the following terms may appear in the specification . if they appear , the following definitions will apply . as used herein , the term “ effective amount ” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue , system , animal or human that is being sought , for instance , by a researcher or clinician . furthermore , the term “ therapeutically effective amount ” means any amount which , as compared to a corresponding subject who has not received such amount , results in improved treatment , healing , prevention , or amelioration of a disease , disorder , or side effect , or a decrease in the rate of advancement of a disease or disorder . the term also includes within its scope amounts effective to enhance normal physiological function . as used herein , the term “ alkyl ” refers to a straight or branched chain hydrocarbon . furthermore , as used herein , the term “ c 1 - 6 alkyl ” refers to an alkyl group as defined above containing at least 1 , and at most 6 , carbon atoms . examples of branched or straight chained “ c 1 - 6 alkyl ” groups useful in the present invention include methyl , ethyl , n - propyl , isopropyl , isobutyl , n - butyl , t - butyl , isopentyl , n - pentyl , n - hexyl , and the like . as used herein , the term “ halogen ” refers to fluorine ( f ), chlorine ( cl ), bromine ( br ), or iodine ( i ). as used herein , the term “ optionally ” means that the subsequently described event ( s ) may or may not occur , and includes both event ( s ), which occur , and events that do not occur . as used herein , the term “ physiologically functional derivative ” refers to any pharmaceutically acceptable derivative of a compound of the present invention , for example , an ester or an amide , which upon administration to a mammal is capable of providing ( directly or indirectly ) a compound of the present invention or an active metabolite thereof . such derivatives are clear to those skilled in the art , without undue experimentation , and with reference to the teaching of burger &# 39 ; s medicinal chemistry and drug discovery , 5th edition , vol 1 : principles and practice , which is incorporated herein by reference to the extent that it teaches physiologically functional derivatives . as used herein , the term “ solvate ” refers to a complex of variable stoichiometry formed by a solute ( in this invention , a compound of formula i or a salt or physiologically functional derivative thereof ) and a solvent . such solvents for the purpose of the invention may not interfere with the biological activity of the solute . examples of suitable solvents include , but are not limited to , water , methanol , ethanol and acetic acid . preferably the solvent used is a pharmaceutically acceptable solvent . examples of suitable pharmaceutically acceptable solvents include , without limitation , water , ethanol and acetic acid . most preferably the solvent used is water . as used herein , the term “ substituted ” refers to substitution with the named substituent or substituents , multiple degrees of substitution being allowed unless otherwise stated . certain of the compounds described herein may contain one or more chiral atoms , or may otherwise be capable of existing as two enantiomers . accordingly , the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures . also included within the scope of the invention are the individual isomers of the compounds represented by formula i above as well as any wholly or partially equilibrated mixtures thereof . the present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted . also , it is understood that all tautomers and mixtures of tautomers are included within the scope of the compounds of formula i . typically , the salts of the present invention are pharmaceutically acceptable salts . salts encompassed within the term “ pharmaceutically acceptable salts ” refer to non - toxic salts of the compounds of this invention . salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen on a substituent in the compound of formula i . representative salts include the following salts : acetate , benzenesulfonate , benzoate , bicarbonate , bisulfate , bitartrate , borate , bromide , calcium edetate , camsylate , carbonate , chloride , clavulanate , citrate , dihydrochloride , edetate , edisylate , estolate , esylate , fumarate , gluceptate , gluconate , glutamate , glycollylarsanilate , hexylresorcinate , hydrabamine , hydrobromide , hydrochloride , hydroxynaphthoate , iodide , isethionate , lactate , lactobionate , laurate , malate , maleate , mandelate , mesylate , methylbromide , methylnitrate , methylsulfate , monopotassium maleate , mucate , napsylate , nitrate , n - methylglucamine , oxalate , pamoate ( embonate ), palmitate , pantothenate , phosphate / diphosphate , polygalacturonate , potassium , salicylate , sodium , stearate , subacetate , succinate , tannate , tartrate , teoclate , tosylate , triethiodide , trimethylammonium and valerate . other salts , which are not pharmaceutically acceptable , may be useful in the preparation of compounds of this invention and these form a further aspect of the invention . while it is possible that , for use in therapy , therapeutically effective amounts of a compound of formula i , as well as salts , solvates and physiological functional derivatives thereof , may be administered as the raw chemical , it is possible to present the active ingredient as a pharmaceutical composition . accordingly , the invention further provides pharmaceutical compositions , which include therapeutically effective amounts of compounds of the formula i and salts , solvates and physiological functional derivatives thereof , and one or more pharmaceutically acceptable carriers , diluents , or excipients . the compounds of the formula i and salts , solvates and physiological functional derivatives thereof , are as described above . the carrier ( s ), diluent ( s ) or excipient ( s ) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof . in accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula i , or salts , solvates and physiological functional derivatives thereof , with one or more pharmaceutically acceptable carriers , diluents or excipients . pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose . such a unit may contain , for example , 0 . 