the terms used to describe the present invention have the following meanings herein . the compounds and intermediates of the present invention may be named according to either the iupac ( international union for pure and applied chemistry ) or cas ( chemical abstracts service ) nomenclature systems . the carbon atom content of the various hydrocarbon - containing moieties herein may be indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety , for example , the prefix ( ca - cb ) alkyl indicate an alkyl moiety of the integer “ a ” to “ b ” carbon atoms , inclusive . thus , for example , ( c1 - c6 ) alkyl refers to an alkyl group of one to six carbon atoms inclusive . the term “ alkyl ” denotes a straight or branched chain of carbon atoms with only hydrogen atom substituents , wherein the carbon chain optionally contains one or more double or triple bonds , or a combination of double bonds and triple bonds . examples of alkyl groups include , but are not limited to , methyl , ethyl , propyl , isopropyl , propenyl , propynyl , hexadienyl , and the like . the term “ alkoxy ” refers to straight or branched , monovalent , saturated aliphatic chains of carbon atoms wherein one of the carbon atoms has been replaced with an oxygen atom . examples of alkoxy groups include , but are not limited to , methoxy , ethoxy and iso - propoxy . the term “ cycloalkyl ” refers to a saturated and optionally unsaturated monocyclic or bicyclic arrangement of aliphatic chains . examples of cycloalkyl groups include , but are not limited to , cyclopropyl , cyclobutyl , cyclopentyl and cyclohexene . cycloalkyl groups may also be optionally fused to aromatic hydrocarbons such as benzene to form fused cycloalkyl groups , such as indanyl and the like . the term “ substituted ” refers to a hydrogen atom on a molecule has been replaced with a different atom or molecule . the atom or molecule replacing the hydrogen atom is denoted as a “ substituent .” the phrase “ therapeutically effective amount ” refers to an amount of a compound that ( i ) treats or prevents the particular disease , condition , or disorder , ( ii ) attenuates , ameliorates , or eliminates one or more symptoms of the particular disease , condition , or disorder , or ( iii ) prevents or delays the onset of one or more symptoms of the particular disease , condition . the phrase “ pharmaceutically acceptable ” indicates that the designated carrier , vehicle , diluent , excipient ( s ), and / or salt is generally chemically and / or physically compatible with the other ingredients comprising the formulation , and physiologically compatible with the recipient thereof . the term “ mammal ” relates to an individual animal that is a member of the taxonomic class mammalia . examples of mammals include , but are not limited to , humans , dogs , cats , horses and cattle . in the present invention , the preferred mammal is a human . in an exemplary embodiment , the compounds of the present invention have the structure shown in formula ( 3 ), wherein r 1 is as defined above for the compounds of formula ( 1 ) and formula ( 2 ). the compounds may be resolved into their pure enantiomers by methods known to those skilled in the art , for example by formation of diastereoisomeric salts which may be separated , for example , by crystallization ; formation of diastereoisomeric derivatives or complexes which may be separated ( for example , by crystallization , gas - liquid or liquid chromatography ); selective reaction of one enantiomer with an enantiomer - specific reagent ( for example , enzymatic esterification ); or gas - liquid or liquid chromatography in a chiral environment , for example , on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent . it will be appreciated that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above , a further step is required to liberate the desired enantiomeric form . alternatively , the specific stereoisomers may be synthesized by using an optically active starting material , by asymmetric synthesis using optically active reagents , substrates , catalysts or solvents , or by converting one stereoisomer into the other by asymmetric transformation . wherein the compounds contain one or more additional stereogenic centers , those skilled in the art will appreciate that all diastereoisomers and diastereoisomeric mixtures of the compounds illustrated and discussed herein are within the scope of the present invention . these diastereoisomers may be islolated by methods known to those skilled in the art , for example , by crystallization , gas - liquid or liquid chromatography . alternatively , intermediates in the course of the synthesis may exist as racemic mixtures and be subjected to resolution by methods known to those skilled in the art , for example by formation of diastereoisomeric salts which may be separated , for example , by crystallization ; formation of diastereoisomeric derivatives or complexes which may be separated , for example , by crystallization , gas - liquid or liquid chromatography ; selective reaction of one enantiomer with an enantiomer - specific reagent , for example , enzymatic esterification ; or gas - liquid or liquid chromatography in a chiral environment , for example , on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent . it will be appreciated that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above , a further step is required to liberate the desired enantiomeric form . alternatively , the specific stereoisomers may be synthesized by using an optically active starting material , by asymmetric synthesis using optically active reagents , substrates , catalysts or solvents , or by converting one stereoisomer into the other by asymmetric transformation . these methods are