15 cl 2 n 3 o 4 s 3 ( 516 . 44 ). hplc - ms ( acidic mobile phase , esi − ): t r = 2 . 04 min , 516 / 514 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm ca . 10 - ca . 9 . 5 ( br . signal , ca . 2h ); 7 . 96 ( dd , j = 1 . 2 , 5 . 0 , 1h ); 7 . 82 ( d , j = 7 . 8 , 1h ); 7 . 59 ( d , j = 3 . 1 , 1h ); 7 . 52 ( partially resolved dd , j = 0 . 8 , 7 . 5 , 1h ); 7 . 49 ( partially resolved dd , j = 1 . 2 , 3 . 9 , 1h ); 7 . 30 ( t , j = 7 . 3 , 1h ); 7 . 21 ( s , 1h ); 7 . 14 ( dd , j = 3 . 8 , 5 . 0 , 1h ); 7 . 10 ( s , 1h ); 6 . 74 ( partially resolved dd , j = 0 . 7 , 3 . 1 , 1h ); 3 . 86 ( s , 3h ). preparation according to method a ( 44 % yield ) from intermediate 1 . c 16 h 14 cl 2 n 2 o 4 s 4 ( 497 . 46 ). hplc - ms ( acidic mobile phase , esi − ): t r = 2 . 20 min , 497 / 495 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm ca . 10 . 2 - ca . 9 . 3 ( 2 br . signals , ca . 2h ); 8 . 00 ( signal appears as partially resolved d , “ j ”= 4 . 0 , 1h ); 7 . 60 ( signal appears as partially resolved d , “ j ”= 2 . 7 , 1h ); 7 . 28 ( s , 1h ); 7 . 18 ( partially hidden dd , j = 3 . 8 , 5 . 0 , 1h ); ca . 7 . 16 ( s , 1h ); 6 . 84 ( signal appears as partially resolved d , “ j ”= 1 . 1 , 1h ); 2 . 38 , 2 . 35 ( 2s , 2 × 3h ). preparation according to method a ( 33 % yield ) from intermediate 1 . c 15 h 11 cl 2 n 3 o 4 s 3 ( 464 . 37 ). hplc - ms ( acidic mobile phase , esi − ): t r = 1 . 94 min , 464 / 462 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm ca . 10 . 4 - ca . 9 . 2 ( br . signal , ca . 1h ); 8 . 88 ( d , j = 1 . 8 , 1h ); 8 . 84 ( dd , j = 1 . 5 , 4 . 8 , 1h ); 8 . 11 ( ddd , j = 1 . 7 , 2 . 5 , 8 . 1 , 1h ); 7 . 98 ( dd , j = 1 . 3 , 5 . 0 , 1h ); 7 . 62 ( dd , j = 4 . 5 , 7 . 8 , 1h ); 7 . 54 ( dd , j = 1 . 4 , 3 . 8 , 1h ); 7 . 29 ( s , 1h ); 7 . 17 ( s , 1h ); 7 . 167 ( partially hidden dd , j = 3 . 8 , 5 . 0 , 1h ). preparation according to method a ( 19 % yield ) from intermediate 1 . c 16 h 10 cl 4 n 2 o 5 s 3 ( 548 . 27 ). hplc - ms ( basic mobile phase , esi − ): t r = 1 . 21 min , 549 / 547 / 545 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm ca . 10 . 8 - ca . 9 . 1 ( br . signal , ca . 2h ); 7 . 99 ( dd , j = 1 . 3 , 5 . 0 , 1h ); 7 . 69 ( s , 2h ); 7 . 56 ( dd , j = 1 . 4 , 3 . 8 , 1h ); 7 . 30 ( s , 1h ); 7 . 17 ( dd , j = 3 . 9 , 5 . 0 , 1h ); 7 . 15 ( s , 1h ). preparation according to method c ( 32 % yield ) from intermediate 1 . c 15 h 14 cl 2 n 4 o 4 s 3 ( 481 . 