6 mg to 1 g , preferably 1 mg to 700 mg , more preferably 5 mg to 100 mg of a compound of the formula i , depending on the condition being treated , the route of administration and the age , weight and condition of the patient , or pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose . preferred unit dosage formulations are those containing a daily dose or sub - dose , as herein above recited , or an appropriate fraction thereof , of an active ingredient . furthermore , such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art . pharmaceutical formulations may be adapted for administration by any appropriate route , for example by the oral ( including buccal or sublingual ), rectal , nasal , topical ( including buccal , sublingual or transdermal ), vaginal or parenteral ( including subcutaneous , intramuscular , intravenous or intradermal ) route . such formulations may be prepared by any method known in the art of pharmacy , for example by bringing into association the active ingredient with the carrier ( s ) or excipient ( s ). pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets ; powders or granules ; solutions or suspensions in aqueous or non - aqueous liquids ; edible foams or whips ; or oil - in - water liquid emulsions or water - in - oil liquid emulsions . for instance , for oral administration in the form of a tablet or capsule , the active drug component can be combined with an oral , non - toxic pharmaceutically acceptable inert carrier such as ethanol , glycerol , water and the like . powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate , as , for example , starch or mannitol . flavoring , preservative , dispersing and coloring agent can also be present . capsules are made by preparing a powder mixture , as described above , and filling formed gelatin sheaths . glidants and lubricants such as colloidal silica , talc , magnesium stearate , calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation . a disintegrating or solubilizing agent such as agar - agar , calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested . moreover , when desired or necessary , suitable binders , lubricants , disintegrating agents and coloring agents can also be incorporated into the mixture . suitable binders include starch , gelatin , natural sugars such as glucose or beta - lactose , corn sweeteners , natural and synthetic gums such as acacia , tragacanth or sodium alginate , carboxymethylcellulose , polyethylene glycol , waxes and the like . lubricants used in these dosage forms include sodium oleate , sodium stearate , magnesium stearate , sodium benzoate , sodium acetate , sodium chloride and the like . disintegrators include , without limitation , starch , methyl cellulose , agar , bentonite , xanthan gum and the like . tablets are formulated , for example , by preparing a powder mixture , granulating or slugging , adding a lubricant and disintegrant and pressing into tablets . a powder mixture is prepared by mixing the compound , suitably comminuted , with a diluent or base as described above , and optionally , with a binder such as carboxymethylcellulose , an aliginate , gelatin , or polyvinyl pyrrolidone , a solution retardant such as paraffin , a resorption accelerator such as a quaternary salt and / or an absorption agent such as bentonite , kaolin or dicalcium phosphate . the powder mixture can be granulated by wetting with a binder such as syrup , starch paste , acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen . as an alternative to granulating , the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules . the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid , a stearate salt , talc or mineral oil . the lubricated mixture is then compressed into tablets . the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps . a clear or opaque protective coating consisting of a sealing coat of shellac , a coating of sugar or polymeric material and a polish coating of wax can be provided . dyestuffs can be added to these coatings to distinguish different unit dosages . oral fluids such as solution , syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound . syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution , while elixirs are prepared through the use of a non - toxic alcoholic vehicle . suspensions can be formulated by dispersing the compound in a non - toxic vehicle . solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers , preservatives , flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners , and the like can also be added . where appropriate , dosage unit formulations for oral administration can be microencapsulated . the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers , wax or the like . the compounds of formula i , and salts , solvates and physiological functional derivatives thereof , can also be administered in the form of liposome delivery systems , such as small unilamellar vesicles , large unilamellar vesicles and multilamellar vesicles . liposomes can be formed from a variety of phospholipids , such as cholesterol , stearylamine or phosphatidylcholines . the compounds of formula i , and salts , solvates and physiological functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled . the compounds may also be coupled with soluble polymers as targetable drug carriers . such polymers can include polyvinylpyrrolidone , pyran copolymer , polyhydroxypropylmethacrylamide - phenol , polyhydroxyethylaspartamidephenol , or polyethyleneoxidepolylysine substituted with palmitoyl residues . furthermore , the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug , for example , polylactic acid , polepsilon caprolactone , polyhydroxy butyric acid , polyorthoesters , polyacetals , polydihydropyrans , polycyanoacrylates and cross - linked or amphipathic block copolymers of hydrogels . pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time . for example , the active ingredient may be delivered from the patch by iontophoresis as generally described in pharmaceutical research , 3 ( 6 ), 318 ( 1986 ). pharmaceutical formulations