described in more detail in texts such as “ chiral drugs ”, cynthia a . challener ( editor ), wiley , 2002 or “ chiral drug separation ” by bingyunh li and donald t . haynia in “ encyclopedia of chemical processing ” by sunggyu lee and lee lee ( editors ), crc press , 2005 . the compounds of the present invention , and the salts thereof , may exist in the unsolvated as well as the solvated forms with pharmaceutically acceptable solvents such as water , ethanol , and the like . selected compounds of formula ( 1 ) and formula ( 2 ) and their salts and solvates may exist in more than one crystal form . polymorphs of compounds represented by formula ( 1 ) and formula ( 2 ) form part of this invention and may be prepared by crystallization of a compound of formula ( 1 ) and formula ( 2 ) under different conditions . for example , using different solvents or solvent mixtures for recrystallization ; crystallization at different temperatures ; various modes of cooling , ranging from very fast to very slow cooling during crystallization . polymorphs may also be obtained by heating or melting a compound of formula ( 1 ) and formula ( 2 ) followed by gradual or fast cooling . the presence of polymorphs may be determined by solid state nmr spectroscopy , ir spectroscopy , differential scanning calorimetry , powder x - ray diffraction or other such techniques . this invention also includes isotopically - labeled compounds , which are identical to those described by formulas ( 1 ) and ( 2 ), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature . examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen , carbon , nitrogen , oxygen , sulfur and fluorine , such as 2 h , 3 h , 13 c , 14 c , 15 n , 18 o , 17 o , 35 s , 36 cl , 125 i , 129 i and 18 f respectively . compounds of the present invention and pharmaceutically acceptable salts of the compounds which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention . certain isotopically - labeled compounds of the present invention , for example those into which an isotope such as 2 h ( deuterium ) are incorporated can afford certain therapeutic advantage resulting from greater metabolic stability , for example , increased in vivo half life or reduced dosage requirements and , hence , may be preferred in some circumstances . isotopically labeled compounds of formulae ( 1 ) and ( 2 ) of this invention , salts and solvates thereof can generally be prepared by carrying out procedures disclosed in the schemes and / or in the examples below , by substituting a readily available isotopically labeled reagent for a non - isotopically labeled reagent . pharmaceutically acceptable salts , as used herein in relation to compounds of the present invention , include pharmaceutically acceptable inorganic and organic salts of said compounds . these salts can be prepared in situ during the final isolation and purification of a compound , or by separately reacting the compound with a suitable organic or inorganic acid and isolating the salt thus formed . representative salts include , but are not limited to , the hydrobromide , hydrochloride , hydroiodide , sulfate , bisulfate , nitrate , acetate , trifluoroacetate , oxalate , besylate , camsylate , palmitate , malonate , stearate , laurate , malate , borate , benzoate , lactate , phosphate , hexafluorophosphate , benzene sulfonate , tosylate , formate , citrate , maleate , fumarate , succinate , tartrate , naphthylate , mesylate , glucoheptonate , lactobionate , and laurylsulphonate salts , and the like . compounds of the present invention may also react to form salts with pharmaceutically acceptable metal and amine cations formed from organic and inorganic bases . the term “ pharmaceutically acceptable metal cation ” contemplates positively charged metal ions derived from sodium , potassium , calcium , magnesium , aluminum , iron , zinc and the like . the term “ pharmaceutically acceptable amine cation ” contemplates the positively charged ions derived from ammonia and organic nitrogenous bases strong enough to form such cations . bases useful for the formation of pharmaceutically acceptable nontoxic base addition salts of compounds of the present invention form a class whose limits are readily understood by those skilled in the art . ( see , for example , berge , et al ., “ pharmaceutical salts ,” j . pharm . sci ., 66 : 1 - 19 ( 1977 )). the present invention further includes prodrugs of compounds of formula ( 1 ) and formula ( 2 ). a prodrug of a compound of formula ( 1 ) and formula ( 2 ) may be formed in a conventional manner with a functional group of the compound , such as with an amino , hydroxy or carboxy group . the term “ prodrug ” means a compound that is transformed in vivo to yield a compound of formula ( 1 ) and formula ( 2 ) or a pharmaceutically acceptable salt or solvate of the compound . the transformation may occur by various mechanisms , such as through hydrolysis in blood . a discussion of the use of prodrugs is provided by t . higuchi and w . stella , “ pro - drugs as novel delivery systems ,” vol . 