40 ). hplc - ms ( basic mobile phase , esi − ): t r = 1 . 44 min , 481 / 479 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm ca . 11 - ca . 10 ( br . signal , ca . 1h ); 9 . 8 - 9 . 5 ( br . signal , 1h ); 7 . 98 ( signal appears as d , “ j ”= 5 . 0 , 1h ); 7 . 81 ( s , 1h ); 7 . 61 ( signal appears as d , “ j ”= 3 . 7 , 1h ); 7 . 53 , 7 . 41 ( 2s , 2 × 1h ); 7 . 16 ( signal appears as t , “ j ”= 4 . 4 , 1h ); 3 . 60 , 2 . 36 ( 2s , 2 × 3h ). c 20 h 15 cl 2 n 3 o 4 s 3 ( 528 . 45 ). hplc - ms ( acidic mobile phase , esi − ): t r = 2 . 14 min , 528 / 526 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm ca . 10 - ca . 9 . 6 ( br . signal , 2h ); 9 . 04 ( partially resolved d , j = 1 . 7 , 1h ); 8 . 37 ( signal appears as s , 1h ); 8 . 25 ( signal appears as t , j = 8 . 5 , 2h ); 7 . 95 ( signal appears as partially resolved d , “ j ”= 5 . 2 , 1h ); 7 . 73 - 7 . 68 ( t - like signal , “ j ”= 7 . 7 , 1h ); 7 . 58 ( s , 1h ); 7 . 43 ( unresolved “ d ”, “ j ”= 2 . 5 , 1h ); 7 . 14 - 7 . 11 ( partially resolved t - like signal , “ j ”= 4 . 3 , 1h ); 6 . 79 ( s , 1h ); 2 . 57 ( s , 3h ). to a solution of n -( 2 - amino - 4 - chlorophenyl ) thiophene - 2 - sulfonamide ( cas rn : 926205 - 90 - 5 ) ( 140 mg , ˜ 0 . 47 mmol ) in pyridine ( 2 . 5 ml ) was added benzofuran - 2 - sulfonyl chloride ( 102 mg , 0 . 47 mmol ) and the mixture was stirred at room temperature for 16 h . more benzofuran - 2 - sulfonyl chloride ( 51 mg , 0 . 24 mmol ) was added and the reaction was stirred for another 24 h , concentrated in vacuo to remove most of solvent . the residual thick syrup was quenched with 6m hcl and diluted with h 2 o . the resulting suspension was filtered and washed with h 2 o (× 3 ). the crude product was purified by flash column chromatography on silica gel ( 25 - 50 % etoac - hexane ) to yield 43 mg of product slightly contaminated with impurities . this material was triturated with ch 2 cl 2 to form a sandy colored solid , which was filtered and rinsed with minimal amount of ch 2 cl 2 to yield 23 mg ( 10 %) of compound 24 . 1h - nmr ( 600 mhz , cd 3 od ) ppm 7 . 73 ( dd , j = 5 . 0 , 1 . 5 hz , 1h ), 7 . 70 - 7 . 72 ( m , 1h ), 7 . 60 - 7 . 63 ( m , 1h ), 7 . 51 ( ddd , j = 8 . 5 , 7 . 2 , 1 . 3 hz , 1h ), 7 . 41 ( dd , j = 3 . 8 , 1 . 2 hz , 1h ), 7 . 37 ( dd , j = 1 . 9 , 0 . 7 hz , 1h ), 7 . 