adapted for topical administration may be formulated as ointments , creams , suspensions , lotions , powders , solutions , pastes , gels , sprays , aerosols or oils . for treatments of the eye or other external tissues , for example mouth and skin , the formulations are preferably applied as a topical ointment or cream . when formulated in an ointment , the active ingredient may be employed with either a paraffinic or a water - miscible ointment base . alternatively , the active ingredient may be formulated in a cream with an oil - in - water cream base or a water - in - oil base . pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier , especially an aqueous solvent . pharmaceutical formulations adapted for topical administration in the mouth include lozenges , pastilles and mouth washes . pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas . pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken , i . e . by rapid inhalation through the nasal passage from a container of the powder held close up to the nose . suitable formulations wherein the carrier is a liquid , for administration as a nasal spray or as nasal drops , include aqueous or oil solutions of the active ingredient . pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists , which may be generated by means of various types of metered , dose pressurised aerosols , nebulizers or insufflators . pharmaceutical formulations adapted for vaginal administration may be presented as pessaries , tampons , creams , gels , pastes , foams or spray formulations . pharmaceutical formulations adapted for parenteral administration include aqueous and non - aqueous sterile injection solutions which may contain anti - oxidants , buffers , bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient ; and aqueous and non - aqueous sterile suspensions which may include suspending agents and thickening agents . the formulations may be presented in unit - dose or multi - dose containers , for example sealed ampoules and vials , and may be stored in a freeze - dried ( lyophilized ) condition requiring only the addition of the sterile liquid carrier , for example water for injections , immediately prior to use . extemporaneous injection solutions and suspensions may be prepared from sterile powders , granules and tablets . it should be understood that in addition to the ingredients particularly mentioned above , the formulations may include other agents conventional in the art having regard to the type of formulation in question , for example those suitable for oral administration may include flavouring agents . a therapeutically effective amount of a compound of the present invention will depend upon a number of factors including , for example , the age and weight of the animal , the precise condition requiring treatment and its severity , the nature of the formulation , and the route of administration , and will ultimately be at the discretion of the attendant physician or veterinarian . however , an effective amount of a compound of formula i for the treatment of or prevention of diseases of the erythroid and hematopoietic systems , caused by hyak3 imbalance or inappropriate activity including , but not limited to , neutropenia ; cytopenia ; anemias , including anemias due to renal insufficiency or to a chronic disease , such as autoimmunity , hiv or cancer , and drug - induced anemias ; and myelosuppression ; or for the treatment or prevention of diseases caused by ck2 imbalance or inappropriate activities , such as cancer or viral infections ; will generally be in the range of 0 . 1 to 100 mg / kg body weight of recipient ( mammal ) per day and more usually in the range of 1 to 10 mg / kg body weight per day . thus , for a 70 kg adult mammal , the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number ( such as two , three , four , five or six ) of sub - doses per day such that the total daily dose is the same . an effective amount of a salt or solvate , or physiologically functional derivative thereof , may be determined as a proportion of the effective amount of the compound of formula i per se . it is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above . compounds of general formula i may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes . in all of the schemes described below , it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry . protecting groups are manipulated according to standard methods of organic synthesis ( t . w . green and p . g . m . wuts ( 1991 ) protecting groups in organic synthesis , john wiley & amp ; sons ). these groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art . the selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of formula i . those skilled in the art will recognize if a stereocenter exists in compounds of formula i . accordingly , the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well . when a compound is desired as a single enantiomer , it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate . resolution of the final product , an intermediate , or a starting material may be effected by any suitable method known in the art . see , for example , stereochemistry of organic compounds by e . l . eliel , s . h . wilen , and l . n . mander ( wiley - interscience , 1994 ). more particularly , the compounds of the formula i can be made by the process of scheme a or b . any person skilled in the art can readily adapt the process of scheme a or b , such the stoichemistry of the reagents , temperature , solvents , etc . to optimize the yield of the products desired . what follow are brief descriptions of the processes a and b . in scheme a , the compounds of formula ii , iii , iv and v can be synthesized as described in example 1 . in step c , compound of formula iv , a compound of formula vi ( about 1 . 1 equivalent ), and tetrakis ( triphenylphosphine ) palladium ( 0 ) ( about 0 . 05 equivalent ) are suspended in a mixture of suitable solvent , such as dme , and 2m aqueous na 2 co 3 under argon atmosphere . the mixture is heated at about 80 ° c . for about 5 h , and then poured into water . the resultant precipitate is filtered , washed with water , and dried under reduced pressure to give a compound of formula v . in step d , a mixture of a compound of formula v , a compound of formula vii ( about 1 . 