14 of the a . c . s . symposium series , and in bioreversible carriers in drug design , ed . edward b . roche , american pharmaceutical association and pergamon press , 1987 . for example , if a compound of the present invention contains an alcohol functional group , a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as cor 7 providing an ester prodrug , conhr 7 providing a carbamate prodrug , coor 7 providing a carbonate prodrug , ch 2 ocor 7 providing and alkylcarbonyloxymethyl prodrug , p ( o )( oh ), providing a phosphate prodrug , p ( o )( o ( c1 - c6 ) alkyl ) 2 providing a phosphate prodrug , p ( o )( och 2 oco ( c1 - c6 ) alkyl ) 2 providing a phosphate prodrug , p ( o )( oh )( och 2 oco ( c1 - c6 ) alkyl ) providing a phosphate prodrug , p ( o )( oh )( oc1 - c6 ) alkyl ) providing a phosphate prodrug , or p ( o )( oh )( c1 - c6 ) alkyl ) providing a phosphonate prodrug , and the corresponding inorganic salts of the phosphate and phosphonate prodrugs , or glycosyl ( the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate ), wherein r 7 is c1 - c6 alkyl , trifluoromethyl , cyclopropyl , cyclohexyl , cyclohexylmethyl , phenyl , phenyl substituted with fluorine , chlorine , bromine , hydroxyl , trifluoromethyl , ( c1 - c4 ) alkyl , ( c1 - c4 ) alkoxy , phenylmethyl , phenylmethyl substituted with fluorine , chlorine , bromine , hydroxyl , trifluoromethyl , ( c1 - c4 ) alkyl , ( c1 - c4 ) alkoxy , 2 -, 3 -, or 4 - pyridinyl , or 2 -, 4 -, or 5 - pyrimidinyl . where r 2 , r 3 , n and p are as defined above . where r 2 , r 3 , n and p are as defined above . where r 2 , r 3 , n and p are as defined above . where r 2 , r 3 and m are as defined above . in general , compounds of the present invention where r 1 represents the moieties shown below as described herein , are prepared by the general synthetic methods outlined in reaction schemes 1 and 2 . in an exemplary embodiment , nr 5 r 6 is morpholine , thiomorpholine or piperazine . referring to reaction scheme 1 , compounds 2 - 5 can be prepared according to literature procedures ( taylor et al ., synthesis 1998 , 775 ). treatment of 2 , 5 - dimethoxyaniline 1 with di - tert - butyl dicarbonate ( boc 2 o ) and triethylamine in methanol or tetrahydrofuran at temperatures ranging from 0 ° c . to room temperature gave the protected aniline derivative 2 . oxidation with bis ( acetoxyiodo ) benzene in methanol at 0 ° c . gave the ketal 3 . monoepoxidation to yield 4 was achieved using 30 % aqueous hydrogen peroxide and a base such as aqueous sodium hydroxide or potassium carbonate in aqueous tetrahydrofuran at temperatures ranging from 0 ° c . to room temperature . selective removal of the boc group with a 4 / 1 dichloromethane / trifluoroacetic acid mixture at temperatures ranging from 0 ° c . to room temperature gave the free amine 5 . alternatively , this deprotection can be achieved using boron trifluoride - diethyl ether complex and activated molecular sieves in a solvent such as dichloromethane at room temperature . the amine 5 was then coupled with an acid chloride ( rc1 ) using a base such as lithium tert - butoxide ( lio t bu ) in a solvent such as anhydrous tetrahydrofuran at − 78 ° c . to give the ketal 6 . the various acid chlorides ( rc1 ) were prepared from the corresponding carboxylic acid by refluxing in neat thionyl chloride . the ketal 6 was de - protected in an acidic media such as trifluoroacetic acid in a solvent such as dichloromethane at temperatures ranging from 0 ° c . to room temperature to give diketone 7 . regioselective reduction of 7 was achieved by treatment with a slight excess of a mild reducing agent such as sodium triacetoxyborohydride ( nabh ( oac ) 3 ) in a solvent such as methanol at temperatures ranging from 0 ° c . to room temperature . an alternative synthetic route is depicted in reaction scheme 2 . treatment of 2 , 5 - line 1 with an acid chloride ( rc1 ) and abase such as pyridine in a solvent such as anhydrous tetrahydrofuran at temperatures ranging from 0 ° c . to room temperature gave 10 . oxidation with bis ( acetoxyiodo ) benzene in methanol at 0 ° c . gave the ketal 11 . monoepoxidation to yield 6 was achieved using 30 % aqueous hydrogen peroxide and a base such as aqueous sodium hydroxide at temperatures ranging from 0 ° c . to room temperature . the ketal 6 was deprotected in an acidic media such as trifluoroacetic acid in a solvent such as dichloromethane at temperatures ranging from 0 ° c . to room temperature to give diketone 7 . regioselective reduction of 7 was achieved by treatment with a slight excess of a mild reducing agent such as sodium triacetoxyborohydride ( nabh ( oac ) 3 ) in a solvent such as methanol at temperatures ranging from 0 ° c . to room temperature . a variation on scheme 1 is shown in scheme 3 . in this case the hydroxyl group is o - acetylated by treatment of the appropriate salicylic acid 12 with acetic anhydride and an acid such as sulfuric acid . this acetylated product is then treated with oxalyl chloride in a solvent such as dichloromethane to give the corresponding acid chloride 13 . this acid chloride is then reacted with the free amine 5 using a base such as lithium tert - butoxide ( lio t bu ) in a solvent such as anhydrous tetrahydrofuran at − 78 ° c . to give the o - acetylated ketal . treatment of the o - acetylated ketal with a base such as potassium carbonate in a solvent such as aqueous methanol gave the deprotected ketal 6 . it was discovered that the diketone intermediates of the general formula ( 7 ) as depicted in reaction schemes ( 1 ) and ( 2 ) also exhibited significant activity as nf - κb inhibitors . thus , diketones of general formula ( 2 ) as described herein are considered as part of the invention . a pharmaceutical composition of the present invention comprises a therapeutically effective amount of a compound of formula ( 1 ), or a pharmaceutically acceptable salt thereof , and a pharmaceutically acceptable carrier , vehicle , diluents or excipient . a preferred pharmaceutical composition of the present invention comprises a therapeutically effective amount of a compound of formula ( 2 ), or a pharmaceutically acceptable salt thereof , and a pharmaceutically acceptable carrier , vehicle , diluents or excipient . the pharmaceutical compositions formed by combining the compounds of this invention and the pharmaceutically acceptable carriers , vehicles or diluents are then readily administered in a variety