34 - 7 . 36 ( m , 1h ), 7 . 29 ( d , j = 2 . 3 hz , 1h ), 7 . 07 ( dd , j = 8 . 8 , 2 . 3 hz , 1h ), 7 . 05 ( dd , j = 5 . 0 , 3 . 8 hz , 1h ), 6 . 95 ( d , j = 8 . 5 hz , 1h ), 4 . 57 ( br . s ., 2h ). to a solution of intermediate 7 ( 158 mg , 0 . 49 mmol ) in pyridine ( 3 . 0 ml ) was added thiophene - 2 - sulfonyl chloride ( 90 mg , 0 . 49 mmol ) and the mixture was stirred at room temperature for 16 h . the solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel ( 25 - 50 % etoac - hexane ) to yield 64 mg of the desired product slightly contaminated with impurities . further purification with preparative tlc ( 50 % etoac - hexane ) yielded 52 mg ( 23 %) of compound 25 . 1 h - nmr ( 600 mhz , cd 3 od ) δ ppm 7 . 76 ( dd , j = 5 . 0 , 1 . 2 hz , 1h ), 7 . 69 ( dd , j = 7 . 9 , 1 . 2 hz , 1h ), 7 . 62 ( dd , j = 8 . 5 , 0 . 6 hz , 1h ), 7 . 51 ( ddd , j = 8 . 4 , 7 . 3 , 1 . 3 hz , 1h ), 7 . 46 ( dd , j = 3 . 8 , 1 . 5 hz , 1h ), 7 . 32 - 7 . 37 ( m , 2h ), 7 . 13 - 7 . 16 ( m , 1h ), 7 . 06 - 7 . 11 ( m , 3h ). preparation : method a ( 63 % yield ) from intermediate 5 . c 25 h 23 cln 2 o 6 s 2 ( 547 . 04 ). hplc - ms ( basic mobile phase , esi − ): t r = 1 . 55 min , 547 / 545 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm 10 . 5 - 9 . 8 ( br . signal , ca . 1h ); 9 . 28 ( s , 1h ); 7 . 79 ( partially resolved dd , j = 0 . 4 , 7 . 6 , 1h ); 7 . 72 ( dd , j = 0 . 8 , 8 . 4 , 1h ); 7 . 66 ( s , 1h ); 7 . 56 ( m , 1h ); 7 . 50 ( d , j = 2 . 3 , 1h ); 7 . 41 ( m , 1h ); 7 . 32 ( dd , j = 2 . 4 , 8 . 7 , 1h ); 7 . 20 - 7 . 10 ( m , 2h ); 7 . 08 ( partially resolved dd , j = 0 . 4 , 8 . 7 , 1h ); 6 . 75 ( d , j = 8 . 7 , 1h ); 2 . 74 ( t , j = 6 . 6 , 2h ); 1 . 76 ( t , j = 6 . 6 , 2h ); 1 . 27 ( s , 6h ). preparation : method a ( 60 % yield ) from intermediate 5 . c 22 h 16 cln 3 o 5 s 3 ( 534 . 03 ). hplc - ms ( basic mobile phase , esi − ): t r = 1 . 36 min , 532 / 534 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm 10 . 4 - 9 . 8 ( br . signal , ca . 1h ); 9 . 8 - 9 . 6 ( broad signal , ca . 1h ); 9 . 59 ( s , 1h ); 8 . 50 ( d , j = 1 . 6 , 1h ); 7 . 98 ( d , j = 8 . 6 , 1h ); 7 . 80 - 7 . 70 ( m , 3h ); 7 . 62 ( s , 1h ); 7 . 56 ( m , 1h ); 7 . 40 ( m , 1h ); 7 . 14 - 7 . 10 ( m , 2h ); 7 . 00 ( dd , partially resolved , j = 1 . 3 , 8 . 5 , 1h ); 2 . 84 ( s , 3h ). preparation : method a ( 20 % yield ) from intermediate 5 . c 25 h 19 cln 4 o 5 s 2 ( 555 . 