5 equivalent ), tris ( dibenzylideneacetone )- dipalladium ( 0 ) or palladium ( ii ) acetate ( about 0 . 05 equivalent ), sodium tert - butoxide ( about 1 . 5 equivalent ), tri - tert - butylphosphonium tetrafluoroborate or ( r )-(+)- 2 , 2 ′- bis ( diphenylphosphino )- 1 , 1 ′- binaphthyl ( r — binap ) ( about 0 . 14 equivalent ) are suspended in a suitable solvent , such as toluene , under argon atmosphere . the mixture is heated at about 100 ° c . for about 5 h , diluted with acoet , and washed with water . the organic phase is separated , concentrated in vacuo , and the residue is purified by chromatography on a silica gel column to afford a compound of ia . step e is a typical hydrolysis step . to a solution of compound ia in the mixture of thf and meoh ( about 5 / 2 ratio ) was added 1n aqueous naoh . the mixture is stirred at room temperature overnight , and then acidified with 1n hcl . the mixture is extracted with an organic solvent , such as chcl 3 , and then washed with water . the organic phase is separated and concentrated in vacuo to yield a compound of further within the scope of formula i , i . e . formula ib , which is typically purified by chromatography on a silica gel column . in step f , sieber amide resin ( 700 mg 0 . 15 mmol ) is treated with 20 % piperidine in dmf ( 1 ml ) in alltech tube for 30 min . the mixture is drained and the resin is washed with dmf ( 3 ×). the mixture of a compound of formula ib ( 0 . 076 mmol ), hobt ( 11 mg ), hbtu ( 29 mg ), diea ( diisopropylethylamine , 0 . 027 ml ) in dmf ( 1 ml ) is added to the resin . the mixture is shaken at room temperature for about 15 h , at which point the liquid is drained . the resin is washed with dmf ( 3 ×), meoh ( 3 ×), ch 2 cl 2 ( 3 ×). it is dried under vacuum and treated with 10 % tfa in ch 2 cl 2 ( 1 ml ) for about 1 h . the solution is concentrated in vacuo to afford a compound further within the scope of formula i , i . e . formula ic , which is typically purified by chromatography on a silica gel column . in scheme a , r7 , r8 and r9 are independently hydrogen , halogen , — oc 1 - 6 alkyl , — cf 3 , or — c 1 - 6 alkyl ; w is —( ch 2 ) n —, in which n is 0 to 2 . in scheme b , a starting compound of formula viii can be made by the standard reaction step b , as exemplified in example 9 . a compound of formula viii is then reacted with trifuric anhydride in the presence of a base such as 2 , 6 - di - t - butyl - 4 - methylpyridine to afford a compound of formula ix . a compound of formula ix is then coupled with an appropriate amine of the formula h 2 n — w — y in the presence of r — binap , pd ( oac ) 2 , and csco 8 to afford a compound of formula id . the ethyl ester group can further be hydrolyzed or replaced with nh 2 via a routine method in step d to afford an additional compound of formula ie , within the scope of formula i . r1 , r2 and r3 are independently hydrogen , — nh 2 , halogen , — oc 1 - 5 alkyl , — cf 3 , — n ( c ═ o ) ch 3 , —( c ═ o ) oh , — cf 3 , —( c ═ o ) nh 2 , — so 2 ch 3 , — so 2 oh , or — c 1 - 6 alkyl ; w is —( ch 2 ) n —, in which n is 0 to 2 ; and as used herein the symbols and conventions used in these processes , schemes and examples are consistent with those used in the contemporary scientific literature , for example , the journal of the american chemical society or the journal of biological chemistry . standard single - letter or three - letter abbreviations are generally used to designate amino acid residues , which are assumed to be in the l - configuration unless otherwise noted . unless otherwise noted , all starting materials were obtained from commercial suppliers and used without further purification . specifically , the following abbreviations may be used in the examples and throughout the specification : g ( grams ); mg ( milligrams ); l ( liters ); ml ( milliliters ); μl ( microliters ); psi ( pounds per square inch ); m ( molar ); mm ( millimolar ); i . v . ( intravenous ); hz ( hertz ); mhz ( megahertz ); mol ( moles ); mmol ( millimoles ); rt ( room temperature ); min ( minutes ); h ( hours ); mp ( melting point ); tlc ( thin layer chromatography ); tr ( retention time ); rp ( reverse phase ); meoh ( methanol ); i - proh ( isopropanol ); tea ( triethylamine ); tfa ( trifluoroacetic acid ); tfaa ( trifluoroacetic anhydride ); thf ( tetrahydrofuran ); dmso ( dimethylsulfoxide ); acoet ( ethyl acetate ); dme ( 1 , 2 - dimethoxyethane ); dcm ( dichloromethane ); dce ( dichloroethane ); dmf ( n , n - dimethylformamide ); dmpu ( n , n ′- dimethylpropyleneurea ); ( cdi ( 1 , 1 - carbonyldiimidazole ); ibcf ( isobutyl chloroformate ); hoac ( acetic acid ); hosu ( n - hydroxysuccinimide ); hobt ( 1 - hydroxybenzotriazole ); mcpba ( meta - chloroperbenzoic acid ; edc ( ethylcarbodinimde hydrochloride ); boc ( tert - butyloxycarbonyl ); fmoc ( 9 - fluorenylmethoxycarbonyl ); dcc ( dicyclohexylcarbodiimide ); cbz ( benzyloxycarbonyl ); ac ( acetyl ); atm ( atmosphere ); tmse ( 2 -( trimethylsilyl ) ethyl ); tms ( trimethylsilyl ); tips ( triisopropylsilyl ); tbs ( t - butyldimethylsilyl ); dmap ( 4 - dimethylaminopyridine ); bsa ( bovine serum albumin ) atp ( adenosine triphosphate ); hrp ( horseradish peroxidase ); dmem ( dulbecco &# 39 ; s modified eagle medium ); hplc ( high pressure liquid chromatography ); bop ( bis ( 2 - oxo - 3 - oxazolidinyl ) phosphinic chloride ); tbaf ( tetra - n - butylammonium fluoride ); hbtu ( o - benzotriazole - 1 - yl - n , n , n ′, n ′- tetramethyluronium hexafluorophosphate ). hepes ( 4 -( 2 - hydroxyethyl )- 1 - piperazine ethane sulfonic acid ); dppa ( diphenylphosphoryl azide ); fhno3 ( fumed hno3 ); and edta ( ethylenediaminetetraacetic acid ). all references to ether are to diethyl ether ; brine refers to a saturated aqueous solution of nacl . unless otherwise indicated , all temperatures are expressed in ° c . ( degrees centigrade ). all reactions are conducted under an inert atmosphere at room temperature unless otherwise noted . 