of dosage forms such as tablets , powders , lozenges , syrups , injectable solutions and the like . these pharmaceutical compositions can , if desired , contain additional ingredients such as flavorings , binders , excipients and the like . thus , for purposes of oral administration , tablets containing various excipients such as sodium citrate , calcium carbonate and / or calcium phosphate , may be employed along with various disintegrants such as starch , alginic acid and / or certain complex silicates , together with binding agents such as polyvinylpyrrolidone , sucrose , gelatin and / or acacia . additionally , lubricating agents such as magnesium stearate , sodium lauryl sulfate and talc are often useful for tabletting purposes . solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules . preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols . when aqueous suspensions of elixirs are desired for oral administration , the active pharmaceutical agent therein may be combined with various sweetening of flavoring agents , coloring matter or dyes and , if desired , emulsifying or suspending agents , together with diluents such as water , ethanol , propylene glycol , glycerin and / or combinations thereof . for parenteral administration , solutions of the compounds or compositions of this invention in sesame or peanut oil , aqueous propylene glycol , or in sterile aqueous solutions may be employed . such aqueous solutions should be suitably buffered if necessary and the liquid diluents first rendered isotonic with sufficient saline or glucose . these particular aqueous solutions are especially suitable for intravenous , intramuscular , subcutaneous and intraperitoneal administration . in this connection , the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art . in an exemplary embodiment , the pharmaceutical preparation is in unit dosage form . in such form , the preparation is subdivided into unit doses containing appropriate quantities of the active component . the unit dosage form can be a packaged preparation , for example , packeted tablets , capsules , and powders in vial or ampoules . the unit dosage form can also be a capsule , cahet , or tablet itself or it can be the appropriate number of any of these packaged forms . methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known to those skilled in the art . for examples of methods of preparing pharmaceutical compositions , see remington : the science and practice of pharmacy , lippincott , williams & amp ; wilkins , 21 st ed . ( 2005 ), which is incorporated by reference in its entirety . to a solution of 2 , 5 - dimethoxyaniline 1 ( 50 g , 326 mmol ) in meoh ( 1 l ) in an ice bath under an inert nitrogen atmosphere was added triethylamine ( 55 ml , 397 mmol ), followed by the drop - wise addition of boc 2 o ( 78 g , 359 mmol ) in methanol ( 150 ml ). the reaction was stirred overnight . after judging incomplete by thin layer chromatography , additional boc 2 o ( 22 g , 69 mmol ) and triethylamine ( 55 ml , 397 mmol ) was added and the solution was stirred 3 days . the methanol was removed and the residue was dissolved in ethyl acetate , which was rinsed with diluted hydrochloric acid ( 2 ×) and brine before drying over anhydrous magnesium sulfate , followed by filtration , and solvent evaporation to afford 50 g ( 61 %) tert - butyl 2 , 5 - dimethoxyphenylcarbamate ( 2 ) as a brown oil . the 1 h nmr was consistent with that reported in the literature ( synthesis 1998 , 775 ). a methanolic ( 700 ml ) solution of compound 2 ( 29 g , 115 mmol ) was cooled in an ice bath before the addition of bis ( acetoxyiodo ) benzene ( 62 g , 194 mmol ) in six portions over a period of 30 minutes . the solution was stirred in the ice bath for 2 hours then brought to room temperature and stirred overnight . the reaction mixture was diluted with ethyl acetate ( 1 . 5 l ) and rinsed with water , dilute hydrochloric acid , and brine . the aqueous was back - extracted once with ethyl acetate and the organics combined before drying over anhydrous magnesium sulfate , followed by filtration , and solvent evaporation . the resulting liquid was purified over silica gel using a gradient of ethyl acetate ( 0 to 2 %) in heptane , giving 6 . 9 g ( 21 %) ( 3 ) as a yellow - orange solid . material was sufficiently pure ( approx . 95 %) by 1 h nmr , which was consistent with that reported in the literature ( synthesis 1998 , 775 ). compound 3 ( 3 . 4 g , 12 . 7 mol ) in tetrahydrofuran ( 93 ml ) was cooled in an ice bath . to the stirring solution , in drop - wise fashion , was added hydrogen peroxide ( 30 % aq ., 22 ml ) and aqueous sodium hydroxide ( 1m , 61 ml ) in tandem using 2 separate addition funnels and utilizing a claisen adapter . the reaction mixture was stirred for 30 minutes in the ice bath and then for 5 hours at room temperature . the flask was cooled in an ice bath and the peroxide was carefully quenched with manganese dioxide . after filtration of the mixture over a small bed of silica gel followed by rinsing of the silica gel with ethyl acetate , the mixture was washed with brine . the organics were then dried over anhydrous magnesium sulfate , filtered , and evaporated . the resulting oil was treated with pentane to precipitate an off white solid after solvent evaporation yielding 2 g ( 56 %) of compound ( 4 ). 1 h nmr indicated 20 % starting material in the mixture , which was easily removed in the next step ( treatment with tfa ). the 1 h nmr of the product was consistent with that reported in the literature ( synthesis 1998 , 775 ). a solution of compound 4 ( 300 mg , 1 . 1 mmol ) in anhydrous dichloromethane ( 6 was stirred in an ice bath under an inert nitrogen atmosphere . to this solution was added trifluoroacetic acid ( 1 . 