03 ). hplc - ms ( acidic mobile phase , esi + ): t r = 2 . 11 min , 555 / 557 [ m + h ] + . 1h - nmr ( dmso - d 6 ): δ ppm 10 . 6 - 9 . 8 ( br . signal , ca . 1h ); 9 . 8 - 9 . 5 ( br . signal , ca . 1h ); 8 . 81 ( d , j = 5 . 3 , 1h ); 8 . 56 ( t , j = 1 . 6 , 1h ); 8 . 40 ( d , j = 7 . 9 , 1h ); 7 . 89 ( d , j = 5 . 3 , 1h ); 7 . 82 ( m , 1h ); 7 . 76 ( d , j = 7 . 6 , 1h ); 7 . 68 ( m , 2h ); 7 . 62 ( s , 1h ); 7 . 54 ( m , 1h ); 7 . 39 ( m , 1h ); 7 . 18 - 7 . 14 ( m , 2h ); 7 . 06 ( d , j = 9 . 1 , 1h ); 2 . 70 ( s , 3h ). preparation : method a ( 11 % yield ) from intermediate 5 . c 18 h 19 cln 2 o 5 s 2 ( 442 . 94 ). hplc - ms ( basic mobile phase , esi − ): t r = 1 . 86 min , 441 / 443 [ m − h ] − . 1h - nmr ( dmso - d 6 ): δ ppm 10 . 8 - 9 . 8 ( br . signal , ca . 1h ); 8 . 91 ( s , 1h ); 7 . 78 ( d , j = 7 . 7 , 1h ); 7 . 72 ( d , j = 8 . 4 , 1h ); 7 . 66 ( s , 1h ); 7 . 56 ( m , 1h ); 7 . 44 - 7 . 36 ( m , 2h ); 7 . 27 ( d , j = 8 . 9 , 1h ); 7 . 23 ( d , j = 2 . 4 , 1h ); 2 . 84 ( d , j = 6 . 5 , 2h ); 2 . 04 ( septuplet , j = 6 . 7 , 1h ); 0 . 91 ( d , j = 6 . 7 , 6h ). preparation : method a ( 51 % yield ) from intermediate 5 . c 23 h 16 cln 3 o 5 s 2 ( 513 . 97 ). hplc - ms ( acidic mobile phase , esi + ): t r = 1 . 86 min , 514 / 516 [ m + h ] + . 1 h - nmr ( dmso - d 6 ): δ ppm 10 . 4 - 9 . 6 ( br . signal , ca . 2h ); 9 . 47 ( d , j = 0 . 7 , 1h ); 8 . 65 ( d , j = 6 . 2 , 1h ); 8 . 45 ( d , j = 8 . 2 , 1h ); 8 . 37 ( d , j = 6 . 1 , 1h ); 8 . 25 ( dd , j = 1 . 2 , 7 . 4 , 1h ); 7 . 76 ( m , 2h ); 7 . 69 ( dd , j = 0 . 7 , 8 . 4 , 1h ); 7 . 59 ( s , 1h ); 7 . 54 ( m , 1h ); 7 . 39 ( m , 1h ); 7 . 08 - 7 . 03 ( m , 2h ); 6 . 87 ( d , j = 8 . 7 , 1h ). preparation : method a ( 54 % yield ) from intermediate 5 . c 22 h 19 cln 2 o 7 s 2 ( 522 . 98 ). 1 h - nmr ( dmso - d 6 ): δ ppm 10 . 6 - 9 . 8 ( br . signal , ca . 1h ); 9 . 02 ( s , 1h ); 7 . 78 ( d , j = 7 . 6 , 1h ); 7 . 71 ( d , j = 8 . 4 , 1h ); 7 . 65 ( s , 1h ); 7 . 55 ( m , 2h ); 7 . 40 ( t , j = 7 . 5 , 1h ); 7 . 15 ( s , 2h ); 7 . 01 ( t partially resolved , j = 1 . 2 , 1h ); 6 . 71 ( d , j = 2 . 2 , 1h ); 6 . 56 ( dd , j = 2 . 3 , 8 . 8 , 1h ); 3 . 91 ( s , 3h ); 3 . 81 ( s , 3h ). preparation : method c ( 16 % yield ) from intermediate 5 . c 21 h 17 cln 2 o 8 s 2 ( 524 . 95 ). hplc - ms ( acidic mobile phase , esi − ): t r = 2 . 30 min , 523 / 525 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm 10 . 