1 h nmr spectra were recorded on a varian vxr - 300 , a varian unity - 300 , a varian unity - 400 instrument , a brucker avance - 400 , or a general electric qe - 300 . chemical shifts are expressed in parts per million ( ppm , δ units ). coupling constants are in units of hertz ( hz ). splitting patterns describe apparent multiplicities and are designated as s ( singlet ), d ( doublet ), t ( triplet ), q ( quartet ), quint ( quintet ), m ( multiplet ), br ( broad ). low - resolution mass spectra ( ms ) were recorded on a joel jms - ax505ha , joel sx - 102 , or a sciex - apiiii spectrometer ; lc - ms were recorded on a micromass 2md and waters 2690 ; high resolution ms were obtained using a joel sx - 102a spectrometer . all mass spectra were taken under electrospray ionization ( esi ), chemical ionization ( ci ), electron impact ( ei ) or by fast atom bombardment ( fab ) methods . infrared ( 1r ) spectra were obtained on a nicolet 510 ft - ir spectrometer using a 1 - mm nacl cell . most of the reactions were monitored by thin - layer chromatography on 0 . 25 mm e . merck silica gel plates ( 60f - 254 ), visualized with uv light , 5 % ethanolic phosphomolybdic acid or p - anisaldehyde solution . flash column chromatography was performed on silica gel ( 230 - 400 mesh , merck ). hplc were recorded on a gilson hplc or shimazu hplc system by the following conditions . column : 50 × 4 . 6 mm ( id ) stainless steel packed with 5 □ m phenomenex luna c - 18 ; flow rate : 2 . 0 ml / min ; mobile phase : a phase = 50 mm ammonium acetate ( ph 7 . 4 ), b phase = acetonitrile , 0 - 0 . 5 min ( a : 100 %, b : 0 % o ), 0 . 5 - 3 . 0 min ( a : 100 - 0 %, b : 0 - 100 %), 3 . 0 - 3 . 5 min ( a : 0 %, b : 100 %), 3 . 5 - 3 . 7 min ( a : 0 - 100 %, b : 100 - 0 %), 3 . 7 - 4 . 5 min ( a : 100 %, b : 0 %); detection : uv 254 nm ; injection volume : 3 μl . to a cooled solution of 2 , 4 - thiazolidinedione ( 5 g , 42 . 7 mmol ) in pocl 3 ( 24 ml ) was added dmf ( 3 . 7 ml , 26 . 4 mmol ). the mixture was stirred at room temperature for 1 hour , and then heated at 90 ° c . for 1 h and 115 ° c . for 4 h . the mixture was poured into a large amount of cold crashed ice . the mixture was extracted with ch 2 cl 2 , washed with water , purified by chromatography on a silica gel column using chcl 8 as an eluant to afford the title compound to afford compound ii ( 3 . 6 g , 48 %) as a brown solid . 1 h nmr ( 400 mhz , cdcl 3 ) ppm 9 . 90 ( s , 1h ). to a solution of compound ii ( 500 mg , 2 . 74 mmol ) in thf ( 18 ml ) and water ( 12 ml ) was added a mixture of sulfanylamide ( 346 mg , 3 . 56 mmol ) and naclo 2 ( 323 mg , 3 . 56 mmol ) in water ( 2 ml ). the mixture was stirred at room temperature for 2 hours , diluted with acoet , and washed with water . the organic phase was separated , concentrated in vacuo to afford the title compound of formula iii ( 440 mg , 88 %) as a yellow solid . to a solution of compound iii ( 1 . 04 g , 5 . 2 mmol ), k 2 co 3 ( 1 . 078 g , 7 . 8 mmol ) in dmf ( 20 ml ) was added mei ( 0 . 36 ml , 6 . 24 mmol ). after stirring at room temperature for 5 hours , the mixture was diluted with acoet , and washed with water . the organic phase was separated , concentrated in vacuo , and then purified by chromatography on a silica gel column using chcl 3 as an eluant to afford the title compound of formula iv ( 832 mg , 79 %) as a pale yellow solid 1 h nmr ( 400 mhz , cdcl 3 ) ppm 3 . 91 ( s , 3h ) a mixture of compound iv ( 810 mg , 3 . 82 mmol ), 4 - methoxyphenyl - boronic acid ( 610 mg , 4 . 2 mmol ), tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 220 mg , 0 . 19 mmol ) was suspended in the mixture of dme ( 20 ml ) and 2m aqueous na 2 co 3 ( 3 . 0 ml under argon atmosphere . the mixture was heated at 80 ° c . for 5 h , and then poured into water . ( normally a separate step of filtering through the celite to remove tetrakis ( triphenylphosphine ) palladium ( 0 ) is required , but in this example , such step was not necessary .) the resultant precipitate was filtrated , washed with water , and dried under reduced pressure to give a compound of formula va ( 580 mg , 52 %) as a yellow solid . 1h nmr ( 400 mhz , cdcl 3 ) ppm 3 . 88 ( s , 3h ), 3 . 92 ( s , 3h ), 6 . 97 ( m , 2h ), 7 . 91 ( m , 2h ). lc / ms : m / z 284 ( m + 1 )+. a mixture of compound va ( 130 mg , 0 . 46 mmol ), aniline ( 0 . 063 ml , 0 . 69 mmol ), tris ( dibenzylideneacetone )- dipalladium ( 0 ) ( 21 mg , 0 . 023 mmol ), sodium tert - butoxide ( 60 mg , 0 . 69 mmol ), tri - tert - butylphosphonium tetrafluoroborate ( 20 mg , 0 . 063 mmol ) was suspended in toluene ( 1 . 0 ml ) under argon atmosphere . the mixture was heated at 100 ° c . for 5 h , diluted with acoet , and washed with water . the organic phase was separated , concentrated in vacuo , and purified by chromatography on a silica gel column using chcl 3 as an eluant to afford the title compound of formula iaa ( 42 mg ) as a yellow solid . 1 h nmr ( 400 mhz , cdcl 3 ) ppm 3 . 87 ( s , 3h ), 3 . 88 ( s , 3h ), 6 . 97 ( m , 2h ), 7 . 02 ( m , 1h ), 7 . 35 ( m , 2h ), 7 . 69 ( m , 2h ), 7 . 97 ( m , 2h ), 9 . 17 ( s , 1h ). lc / ms : m / z 341 ( m + 1 )+. to a solution of compound iaa ( 34 mg , 0 . 1 mmol ) in the mixture of thf ( 0 . 5 ml ) and meoh ( 0 . 2 ml ) was added 1n aqueous naoh ( 0 . 1 ml ). the mixture was stirred at room temperature overnight , and then acidified with 1n hcl . the mixture was extracted with chcl 3 , and then washed with water . the organic phase was separated , concentrated in vacuo , and purified by chromatography on a silica gel column using meoh / chcl 3 ( 0 : 1 - 1 : 10 ) as an eluant to afford the title compound of formula iba ( 24 mg , 69 %) as a yellow solid . 1h nmr ( 400 mhz , cdcl 3 ) ppm 3 . 88 ( s , 3h ), 7 . 00 ( m , 2h ), 7 . 11 ( m , 2h ), 7 . 35 ( m , 2h ), 7 . 68 ( m , 2h ), 7 . 99 ( m , 2h ), 9 . 28 ( s , 1h ). lc / ms : m / z 327 ( m + 1 )+; a mixture of compound iv ( 2 . 12 g , 10 mmol ), 3 - methoxyphenyl - boronic acid ( 1 . 67 g , 4 . 6 mmol ), tetrakis ( triphenyl phosphine ) palladium ( 0 ) ( 578 mg , 0 . 23 mmol ) was suspended in the mixture of dme ( 50 ml ) and 2m aqueous na 2 co 3 ( 8 . 0 ml ) under argon atmosphere . the mixture was heated at 80 ° c . for 5 h , and then poured into water . the resultant precipitation was filtrated , washed with water , and dried under reduced pressure to give afford a compound of formula vb ( 1 . 