5 ml ) drop - wise and the solution was brought to room temperature , stirring 3 hours . after judging complete by thin layer chromatography , the solvents were evaporated and the residue was dissolved in ethyl acetate . solid sodium bicarbonate ( 2 g ) was carefully added and the solution was stirred 10 minutes . the salt was filtered and rinsed with ethyl acetate before evaporation of the solvent . the crude compound was purified over silica gel using a gradient of ethyl acetate ( 0 to 100 %) in heptane . the product eluted in 100 % ethyl acetate giving 178 mg ( 91 %) of compound ( 5 ). the 1 h nmr of the product was consistent with that reported in the literature ( synthesis 1998 , 775 ). in a 25 - ml round bottom flask , 2 - hydroxy - 4 -( trifluoromethyl ) benzoic acid ( 309 mg , 1 . 5 mmol ) was dissolved in dichloromethane ( 6 . 0 ml ). the solution was cooled to 0 ° c . and flushed with nitrogen . to the solution was added oxalyl chloride ( 209 mg , 1 . 65 mmol ) followed by dimethylformamide ( 2 drops ). the reaction was stirred at 0 ° c . for 20 min and then allowed to warm to room temperature . once the solution turned cleared , the volatiles were removed by rotory evaporation . in a 25 ml round bottom flask , epoxyamine ( 5 ) ( 100 mg , 0 . 54 mmol ) was dissolved in tetrahydrofuran ( 4 ml ). the solution was cooled to − 78 ° c . and stirred under nitrogen . after 10 minutes , lithium tert - butoxide ( 0 . 81 ml , 0 . 81 mmol , 1 . 0 m in tetrahydrofuran ) was added and the mixture was stirred at − 78 ° c . for 20 minutes . the acid chloride obtained above ( 1 . 5 mmol ) was dissolved in 2 ml of tetrahydrofuran and transferred to the reaction mixture via a cannula . the round bottom flask containing the acid chloride was rinsed with tetrahydrofuran ( 2 × 0 . 5 ml ). the reaction mixture was stirred at − 78 ° c . for 30 minutes and then stirred at room temperature . once the reaction was complete by tlc , the mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride . the layers were separated and the organic layer was washed with brine , dried with sodium sulfate , filtered and concentrated to yield a brown oil which was a mixture of the title compound ( 6a ) and o - aroylated compound . the crude mixture of 6a was dissolved in methanol : water ( 8 : 1 , 5 . 4 ml ) and potassium carbonate ( 28 mg , 0 . 2 mmol ) was added . the reaction was monitored by lc / nis and more potassium carbonate ( 70 mg , 0 . 5 mmol ) was added . once complete by lc / ms , the reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate . the organic layer was separated , washed with brine , dried with sodium sulfate , filtered and concentrated . the crude oil was purified via silica gel chromatography to yield 6a as yellow oil ( 85 mg , 42 %). the product structure was confirmed by 1 h nmr . nmr ( cdcl 3 ): δ11 . 50 ( br . s , 1h ), 8 . 65 ( br . s , 1h ), 7 . 50 ( m , 1h ), 7 . 35 ( m , 1h ), 7 . 25 ( m , 2h ), 3 . 85 ( m , 1h ), 3 . 70 ( s , 3h ), 3 . 60 ( m , 1h ), 3 . 35 ( s , 3h ) ppm the ketal 6a ( 85 mg , 0 . 23 mmol ) was dissolved in dichloromethane ( 1 . 0 ml ) and cooled to 0 ° c . to this solution , trifluoroacetic acid ( 0 . 61 ml ) was added slowly . the ice bath was removed and the reaction was stirred at room temperature overnight . after lc / ms confirmed completion of the reaction , the solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate . the aqueous layer was washed twice with ethyl acetate . the organic layers were combined , washed with water and brine , dried with sodium sulfate , filtered , and concentrated to yield 7a as a brown oil ( 70 mg , 90 %) which was used without further purification . the product structure was confirmed by h nmr . nmr ( cdcl 3 ): δ11 . 40 ( br . s ., 1h ), 8 . 85 ( br . s ., 1h ), 7 . 65 ( m , 2h ), 7 . 30 ( m , 1h ), 7 . 25 ( m , 1h ), 4 . 00 ( m , 1h ), 3 . 90 ( m , 1h ) ppm . the diketone 7a ( 65 mg , 0 . 199 mmol ) was dissolved in methanol ( 1 . 0 ml ). sodium triacetoxyborohydride ( 42 mg , 0 . 199 mmol ) was added to the solution and stirred at room temperature . after 30 minutes , lc / ms showed starting material still present so more sodium triacetoxyborohydride ( 25 mg , 0 . 12 mmol ) was added . once the reaction was complete by lc / ms , it was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride . the organic layer was washed with brine , dried with sodium sulfate , filtered and concentrated . a crude brown solid was obtained and some methanol was added . the solution was filtered and 8a was obtained as a white solid ( 10 mg , 15 %). the product structure was confirmed by 1 h nmr . nmr ( dmso - d 6 ): δ8 . 00 ( m , 1h ), 7 . 25 ( m , 1h ), 6 . 95 ( m , 1h ), 6 . 75 ( m , 1h ), 4 . 80 ( m , 1h ), 3 . 80 ( m , 1h ), 3 . 45 ( m , 1h ) ppm . employing the general method of example 1 , the following compounds were prepared : example 2 (±)- 4 - chloro - 2 - hydroxy - n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl ) benzamide . the product structure was confirmed by 1 h nmr . nmr ( dmso - d 6 ): δ7 . 80 ( m , 1h ), 6 . 80 ( m , 2h ), 6 . 60 ( m , 1h ), 4 . 80 ( m , 1h ), 3 . 80 ( m , 1h ), 3 . 45 ( m , 1h ) ppm . (±)- 2 - hydroxy - n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl )- 4 - methylbenzamide . the product structure was confirmed by 1 h nmr . nmr ( dmso - d 6 ): δ7 . 85 ( m , 1h ), 6 . 80 ( m , 2h ), 6 . 70 ( m , 1h ), 4 . 80 ( m , 1h ), 3 . 80 ( m , 1h ), 3 . 45 ( m , 1h ), 2 . 40 ( s , 3h ) ppm . (±)- 2 - hydroxy - n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl )- 3 - methylbenzamide . the product structure was confirmed by 1 h nmr . nmr ( acetone - d 6 ): δ7 . 80 ( m , 1h ), 7 . 40 ( m , 1h ), 6 . 90 ( m , 2h ), 5 . 00 ( m , 1h ), 3 . 80 ( m , 1h ), 3 . 45 ( m , 1h ), 2 . 