9 - 9 . 5 ( br . signal , ca . 2h ); 8 . 61 ( d , j = 0 . 9 , 1h ); 7 . 79 ( d , j = 7 . 4 , 1h ); 1 . 71 ( dd , j = 0 . 7 , 8 . 4 , 1h ); 7 . 67 ( s , 1h ); 7 . 55 ( m , 1h ); 7 . 40 ( m , 1h ); 7 . 26 - 7 . 21 ( m , 2h ); 7 . 19 ( d , j = 2 . 2 , 1h ); 7 . 13 ( d , j = 8 . 6 , 1h ); 4 . 25 ( quartet , j = 7 . 1 , 2h ); 1 . 27 ( t , j = 7 . 1 , 3h ). preparation : method c ( 30 % yield ) from intermediate 5 . c 18 h 11 cl 3 n 2 o 5 s 3 ( 537 . 84 ). hplc - ms ( basic mobile phase , esi − ): t r = 1 . 70 min , 535 / 537 [ m − h ] − . 1 h - nmr ( dmso - d 6 ): δ ppm 10 . 6 - 9 . 4 ( br . signal , ca . 2h ); 7 . 80 ( dd , j = 0 . 7 , 7 . 8 , 1h ); 7 . 73 - 7 . 69 ( m , 2h ); 7 . 55 ( m , 1h ); 7 . 40 ( m , 1h ); 7 . 33 - 7 . 20 ( m , 3h ); 7 . 09 ( d , j = 8 . 7 , 1h ). preparation : method c ( 28 % yield ) from intermediate 5 . c 19 h 12 cl 3 n 3 o 5 s 2 ( 532 . 80 ). hplc - ms ( acidic mobile phase , esi + ): t r = 2 . 36 min , 532 / 534 [ m + h ] + . 1 h - nmr ( dmso - d 6 ): δ ppm 10 . 7 - 9 . 5 ( br . signal , ca . 2h ); 8 . 60 ( d , j = 2 . 2 , 1h ); 8 . 37 ( d , j = 2 . 2 , 1h ); 7 . 80 ( d , j = 7 . 4 , 1h ); 7 . 72 ( dd , j = 0 . 7 , 8 . 4 , 1h ); 7 . 67 ( s , 1h ); 7 . 56 ( m , 1h ); 7 . 40 ( m , 1h ); 7 . 22 ( m , 2h ); 7 . 04 ( dd partially resolved , j = 0 . 5 , 2 . 3 , 1h ). preparation : method b ( 17 % yield ) from intermediate 5 . c 22 h 17 cln 2 o 8 s 2 ( 536 . 96 ). hplc - ms ( acidic mobile phase , esi + ): t r = 1 . 68 min , 537 / 539 [ m + h ] + . 1 h - nmr ( dmso - d 6 ): δ ppm 11 . 0 - 10 . 7 ( br . signal , ca . 1h ); 10 . 67 ( s , 1h ); 8 . 42 ( d , j = 8 . 9 , 1h ); 8 . 29 ( d , j = 2 . 3 , 1h ); 7 . 78 ( m , 2h ); 7 . 66 - 7 . 62 ( m , 2h ); 1 . 53 ( m , 1h ); 7 . 44 - 7 . 36 ( m , 2h ); 7 . 23 ( d , j = 8 . 7 , 1h ); 6 . 77 ( d , j = 2 . 5 , 1h ); 4 . 14 ( s , 3h ). preparation : method b ( 27 % yield ) from intermediate 5 . c 23 h 19 cln 2 o 8 s 2 ( 550 . 99 ). hplc - ms ( acidic mobile phase , esi +): t r = 1 . 77 min , 551 / 553 [ m + h ] + . 1 h - nmr ( dmso - d 6 ): δ ppm 10 . 9 - 10 . 6 ( br . signal , ca . 1h ); 10 . 48 ( s , 1h ); 8 . 31 ( d , j = 8 . 9 , 1h ); 8 . 25 ( d , j = 2 . 3 , 1h ); 7 . 79 - 7 . 75 ( m , 2h ); 7 . 66 - 7 . 59 ( m , 2h ); 7 . 53 ( m , 1h ); 7 . 43 - 7 . 36 ( m , 2h ); 7 . 22 ( d , j = 8 . 7 , 1h ); 6 . 78 ( d , j = 2 . 5 , 1h ); 4 . 44 ( quartet , j = 7 . 0 , 2h ); 1 . 