06 g , 43 %) as a yellow solid 1h nmr ( 400 mhz , cdcl3 ) ppm 3 . 88 ( s , 3h ), 3 . 93 ( s , 3h ), 7 . 05 ( m , 1h ), 7 . 26 ( m , 1h ), 7 . 50 ( m , 2h ). lc / ms : m / z 284 ( m + 1 )+. a mixture of compound vb ( 200 mg , 0 . 7 mmol ), 2 - trifluoromethylaniline ( 0 . 13 ml , 1 . 05 mmol ), tris ( dibenzylideneacetone ) dipalladium ( 0 ) ( 32 mg , 0 . 035 mmol ), sodium tert - butoxide ( 51 mg , 1 . 05 mmol ), tri - tert - butylphosphonium tetrafluoroborate ( 15 mg , 0 . 11 mmol ) was suspended in toluene ( 1 . 0 ml ) under argon atmosphere . the mixture was heated at 100 ° c . for 5 h , diluted with acoet , and washed with water . the organic phase was separated , concentrated in vacuo , and purified by chromatography on a silica gel column using chcl 3 as an eluant to afford compound of formula lab ( 95 mg ) as a yellow solid . lc / ms : m / z 409 ( m + 1 )+. to a solution of compound iab ( 95 mg , 0 . 28 mmol ) in the mixture of thf ( 1 . 0 ml ) and meoh ( 0 . 5 ml ) was added 2n aqueous naoh ( 0 . 35 ml ). the mixture was stirred at room temperature overnight , and then acidified with 1n hcl , and diluted with chcl 3 , washed with water . the organic phase was separated , concentrated in vacuo , and purified by chromatography on a silica gel column using meoh / chcl3 ( 0 : 1 - 1 : 10 ) as an eluant to afford the compound of formula ibb ( 45 mg , 47 %) as a yellow solid . 1 h nmr ( 400 mhz , cdcl 3 ) ppm 3 . 85 ( s , 3h ), 7 . 16 ( m , 1h ), 7 . 18 ( m , 1h ), 7 . 49 ( m , 211 ), 7 . 60 ( m , 1h ), 7 . 72 ( m , 2h ), 8 . 44 ( m , 1h ), 9 . 28 ( brs , 1h ). lc / ms : m / z 395 ( m + 1 )+; sieber amide resin ( 700 mg 0 . 15 mmol ) was treated with 20 % piperidine in dmf ( 1 ml ) in alltech tube for 30 min . the mixture was drained and the resin was washed with dmf ( 3 ×). the mixture of 5 - carboxyl - 2 -( 4 - methoxyphenyl )- 4 -( 2 - trifluoromethyl ) anilinothiazole ( ibb ) ( 30 mg , 0 . 076 mmol ), hobt ( 11 mg ), hbtu ( 29 mg ), diea ( 0 . 027 ml ) in dmf ( 1 ml ) was added to the resin . the mixture was shaken at room temperature for 15 h , at which point was drained . the resin was washed with dmf ( 3 ×), meoh ( 3 ×), ch 2 cl 2 ( 3 ×). it was dried under vacuum and treated with 10 % tfa in ch 2 cl 2 ( 1 ml ) for 1 h . the solution was concentrated in vacuo , and purified by chromatography on a silica gel column using chcl 3 as an eluant to afford the title compound of formula ica ( 7 mg , 23 %) as a yellow solid . 1 h nmr ( 400 mhz , cdcl 3 ) ppm 3 . 88 ( s , 3h ), 5 . 38 ( brs , 2h ), 7 . 03 ( m , 1h ), 7 . 07 ( m , 1h ), 7 . 38 ( m , 1h ), 7 . 53 ( m , 3h ), 7 . 62 ( m , 1h ), 8 . 41 ( m , 1h ), 10 . 37 ( brs , 1h ). lc / ms : m / z 394 ( m + 1 )+ the compounds in examples 3 - 7 were obtained by process of scheme a starting from 2 , 4 - thiazolidinedione as in example 1 . 1h nmr ( 400 mhz , dmso - d6 ) ppm 3 . 85 ( s , 3h ), 6 . 80 ( m , 1h ), 7 . 13 ( m , 2h ), 7 . 38 ( m , 2h ), 7 . 72 ( m , 1h ), 7 . 99 ( m , 1h ), 9 . 43 ( brs , 1h ). lc / ms : m / z 345 ( m + 1 )+ 1h nmr ( 400 mhz , dmso - d6 ) ppm 3 . 85 ( s , 3h ), 7 . 10 ( m , 2h ), 7 . 21 ( m , 1h ), 7 . 71 ( m , 2h ), 7 . 98 ( m , 2h ), 8 . 45 ( m , 1h ), 9 . 79 ( brs , 1h ). lc / ms : m / z 395 ( m + 1 )+ 1h nmr ( 400 mhz , dmso - d6 ) ppm 3 . 86 ( 8 , 3h ), 7 . 01 ( m , 1h ), 7 . 17 ( m , 1h ), 7 . 36 ( m , 2h ), 7 . 49 ( m , 2h ), 7 . 61 ( m , 1h ), 7 . 69 ( m , 2h ), 9 . 25 ( brs , 1h ). lc / ms : m / z 327 ( m + 1 )+ 1 h nmr ( 400 mhz , dmso - d6 ) ppm 3 . 86 ( s , 3h ), 7 . 00 ( m , 1h ), 7 . 16 ( m , 1h ), 7 . 27 ( m , 2h ), 7 . 48 ( m , 1h ), 7 . 51 ( m , 1h ), 7 . 62 ( m , 1h ), 8 . 46 ( m , 1h ), 9 . 75 ( brs , 1h ). lc / ms : m / z 345 ( m + 1 )+ a mixture of 2 , 3 - dihydrobenzofuran - 5 - thioamide ( 680 mg , 3 . 5 mmol ) and diethyl 2 - chloromalonate ( 630 mg , 3 . 5 mmol ) in dry ethanol ( 15 ml ) was heated at 80 degree for 5 hours . after cooling , the formed yellowish solid was collected by filtration and the solid was washed with ethanol to give the title compound ( 550 mg ): lc - ms m / e 292 ( m + 1 ). under an argon atmosphere , to a mixture of 2 -( 2 , 3 - dihydrobenzofuran - 5 - yl )- 4 - oxo - 4 , 5 - dihydrothiazole - 5 - carboxylic acid ethyl ester ( 500 mg , 1 . 72 mmol ) and 2 , 6 - di - t - butyl - 4 - methylpyridine ( 388 mg , 1 . 9 mmol ) in ch 2 cl 2 ( 10 ml ) was added dropwise trifuric anhydride ( 510 mg , 1 . 81 mmol ) at 0 degree . stirring was continued for 2 h at room temperature . the mixture was washed with h 2 o and the product was extracted with ch 2 cl 2 , dried over mgso 4 , and evaporated . ether was added to the residue and the formed solid ( 2 , 6 - di - t - butyl - 4 - methylpyridine ) was filtered off . the ethereal filtrate was then evaporated and the residue was chromatographed on silica gel eluted with hexane / ethyl acetate = 4 / 1 to provide the title compound ( 541 mg ): lc - ms m / e 424 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 1 . 23 ( d , 3h ), 3 . 21 ( t , 2h ), 4 . 29 ( q , 2h ), 4 . 60 ( t , 2h ), 6 . 87 ( d , 1h ), 7 . 74 ( dd , 1h ), 7 . 84 ( d , 1h ). a mixture of 2 -( 2 , 3 - dihydrobenzofuran - 5 - yl )-( 4 - trifluoromethanesulfonyloxy ) thiazole - 5 - carboxylic acid ethyl ester ( 150 mg , 0 . 35 mmol ), ( r )-(+)- 2 , 2 ′- bis ( diphenylphosphino )- 1 , 1 ′- binaphtyl ( r — binap , 22 mg ), pd ( oac ) 2 ( 8 mg ), 2 - chloroaniline ( 90 mg , 0 . 70 mmol ), and csco 3 ( 185 mg , 0 . 52 mmol ) in toluene ( 1 . 5 ml ) was heated at 70 degree for 2 h under an argon atmosphere . the reaction mixture was directly purified by silica - gel column chromatography using acoet / hexane = 1 / 5 to give the title compound ( 88 mg ): lc - ms m / e 401 ( m + 1 ), 1 h nmr ( cdcl 3 ) δ 1 . 40 ( t , 3h ), 3 . 30 ( t , 2h ), 5 . 39 ( q , 2h ), 4 . 68 ( t , 2h ), 6 . 85 ( d , 1h ), 6 . 94 ( t , 1h ), 7 . 32 ( t , 1h ), 7 . 40 ( d , 1h ), 7 . 82 ( d , 1h ), 7 . 87 ( d , 1h ), 8 . 63 ( d , 1h ), 9 . 