25 ( s , 3h ) ppm . (±)- 2 - hydroxy - n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl )- 4 - methoxybenzamide . the product structure was confirmed by 1 h nmr . nmr ( acetone - d 6 ): δ7 . 85 ( m , 1h ), 7 . 00 ( m , 1h ), 6 . 60 ( m , 2h ), 5 . 00 ( m , 1h ), 3 . 90 ( m , 1h ), 3 . 85 ( s , 3h ), 3 . 40 ( m , 1h ) ppm . (±)- 3 - chloro - 2 - hydroxy - n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl ) benzamide . the product structure was confirmed by 1 h nmr . nmr ( acetone - d 6 ): δ7 . 90 ( m , 1h ), 7 . 55 ( m , 1h ), 7 . 00 ( m , 1h ), 6 . 90 ( m , 1h ), 4 . 80 ( m , 1h ), 3 . 90 ( m , 1h ), 3 . 40 ( m , 1h ) ppm . (±)- 3 - hydroxy - n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl )- 2 - naphthamide . the product structure was confirmed by 1 h nmr . nmr ( acetone - d 6 ): δ8 . 70 ( m , 1h ), 7 . 95 ( m , 1h ), 7 . 80 ( m , 1h ), 7 . 50 ( m , 2h ), 7 . 35 ( m , 1h ), 6 . 90 ( m , 1h ), 4 . 95 ( m , 1h ), 3 . 90 ( m , 1h ), 3 . 40 ( m , 1h ) ppm . (±)- 1 - hydroxy - n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl )- 2 - naphthamide . 1 h nmr . nmr ( dmso - d 6 ): δ8 . 40 ( m , 1h ), 7 . 80 ( m , 2h ), 7 . 60 ( m , 3h ), 6 . 90 ( m , 1h ), 6 . 65 ( m , 1h ), 4 . 90 ( m , 1h ), 3 . 85 ( m , 1h ), 3 . 45 ( m , 1h ) ppm . (±)- 5 - bromo - 2 - hydroxy - n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl ) benzamide . 1 h nmr . nmr ( dmso - d 6 ): δ7 . 90 ( m , 1h ), 7 . 50 ( m , 1h ), 6 . 95 ( m , 1h ), 6 . 90 ( m , 1h ), 6 . 65 ( m , 1h ), 4 . 80 ( m , 1h ), 3 . 85 ( m , 1h ), 3 . 45 ( m , 1h ) ppm . (±)- 4 -( dimethylamino )- 2 - hydroxy - n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl ) benzamide . 1 h nmr . nmr ( dmso - d 6 ): δ7 . 70 ( m , 1h ), 6 . 95 ( m , 1h ), 6 . 60 ( br . s , 1h ), 6 . 30 ( m , 1h ), 6 . 00 ( m , 1h ), 4 . 75 ( m , 1h ), 3 . 85 ( m , 1h ), 3 . 45 ( m , 1h ), 2 . 90 ( s , 6h ) ppm . (±)- 3 - hydroxy - n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl )- 7 - methoxy - 2 - naphthamide . 1 h nmr . nmr ( dmso - d 6 ): δ 11 . 6 ( br . s , 1h ), 8 . 50 ( m , 1h ), 7 . 65 ( m , 1h ), 7 . 40 ( m , 1h ), 7 . 30 ( m , 1h ), 7 . 20 ( m , 1h ), 6 . 95 ( m , 1h ), 6 . 70 ( m , 1h ), 4 . 90 ( m , 1h ), 3 . 85 ( m , 1h ), 3 . 80 ( s , 3h ), 3 . 45 ( m , 1h ) ppm . (±)- n -( 2 , 5 - dioxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl )- 2 - hydroxy - 1 - naphthamide . nmr . nmr ( dmso - d 6 ): δ11 . 1 ( br . s , 1h ), 10 . 3 ( br . s , 1h ), 8 . 05 ( m , 1h ), 7 . 90 ( m , 2h ), 7 . 50 ( m , 2h ), 7 . 40 ( m , 1h ), 7 . 25 ( m , 1h ), 4 . 20 ( m , 1h ), 4 . 00 ( m , 1h ), 3 . 50 ( m , 1h ) ppm . (±)- 5 - bromo - 2 - hydroxy - n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl )- 3 - methylbenzamide . nmr . nmr ( dmso - d 6 ): δ7 . 95 ( m , 1h ), 7 . 50 ( m , 1h ), 6 . 95 ( m , 1h ), 4 . 80 ( m , 1h ), 3 . 85 ( m , 1h ), 3 . 45 ( m , 1h ), 2 . 25 ( s , 3h ) ppm . (±)- 5 - bromo - n -( 2 , 5 - dioxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl )- 2 - hydroxy - 3 - methylbenzamide . 1 h nmr . nmr ( dmso - d 6 ): δ 7 . 90 ( m , 1h ), 7 . 50 ( m , 2h ), 4 . 05 ( m , 1h ), 3 . 85 ( m , 1h ), 2 . 25 ( m , 3h ) ppm . (±)- 7 - bromo - 3 - hydroxy - n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl )- 2 - naphthamide . 1 h nmr . nmr ( dmso - d 6 ): δ8 . 60 ( m , 1h ), 8 . 25 ( m , 1h ), 7 . 70 ( m , 1h ), 7 . 60 ( m , 1h ), 7 . 25 ( m , 1h ), 6 . 95 ( m , 1h ), 6 . 70 ( m , 1h ), 4 . 90 ( m , 1h ), 3 . 85 ( m , 1h ), 3 . 45 ( m , 1h ) ppm . (±)- 3 , 4 - difluoro - n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl )- 2 - methoxybenzamide . 1 h nmr . nmr ( dmso - d 6 ): δ10 . 50 ( br . s , 1h ), 7 . 80 ( m , 1h ), 7 . 40 ( m , 1h ), 6 . 90 ( m , 1h ), 4 . 90 ( m , 1h ), 4 . 20 ( s , 3h ), 3 . 85 ( m , 1h ), 3 . 45 ( m , 1h ) ppm . (±)- 2 - hydroxy - n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl )- 6 - isopropyl - 3 - methylbenzamide . 1 h nmr . nmr ( dmso - d 6 ): δ 7 . 10 ( m , 1h ), 6 . 95 ( m , 1h ), 6 . 80 ( m , 1h ), 4 . 75 ( m , 1h ), 3 . 85 ( m , 1h ), 3 . 45 ( m , 1h ), 3 . 00 ( m , 1h ), 2 . 20 ( s , 6h ) ppm . (±)- 4 -( dimethylamino )- n -( 2 , 5 - dioxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl )- 2 - hydroxybenzamide . 1 h nmr . nmr ( dmso - d 6 ): δ 11 . 60 ( br . s , 1h ), 11 . 00 ( br . s , 1h ), 7 . 70 ( m , 1h ), 6 . 40 ( m , 1h ), 6 . 10 ( m , 1h ), 4 . 10 ( m , 1h ), 3 . 85 ( m , 1h ), 3 . 00 ( s , 6h ) ppm . (±)- 4 -( dimethylamino )- 2 - hydroxy - n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl ) benzamide trifluoroacetate . 1 h nmr . nmr ( dmso - d 6 ): δ11 . 4 ( s , 1h ), 10 . 80 ( s , 1h ), 7 . 70 ( m , 1h ), 6 . 90 ( m , 1h ). 6 . 65 ( m , 1h ), 6 . 30 ( m , 1h ), 6 . 00 ( m , 1h ), 4 . 80 ( m , 1h ), 3 . 85 ( m , 1h ), 3 . 45 ( m , 1h ), 2 . 90 ( s , 6h ) ppm . (±)- 4 -( dimethylamino )- n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl )- 2 - methoxybenzamide . 1 h nmr . nmr ( dmso - d 6 ): δ11 . 70 ( s , 1h ), 7 . 80 ( m , 1h ), 6 . 80 ( m , 1h ), 6 . 40 ( m , 1h ), 6 . 20 ( m , 1h ), 4 . 80 ( m , 1h ), 3 . 85 ( m , 1h ), 3 . 45 ( m , 1h ), 3 . 00 ( s , 6h ) ppm . (±)- 7 - chloro - 3 - hydroxy - n -( 2 - hydroxy - 5 - oxo - 7 - oxabicyclo [ 4 . 1 . 0 ] hept - 3 - en - 3 - yl )- 2 - naphthamide . nmr ( dmso - d 6 ): δ 12 . 0 ( br . s , 1h ), 8 . 60 ( m , 1h ), 8 . 15 ( m , 1h ), 7 . 70 ( m , 1h ), 7 . 50 ( m , 1h ), 7 . 25 ( m , 1h ), 6 . 95 ( m , 1h ), 6 . 70 ( m , 1h ), 4 . 90 ( m , 1h ), 3 . 85 ( m , 1h ), 3 . 45 ( m , 1h ) ppm . employing the general method of example 1 , the following compounds may be prepared : two reporter cell assays were used to determine the ability of the compound of example 10 to inhibit nf - κb driven transcription . the first assay was a 293 - cell based assay with a stably integrated pnf - κb - luc reporter plasmid containing 3 nf - κb promoter elements . the second assay was a 293 - cell based assay with a stably integrated ptrh1 - nf - κb - dscgfp reporter containing 4 nf - κb promoter elements . cells were treated with 0 , 0 . 