47 ( t , j = 6 . 9 , 3h ). to a solution intermediate 10 ( 72 mg , 0 . 28 mmol ) in pyridine ( 2 ml ) was added 4 - chloro - 3 - trifluoromethyl - benzenesulfonyl chloride ( 49 μl , 0 . 28 mmol ) and the reaction was stirred at room temperature for 3 days , concentrated in vacuo . the crude product was purified by flash column chromatography on silica gel ( 50 %- 75 % etoac in hexanes ) to yield compound 37 ( 26 mg , 18 %). 1 h nmr ( acetone - d 6 ) δ ppm : 8 . 27 ( d , j = 2 . 1 hz , 1h ), 8 . 14 ( dd , j = 8 . 4 , 2 . 2 hz , 1h ), 7 . 97 ( dd , j = 7 . 6 , 1 . 5 hz , 1h ), 7 . 83 ( dd , j = 6 . 4 , 1 . 5 hz , 1h ), 7 . 78 ( d , j = 8 . 2 hz , 1h ), 7 . 71 ( dd , j = 5 . 0 , 1 . 5 hz , 1h ), 7 . 51 ( dd , j = 3 . 7 , 1 . 3 hz , 1h ), 7 . 05 ( dd , j = 5 . 0 , 3 . 5 hz , 1h ), 6 . 88 ( dd , j = 7 . 8 , 6 . 3 hz , 1h ). to a solution of intermediate 11 ( 75 mg , 0 . 26 mmol ) in pyridine ( 2 ml ) was added 4 - chloro - 3 - trifluoromethyl - benzenesulfonyl chloride ( 143 mg , 0 . 52 mmol ) and the reaction was stirred at 100 ° c . for 6 h , concentrated in vacuo . the crude product was purified by flash column chromatography on silica gel ( 50 %- 100 % etoac in hexanes ), followed by ptlc ( etoac ) to yield compound 38 ( 24 mg , 17 %). 1 h nmr ( acetone - d 6 ) δ ppm : 8 . 52 ( d , j = 8 . 5 hz , 1h ), 8 . 47 ( s , 1h ), 7 . 88 - 8 . 01 ( m , 1h ), 7 . 69 ( d , j = 8 . 2 hz , 1h ), 7 . 58 ( d , j = 4 . 7 hz , 1h ), 7 . 42 - 7 . 51 ( m , 1h ), 7 . 17 - 7 . 28 ( m , 1h ), 6 . 91 - 7 . 01 ( m , 1h ). the synthetic methods used in the preparation of the other compounds of the invention is summarized in table 1 . compounds 39 through 261 where prepared starting from intermediate 1 . compound 262 was prepared from intermediate 7 . compound 263 through 484 were prepared starting from intermedite 5 . hek - gqi5 cells stably expressing ccr2 were cultured in ( dmem high glucose , 10 % fbs , 1 % psa , 400 μg / ml geneticin and 50 μg / ml hygromycin . appropriate positive control chemokines ( mcp - 1 , mip1a or rantes ) was used as the positive control agonist for screening compound - induced calcium activity assayed on the flipr tetra . the drug plates were prepared in 384 - well microplates using the ep3 and the multiprobe robotic liquid handling systems . compounds were synthesized and tested for ccr2 activity . table 2 shows activity for ccr2 receptor ( ic 50 ) nm