73 ( sbr , 1h ). a mixture of 4 -( 2 - chloro - phenylamino )- 2 -( 2 , 3 - dihydro - benzofuran - 5 - yl )- thiazole - 5 - carboxylic acid ethyl ester ( 80 mg ), 1n - naoh ( 1 ml ), thf ( 1 ml ) and etoh ( 1 ml ) was heated at 70 degree overnight . the mixture was neutralized with 1n — hcl to provide a precipitate . filtration gave a yellowish solid ( 43 mg ): lc - ms m / e 373 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 3 . 29 ( t , 2h ), 4 . 64 ( t , 2h ), 6 . 92 ( d , 1h ), 6 . 97 ( t , 1h ), 7 . 39 ( t , 1h ), 7 . 48 ( d , 1h ), 7 . 83 ( d , 1h ), 7 . 91 ( s , 1h ), 8 . 59 ( d , 1h ), 10 . 20 ( sbr , 1h ). 4 -( 2 - chloro - phenylamino )- 2 -( 2 , 3 - dihydrobenzofuran - 5 - yl )- thiazole - 5 - carboxylic acid ( 20 mg ) and hbtu ( 27 mg ) in dmf ( 1 ml ) was added aq . nh 3 ( 3 drops ) and et 3 n ( 3 drops ). the mixture was stirred for 2 h at room temperature . the mixture was washed with h2o and the products were extracted with acoet . after evaporation , the residue was purified by silica - gel chromatography using acoet only to acoet / meoh = 100 / 2 as an eluant to give the title compound ( 16 mg ): lc - ms m / e 372 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 3 . 30 ( t , 2h ), 4 . 65 ( t , 2h ), 6 . 95 ( d , 1h ), 6 . 96 ( t , 1h ), 7 . 38 ( t , 1h ), 7 . 48 ( d , 1h ), 7 . 55 ( sbr , 2h ), 7 . 78 ( d , 1h ), 7 . 88 ( s , 1h ), 8 . 57 ( d , 1h ), 10 . 78 ( s , 1h ). 1 h nmr ( dmso - d 6 ) δ 3 . 29 ( t , 2h ), 4 . 64 ( t , 2h ), 6 . 84 ( dt , 1h ), 6 . 94 ( d , 1h ), 7 . 54 ( dd , 1h ), 7 . 81 ( d , 1h ), 7 . 88 ( s , 1h ), 8 . 45 ( dd , 1h ), 10 . 23 ( sbr , 1h ). lc - ms m / e 361 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 3 . 84 ( s , 3h ), 6 . 86 ( t , 1h ), 7 . 08 ( d , 2h ), 7 . 32 ( t , 1h ), 7 . 41 ( d , 1h ), 7 . 93 ( d , 2h ), 8 . 59 ( d , 1h ), 10 . 87 ( sbr , 1h ). lc - ms m / e 418 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 2 . 11 ( s , 3h ), 3 . 87 ( s , 3h ), 7 . 08 ( d , 3h ), 7 . 40 ( d , 1h ), 8 . 23 ( d , 2h ), 9 . 25 ( a , 1h ), 9 . 87 ( brs , 1h ), 10 . 11 ( brs , 1h ). lc - ms m / e 404 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 3 . 87 ( s , 3h ), 7 . 11 ( d , 2h ), 7 . 42 ( s , 1h ), 7 . 50 ( dd , 1h ), 7 . 60 ( d , 1h ), 8 . 05 ( d , 2h ), 8 . 06 ( m , 1h ), 9 . 20 ( d , 1h ), 9 . 85 ( brs , 1h ), 13 . 38 ( brs , 1h ). lc - ms m / e 441 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 3 . 87 ( s , 3h ), 7 . 10 ( d , 2h ), 7 . 21 ( dd , 1h ), 7 . 45 ( d , 1h ), 8 . 06 ( d , 2h ), 9 . 08 ( d , 1h ), 9 . 83 ( brs , 1h ), 13 . 32 ( brs , 1h ). lc - ms m / e 376 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 3 . 86 ( s , 3h ), 6 . 22 ( d , 1h ), 7 . 08 ( d , 1h ), 7 . 09 ( d , 2h ), 7 . 89 ( d , 1h ), 8 . 10 ( d , 2h ), 9 . 71 ( brs , 1h ). lc - ms m / e 439 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 3 . 25 ( s , 3h ), 3 . 87 ( s , 3h ), 7 . 11 ( d , 2h ), 7 . 95 ( dd , 1h ), 8 . 04 ( d , 1h ), 8 . 08 ( d , 2h ), 8 . 90 ( d , 1h ), 10 . 25 ( brs , 1h ). lc - ms m / e 405 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 3 . 87 ( 9 , 3h ), 7 . 11 ( d , 2h ), 7 . 97 ( m , 2h ), 8 . 06 ( d , 2h ), 8 . 76 ( d , 1h ), 10 . 17 ( sbr , 1h ). lc - ms m / e 332 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 7 . 05 ( t , 1h ), 7 . 43 ( t , 1h ), 7 . 53 ( d , 1h ), 7 . 62 ( dd , 1h ), 8 . 44 ( d , 1h ), 8 . 60 ( d , 1h ), 8 . 77 ( d , 1h ), 9 . 27 ( s , 1h ), 9 . 83 ( s , 1h ). lc - ms m / e 367 ( m + 1 ), lc - ms m / e 367 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 7 . 64 ( dd , 1h ), 8 . 18 ( d , 1h ), 8 . 69 ( s , 1h ), 8 . 70 ( d , 2h ), 9 . 02 ( m , 2h ), 13 . 4 ( brs , 1h ) lc - ms m / e 299 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 7 . 33 ( dd , 1h ), 7 . 56 ( dd , 1h ), 8 . 09 ( d , 1h ), 8 . 17 ( d , 1h ), 8 . 33 ( d , 1h ), 8 . 67 ( d , 1h ), 8 . 70 ( d , 1h ), 9 . 17 ( d , 1h ), 10 . 5 ( sbr , 1h ). lc - ms m / e 332 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 6 . 89 ( t , 1h ), 7 . 34 ( t , 1h ), 7 . 43 ( dd , 1h ), 7 . 91 ( d , 1h ), 8 . 58 ( d , 1h ), 8 . 72 ( d , 2h ), 10 . 95 ( sbr , 1h ). lc - ms m / e 360 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 2 . 93 ( t , 2h ), 3 . 79 ( q , 2h ), 7 . 10 ( tbr , 1h ), 7 . 23 ( m , 2h ), 7 . 30 ( m , 1h ), 7 . 36 ( s , 1h ), 7 . 87 ( d , 2h ), 8 . 73 ( d , 2m ). lc - ms m / e 359 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 2 . 91 ( t , 2h ), 3 . 75 ( q , 2h ), 7 . 22 - 7 . 35 ( m , 6h ), 7 . 59 ( t , 1h ), 7 . 81 ( d , 2h ), 8 . 73 ( d , 2h ). lc - ms m / e 350 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 6 . 80 ( dt , 1h ), 7 . 53 ( dd , 1h ), 7 . 61 ( dd , 1h ), 8 . 37 ( d , 1h ), 8 . 45 ( dd , 1h ), 8 . 73 ( dd , 1h ), 9 . 20 ( d , 1h ). lc - ms m / e 349 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 6 . 48 ( t , 1h ), 7 . 53 ( t , 1h ), 7 . 65 ( dd ; 1 ), 7 . 6 - 8 . 0 ( sbr , 2h ), 8 . 34 ( d , 1h ), 8 . 43 ( d , 1h ), 8 . 77 ( d , 1h ), 9 . 17 ( s , 1h ), 10 . 97 ( sbr , 1h ). lc - ms m / e 365 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 7 . 17 ( t , 1h ), 7 . 61 ( dd , 1h ), 7 . 6 - 8 . 0 ( sbr , 2h ), 7 . 69 ( m , 2h ), 8 . 32 ( dt , 1h ), 8 . 43 ( d , 1h ), 8 . 74 ( dd , 1h ), 9 . 16 ( d , 1h ), 10 . 74 ( s , 1h ). lc - ms m / e 346 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 4 . 72 ( d , 2h ), 7 . 37 ( d , 2h ), 7 . 42 ( d , 2h ), 7 . 54 ( dd , 1h ), 7 . 60 ( tbr , 1h ), 8 . 27 ( dt , 1h ), 8 . 70 ( dd , 1h ), 9 . 10 ( d , 1h ). lc - ms m / e 346 ( m + 1 ), 1 h nmr ( dmso - d 6 ) δ 7 . 42 ( m , 2h ), 7 . 57 ( m , 2h ), 7 . 65 ( dd , 1h ), 7 . 69 ( t , 1h ), 8 . 38 ( dt , 1h ), 8 . 82 ( dd , 1h ), 9 . 22 ( d , 1h ) as demonstrated by the representative compounds of the present invention in table 1 , the compounds of the present invention have valuable pharmacological properties due to their potent ability to inhibit the hyak3 and ck2 kinase enzyme . yak3 scintillation proximity assays using ser164 of myelin basic protein as the phosphoacceptor the source of ser164 substrate peptide the biotinylated ser164 , s164a peptide ( biotinyl — lggrdsrags * pmarr — oh ), sequence derived from the c - terminus of bovine myelin basic protein ( mbp ) with ser162 substituted as ala162 , was purchased from california peptide research inc . ( napa , calif . ), and its purity was determined by hplc . phosphorylation occurs at position 164 ( marked s * above ). the calculated molecular mass of the peptide was 2166 dalton . solid sample was dissolved at 10 mm in dmso , aliquoted , and stored at − 20 ° c . until use . the source of hyak3 enzyme : glutathione - s - transferase ( gst )- hyak3 - his6 containing amino acid residues 124 - 526 of human yak3 ( aa 124 - 526 of seq id no 2 . in u . s . pat . no . 