2 , 1 , 10 , 20 and 40 μm of the compound of example 10 for 2 hours then were induced with 20 ng / ml tnf - α for 18 hours . following the induction , luminescence or fluorescence was quantified using a beckman - coulter 2300 plate reader . fig1 a and b shows the dose response curve generated from the luminescence and fluorescence data respectively . the compound of example 10 was observed to inhibit the expression of the luciferase gene in a dose dependent manner with a median ic 50 ( inhibitory concentration of 50 %) of 8 . 7 μm . the compound of example 10 also inhibited the expression of the green fluorescent protein gene in a dose dependent manner with a median ic 50 of 2 . 5 μm . these values represent the median value generated from three independent experiments . as a control , 0 . 5 % dmso treated and untreated cells were compared to verify that the compound of example 10 had no effect on the expression of luciferase or in the readout of the assay . there was a slight decrease in the output from the assay in the dmso treated population although it was not statistically significant . as a result of the controls , the decrease in activity in the drug treated samples was compared to the dmso control sample . the binding activity of nf - κb heterodimer or homodimer subunits from activated nuclear extracts or purified recombinant nf - κb proteins exposed to the drug compounds was evaluated using the transam nf - κb family binding elisa ( active motif ). 3 - 5 μg of nuclear extracts from tnfα activated hela or raji cells ( active motif ) or 20 ng of purified recombinant proteins ( p65 and p50 from active motif , p52 from santa cruz ) were incubated for 1 hour at room temperature with 20 μl drug compounds diluted in complete lysis buffer without dtt . treated samples were then transferred to 30 μl complete binding buffer ( with dtt ) in microplate wells pre - coated with the nf - κb consensus oligonucleotide . controls included non - specific binding ( nsb ) wells containing lysis buffer without any extract or recombinant protein ( for background ), nuclear extract or recombinant protein treated with dmso only ( for maximal binding ), and wells containing the extract : protein plus 20 pmoles free wild - type nf - κb oligonucleotide as a competitor or 20 pmoles free mutant nf - κb oligonucleotide as a control to demonstrate specificity . the plate was incubated for 1 hour at room temperature with gentle shaking and then washed 3 times with 200 μl 1 × wash buffer . nf - κb p65 , p50 , p52 , relb , or c - rel subunits bound to the plate were detected with 100 μl of the primary antibody ( diluted 1 : 1000 in 1 × antibody buffer ) specific for that subunit . the plate was incubated for 1 hour at room temperature and then washed 3 times with 200 μl 1 × wash buffer . next , 100 μl of a hrp conjugated goat anti - rabbit antibody ( diluted 1 : 1 , 000 in 1 × antibody buffer ) was added to each well . the plate was incubated for 1 hour at room temperature and then washed 4 times with 200 μl 1 × wash buffer . 100 μl of room temperature developing solution was added to each well . the reaction was allowed to develop for 2 - 10 minutes until a medium dark blue color developed ( depending on the subunit activity in the lot of extract or lot of recombinant protein used ) and then the reaction was stopped with 100 μl stop solution yielding a yellow color . absorbance was recorded using a becton - dickinson dtx 880 multimode detector at 450 nm with a reference wavelength subtracted at 620 nm . fig2 , 3 and 4 illustrate the effect of example 10 on inhibiting rela , relb and c - rel binding to nf - κb sites . raw 264 . 7 cells were seeded at 4 × 10 4 cells per well n complete growth medium in 96 well white tc plates with clear bottoms one day prior to the assay . the next day the cells were washed once and 100 μl fresh growth media was added . cells were pretreated with 0 . 5 μl from a 6 point 200 × dilution series of the test compounds in dmso for 2 hours . following pretreatment with the drugs , the inflammatory response was induced by adding 5 μl of a 20 μg / ml solution of lps ( sigma ). the cells were incubated in the presence of the drugs and 1 μg / ml lps for another 20 - 24 hours . typically after treatment the total dmso was 0 . 05 % of the culture volume and the final concentrations of the compounds were approximately : 40 , 20 , 10 , 1 , 0 . 2 and 0 μm depending on the mw of each compound . modified dilution series were prepared as needed to get adequate dose response curves without changing the % dmso . samples were run in duplicate or triplicate and included dmso treated control wells with and without lps stimulation . drugs with a known activity such as parthenolide or dhmeq were run as experimental controls . after 20 - 24 hours lps activation , the media supernatant was collected from the cells and replaced with fresh media . the supernatant samples were cleared by centrifugation at 1 , 000 × g for 5 minutes , transferred to fresh storage plates , and stored frozen at − 30 ° c . after determining the appropriate supernatant dilutions experimentally , mil - 6 levels in the supernatants were quantified using quantikine ™ mouse il - 6 immunoassay ( r & amp ; d systems ) according to the manufacturer &# 39 ; s protocol . 