6 , 323 , 318 ) was purified from baculovirus expression system in sf9 cells using glutathione sepharose 4b column chromatography followed by ni - nta - agarose column chromatography . purity greater than 65 % typically was achieved . samples , in 50 mm tris , 150 mm nacl , 10 % glycerol , 0 . 1 % triton , 250 mm imidazole , 10 mm β - mercapto ethanol , ph 8 . 0 . were stored at − 80 ° c . until use . kinase assay of purified hyak3 : assays were performed in 96 well ( costar , catalog no . 3789 ) or 384 well plates ( costar , catalog no . 3705 ). reaction ( in 20 , 25 , or 40 μl volume ) mix contained in final concentrations 25 mm hepes buffer , ph 7 . 4 ; 10 mm mgcl 2 ; 10 mm β - mercapto ethanol ; 0 . 0025 % tween - 20 ; 0 . 001 mm atp , 0 . 1 □ ci of [□- 33p ] atp ; purified hyak3 ( 7 - 14 ng / assay ; 4 nm final ); and 4 μm ser164 peptide . compounds , titrated in dmso , were evaluated at concentrations ranging from 50 μm to 0 . 5 nm . final assay concentrations of dmso did not exceed 5 %, resulting in less than 15 % loss of yak3 activity relative to controls without dmso . reactions were incubated for 2 hours at room temperature and were stopped by a 75 ul addition of 0 . 19 μg streptavidin scintillation proximity beads ( amersham pharmacia biotech , catalog no . rpnq 0007 ) in pbs , ph 7 . 4 , 10 mm edta , 0 . 1 % triton x - 100 , 1 mm atp . under the assay conditions defined above , the km ( apparent ) for atp was determined to be 7 . 2 +/− 2 . 4 μm . compounds of the present invention were also tested for casein kinase 2 alpha ( ck2α ) inhibitory activity in substrate phosphorylation assays . this assay examines the ability of small molecule organic compounds to inhibit the serine phosphorylation of a peptide substrate . the biotinylated peptide ( biotin — ggrrrddds * ddd - oh ), was purchased from biosource international , inc . ( camarillo , calif . ), and its purity was determined by hplc . phosphorylation of serine ( s *) occurs under assay conditions described . the calculated molecular mass of the peptide was 1713 dalton . solid sample was dissolved at 10 mm in dmso , aliquoted , and stored at − 20 ° c . until use . recombinant expression of casein kinase 2 alpha ( ck2α ), using baculovirus - based vectors in sf21 insect cells and purified by p11 phosphocellulose ( whatman ) chromatography of the clarified cell lysate , produced constitutively active enzyme . ck2α was co - expressed with ck2β . samples were stored at − 20 ° c . in the presence of 50 % glycerol until use . assays were performed in 384 well plates ( costar , catalog no . 3705 ). compounds first were delivered to the plate in one microliter dmso , followed by reaction mix ( in 40 ul volume ), which contained in final concentrations 25 mm hepes buffer , ph 7 . 4 ; mm mgcl 2 ; 150 mm nacl ; 1 mm β - mercapto ethanol ; 0 . 0025 % tween - 20 ; 0 . 001 mm atp , 0 . 1 μci of [ γ - 33p ] atp ; purified ck2α ( 6 ng / assay ), and 0 . 001 mm peptide . reactions were incubated for 3 hours at room temperature and were stopped by a 0 . 040 ml addition of 0 . 16 mg streptavidin scintillation proximity beads ( in pbs , ph 7 . 4 , 10 mm edta , 0 . 1 % triton x 100 , 1 mm atp ). quenched reactions remained overnight before 1 minute centrifugation ( at 500 × g ), followed by counting in a packard topcount . the data for dose responses were plotted as % inhibition , calculated with the data reduction formula 100 *( 1 −[( u1 − c2 )/( c1 − c2 )]), versus concentration of compound , where u is the unknown value , c1 is the average control value obtained for dmso , and c2 is the average control value obtained for 0 . 05m edta data were fitted to the curve described by : y =(( vmax * x )/( k + x )) where vmax is the upper asymptote and k is the ic50 . the results for each compound were recorded as pic50 calculated as follows : pic50 =− log 10 ( k ) in table 2 . the above biological data clearly shows that the present compounds are useful for treating or preventing disease states in which hyak3 proteins are implicated , especially diseases of the erythroid and hematopoietic systems , including anemias due to renal insufficiency or to chronic disease , such as autoimmunity , hiv or cancer and drug - induced anemias , myelodysplastic syndrome , aplastic anemia and myelosuppression ; cytopenia . the present method is especially useful in treating diseases of the hematopoietic system , particularly anemias . such anemias include an anemia selected from the group comprising : aplastic anemia and myelodysplastic syndrome . such anemias also include those wherein the anemia is a consequence of a primary disease selected from the group consisting of : cancer , leukemia and lymphoma . such anemias also include those wherein the anemia is a consequence of a primary disease selected from the group consisting of : renal disease , failure or damage . such anemias include those wherein the anemia is a consequence of chemotherapy or radiation therapy , in particular wherein the chemotherapy is chemotherapy for cancer or azt treatment for hiv infection . such anemias include those wherein the anemia is a consequence of a bone marrow transplant or a stem cell transplant . such anemias also include anemia of newborn infants . such anemias also include those which are a consequence of viral , fungal , microbial or parasitic infection . the present invention provides a method of enhancement of normal red blood cell numbers . such enhancement is desirable for a variety of purposes , especially medical purposes such as preparation of a patient for transfusion and preparation of a patient for surgery . the above biological data also clearly shows that the present compounds are useful for treating or preventing disease states in which ck2 proteins are implicated , especially cancers and viral infections .