50 of the supernatants diluted in calibrator diluent were added to 50 μl of assay diluent in microplate wells pre - coated with an anti - mouse il - 6 capture antibody . controls included a calibrated positive il - 6 control sample , non - specific binding ( nsb ) wells containing calibrator diluent but no il - 6 , and a recombinant mouse il - 6 standard dilution series ( 10 - 1000 pg / ml ). the plates were incubated at room temperature for 2 hours with shaking and then washed 5 times with 400 μl 1 × wash buffer . 100 of an hrp - conjugated anti - mouse il - 6 antibody was added to each well to detect il - 6 captured on the plate . the plates were incubated at room temperature for 2 hours and then washed 5 times with 400 μl 1 × wash buffer . equal volumes of color reagents a and b were mixed and 100 μl of this hrp substrate solution was added to each well on the plate . the blue color was allowed to develop for 30 minutes and then the reaction was stopped using 100 μl of stop solution yielding a yellow color . absorbance at 450 nm with a reference wavelength subtracted at 595 nm was recorded using a becton - dickinson dtx 880 multimode detector . the concentration of mil - 6 in the unknown samples was determined from a curve - fit of the mil - 6 standard absorbance data and multiplying by the dilution factor . the maximum activity achieved in the absence of the inhibitor ( dmso + lps treated wells ) was arbitrarily given a value of 100 %; likewise the minimum activity in the absence of the stimulant ( no lps ) was assigned a value of 0 %. inhibition of the amount of mil - 6 cytokine released in the drug treated wells was calculated relative to the maximum activation in the dmso + lps treated control wells ( ie . % inhibition = 100 −( drug + lps treated )/( dmso + lps treated )). dose response curves were used to determine the effective concentration to inhibit 50 % of the mil - 6 cytokine released ( ic 50 ) by means of a sigmaplot macro which fits a sigmoidal dose - response curve to the ( log 10 ) μm concentration versus % inhibition . in the case when compounds did not reach maximum inhibition at the concentrations tested , the curve fit was assisted with forced maximum ( 100 %) and minimum ( 0 %) values . this technique yields an objective value for the ic 50 provided that 50 % inhibition was approached at the concentrations tested . fig5 illustrates the effect of the compound of example 10 on inhibiting il - 6 release . after determining the appropriate supernatant dilutions experimentally , pge2 levels in the supernatants were quantified using parameter ™ pge2 immunoassay ( r & amp ; d systems ) according to the manufacturer &# 39 ; s protocol . 1004 of the supernatants diluted in calibrator diluent and 50 μl of a primary monoclonal anti - pge2 antibody were added to the microplate wells pre - coated with a goat anti - mouse ig capture antibody . then 50 μl of an hrp conjugated pge2 competitor was added . controls included non - specific binding ( nsb ) wells containing calibrator diluent but no primary antibody and a recombinant pge2 standard dilution series ( 40 - 5000 pg / ml ). the plates were incubated at room temperature for 2 hours with shaking and then washed 5 times with 400 μl 1 × wash buffer . equal volumes of color reagents a and b were mixed and 200 μl of this hrp substrate solution was added to each well on the plate . the blue color was allowed to develop for 30 minutes and then the reaction was stopped using 50 μl of stop solution yielding a yellow color . absorbance at 450 nm with a reference at 595 nm was recorded using a becton - dickinson dtx 880 multimode detector . the concentration of pge2 in the unknown samples was determined from a curve - fit of the pge2 standard absorbance data and multiplying by the dilution factor . the maximum activity achieved in the absence of the inhibitor ( dmso + lps treated wells ) was arbitrarily given a value of 100 %; likewise the minimum activity in the absence of the stimulant ( no lps treated wells ) was assigned a value of 0 %. inhibition of the amount of pge2 released in the drug treated wells was calculated relative to the maximum activation in the dmso + lps treated control wells ( i . e ., % inhibition = 100 −( drug + lps treated )/( dmso + lps treated )). dose response curves were used to determine the effective concentration to inhibit 50 % of the pge2 released ( ic 50 ) by means of a sigmaplot macro which fits a sigmoidal dose - response curve to the ( log 10 ) μm concentration versus inhibition . in the case when compounds did not reach maximum inhibition at the concentrations tested , the curve fit was assisted with forced maximum ( 100 %) and minimum ( 0 %) values . this technique yields an objective value for the ic 50 provided that 50 % inhibition was approached at the concentrations tested . cryogenically stored rpmi 8226 and u266b1 cells ( atcc , manassas , va .) were thawed and cultured according to the vendor &# 39 ; s recommendations . cells were plated in 96 - well white - wall tissue culture plates at a concentration of 2 × 10 5 cells / ml ( 0 . 1 ml per well ) and incubated overnight at 37 ° c . in a humidified 5 % co 2 atmosphere . compounds were added to each well at the indicated concentrations ( 0 . 5 μl of 200 × dmso stock ) and incubated with the cells for 48 hours . cell viability was detected by adding 100 μl celltiter - glo reagent ( promega , madison , wis .) to each well , mixing with pipette , and incubating at room temperature for 10 minutes . luminescence was read with a dtx 880 multimode detector ( beckman coulter , fullerton , calif .). data was analyzed with sigmaplot 11 ( systat software , san jose , calif .) software . fig6 and 7 illustrate the effect of the compound of example 10 on the growth inhibition in multiple myeloma cells . in addition to the compound of example 10 , table 1 lists other compounds for their activities to inhibit 1 ) nf - 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