Patent Application: US-52225303-A

Abstract:
the present invention provides a method for treating diseases caused by and / or associated with an altered protein kinase activity which comprises administering to a mammal in need thereof an effective amount of a pyrrolo - pyrazole or pyrazolo - azepine . the invention also provides specific pyrrolo - pyrazoles and pyrazolo - azepines , useful intermediates , a library comprising at least two of them , a process for their preparation and the pharmaceutical compositions containing them , which are useful in the treatment of diseases caused by and / or associated with an altered protein kinase activity such as cancer , cell proliferative disorders , viral infections , autoimmune diseases and neurodegenerative disorders .

Description:
the compounds of formula ( i ), object of the present invention , may have asymmetric carbon atoms and may therefore exist either as racemic admixtures or as individual optical isomers . accordingly , all the possible isomers and their admixtures and of both the metabolites and the pharmaceutically acceptable bio - precursors ( otherwise referred to as pro - drugs ) of the compounds of formula ( i ), as well as any therapeutic method of treatment comprising them , are also within the scope of the present invention . as it will be readily appreciated , depending on the values of m and n , the ring condensed to the pyrazole may consist of 5 or 7 atoms ; as to the pyrazole ring , two isomers are possible and therefore the r 2 substituent may be on one of the two nitrogens . accordingly , in the present invention and unless otherwise indicated , the general formula i comprises the compounds of formula ia , ib , ic , id , ie and if : wherein r , r 1 , r 2 , r a , r b , r c and r d are as defined above . as used herein , unless otherwise specified , with the term straight or branched c 1 - c 6 alkyl , we intend a group such as , for instance , methyl , ethyl , n - propyl , isopropyl , n - butyl , isobutyl , sec - butyl , tert - butyl , n - pentyl , neopentyl , n - hexyl , isohexyl , and the like . with the term aryl we intend an aromatic carbocycle such as , for instance , phenyl , biphenyl , 1 - naphthyl , 2 - naphthyl , and the like . clearly , aryl groups may also refer to aromatic carbocyclic further fused or linked to non aromatic heterocyclic rings , typically 5 to 7 membered heterocycles . with the term heterocyclyl , hence encompassing aromatic heterocycles , we further intend a saturated or partially unsaturated 5 to 7 membered carbocycle wherein one or more carbon atoms are replaced by heteroatoms such as nitrogen , oxygen and sulphur , for instance , 1 , 3 - dioxolane , pyran , thiophene , furan , pyrrole , imidazole , pyrazole , thiazole , isothiazole , oxazole , isoxazole , pyridine , pyrazine , pyrimidine , pyridazine , pyrrolidine , pyrroline , imidazolidine , imidazoline , piperidine , piperazine , morpholine , tetrahydrofurane , tetrahydropyran , tetrahydrothiopyran , imidazolidine , pyrazolidine , pyrazoline , piperidine , azabicyclononane and the like . also the heterocycles may be optionally fused and , unless otherwise indicated , we intend any of the above defined heterocycles further condensed , through any one of the available bonds , with 5 - or 6 - membered , saturated or unsaturated heterocyclyl ring , or to a c 3 - c 6 cycloalkyl ring , or to a benzene or naphthalene ring such as , for instance , quinoline , isoquinoline , chroman , chromene , thionaphthalene , indoline , and the like . with the term c 2 - c 6 alkenyl , we intend a straight or branched alkenyl group such as vinyl , allyl , crotyl , 2 - methyl - 1 - propenyl , 1 - methyl - 1 - propenyl , butenyl , pentenyl . the c 2 - c 6 alkynyl group is a straight or branched alkynyl group such as ethynyl , propargyl , 1 - propynyl , 1 - butynyl , 2 - butynyl . with the term saturated or unsaturated c 3 - c 6 cycloalkyl group we intend , for instance , cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , cyclopentenyl cyclohexenyl , and the like . unless otherwise specified , saturated or unsaturated cycloalkyl groups can be further condensed with 1 or 2 benzene rings are , for instance , 1 , 2 , 3 , 4tetrahydro - naphthalene - 2 - yl , fluorene - 9 - yl , and the like . the term “ c 5 - c 8 ( hetero ) cycloalkyl ” as used herein refers to a 5 - to 8 - membered , substituted or unsubstituted , saturated or unsaturated heterocyclyl ring , containing at least one boro and two oxygen atoms , any ring carbon may be oxidized as a carbonyl , and wherein said ring may be optionally fused to a second 5 - or 6 - membered , saturated or unsaturated heterocyclyl ring , or to a c 3 - c 7 cycloalkyl ring , or to a benzene or naphthalene ring . the term “ aryl c 1 - c 6 alkyl ” refer to a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms substituted with at least one aryl group as defined above , such as , for instance , benzyl , phenylethyl , benzhydryl , benzyloxy and the like . the “ aryl c 2 - c 6 alkenyl group ” is an alkenyl group of 2 to 6 carbon atoms linked to a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 carbon atoms . examples of aryl alkenyl groups are styryl , 2 - phenyl - 1 - propenyl , 3 - phenyl - 2 - butenyl , 2 - naphthylethenyl . the “ aryl c 2 - c 6 alkynyl group ” is an alkynyl group of 2 to 6 carbon atoms linked to a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 carbon atoms . examples of aryl alkynyl groups are 2 - phenylethynyl , 2 - naphthylethynyl . the ( heterocyclyl ) c 1 - c 6 alkyl group is an alkyl group of 1 to 6 carbon atoms linked to a heterocyclyl group . the ( heterocyclyl ) c 2 - c 6 alkenyl group is an alkenyl group of 2 to 6 carbon atoms linked to a heterocyclic group . the ( heterocyclyl ) c 2 - c 6 alkynyl group is an alkynyl group of 2 to 6 carbon atoms linked to a heterocyclic group . from all of the above , it is clear to the skilled man that any of the groups or substituents being defined , for instance , as arylalkyl , alkoxy , cycloalkoxy , aryloxy , arylalkyloxy and the like , have to be construed from the names of the groups from which they originate . as an example , unless specifically noted otherwise , any arylalkyloxy group has to be intended as an alkyloxy wherein the alkyl moiety is substituted by at least one aryl , both aryl and alkyl being as above defined . with the term halogen atom , we intend fluoro , bromo , chloro or iodo atom . the term “ optionally substituted ” means that the group may be substituted or unsubstituted ; the substituents which may be present in the alkyl , cycloalkyl , aryl , arylalkyl , arylalkenyl , arylalkyl , alkoxy , aryloxy , cycloalkoxy , alkenyl , alkynyl or heterocyclyl groups in any of the above definitions include the following : mercapto ( i . e ., — sh ), and acetyl or phenylacetyl esters thereof ( i . e ., — scoch 3 and — scoch 2 c 6 h 5 ); amino ( i . e ., — nh2 or — nhr i or — nr i r ii , wherein r i and r ii , which are the same or different , are straight or branched c 1 - c 6 alkyl , phenyl , biphenyl ( i . e ., — c 6 h 4 — g 6 h 5 ), or benzyl groups , optionally substituted by hydroxy , methoxy , methyl , amino , methylamino , dimethylamino , chloro or fluoro ; or r i and r ii taken together with the nitrogen atom to which they are attached form a heterocyclic ring such as morpholino , pyrrolidino , piperidino , pyperazino or n - methylpyperazino ; carboxy ( i . e . — cooh ), or esters thereof ( i . e ., — coor i ), or amides thereof ( i . e ., — conh 2 , — conhr i or — conhr i r ii ), wherein r i and r ii are as defined above , and including morpholino - amides , pyrrolidino - amides , and carboxymethylamides — conhch 2 cooh ; acyl , i . e ., — c ( o ) r i , wherein r i is as defined above , including monofluoroacetyl , difluoroacetyl , trifluoroacetyl ; acyloxy , i . e ., — oc ( o ) r i wherein r i is as defined above , or formyloxy , acylamino , i . e ., — nhc ( o ) r i , or — nhc ( o ) or i , wherein r i is as defined above or is a group —( ch 2 ) t cooh where t is 1 , 2 or3 ; ureido , i . e ., — nh ( co ) nh 2 , — nh ( co ) nhr i , — nh ( co ) nr i r ii , wherein r i and r ii are as defined above , including — nh ( co )-( 4morpholino ), — nh ( co )—( 1 - pyrrolidino ), — nh ( co )—( 1 - piperazino ), — nh ( co )-( 4 - methyl - 1 - piperazino ); sulfonamido , i . e ., — nhso 2 r i wherein r i is as defined above ; a group —( ch 2 ) t cooh , and esters and amides thereof , i . e ., —( ch 2 ) t coor i and —( ch 2 ) t conh 2 , —( ch 2 ) t conhr i , — ch 2 ) t conr i r ii , wherein t , r i and r ii are as defined above ; a group — nh ( so 2 ) nh 2 , — nh ( so 2 ) nhr i , — nh ( so 2 ) nr i r ii , wherein r i and r ii are as defined above , including — nh ( so 2 )-( 4morpholino ), — nh ( so 2 )( 1 - pyrrolidino ), — nh ( so 2 )( 1 - piperazino ), — nh ( so 2 )-( 4methyl - 1 - piperazino ); a group — oc ( o ) or i , wherein r i is as defined above ; a group — or i , wherein r i is as defined above , including — och 2 cooh ; a group — sr i , wherein r i is as defined above , including — sch 2 cooh ; a group — s ( o ) r i , wherein r i is as defined above ; a group — s ( o 2 ) r i , wherein r i is as defined above ; a group — so 2 nh 2 , — so 2 nhr i , or — so 2 nr i r ii , wherein r i and r ii are as defined above ; substituted methyl selected from chloromethyl , fluoromethyl , difluoromethyl , trifluoromethyl , aminomethyl , n , n - dimethylaminoethyl , azidomethyl , cyanomethyl , carboxymethyl , sulfomethyl , carbamoylmethyl , carbamoyloxymethyl , hydroxymethyl , methoxycarbonylmethyl , ethoxycarbonylmethyl , tert - butoxycarbonylmethyl and guanidinomethyl . when present , carboxy , hydroxy , mercapto and amino groups may be either free or in a protected form . protected forms of said groups are any of those generally known in the art . preferably , carboxy groups are protected as esters thereof , in particular methyl , ethyl , tert - butyl , benzyl , and 4nitrobenzyl esters . preferably , hydroxy groups are protected as silyl - ethers , ethers or esters thereof , in particular trimethyl silyl , tert - butyldiphenyl silyl , triethyl silyl , triisopropyl silyl or tert - butyldimethylsilyl ethers , methoxymethyl ethers , tetrahydropyranyl ethers , benzyl ethers , acetates or benzoates . preferably , mercapto groups are protected as thioethers or thioesters , in particular tert - butyl thioethers , thioacetates or thiobenzoates . preferably , amino groups are protected as carbamates , e . g . tert - butoxycarbonyl derivatives , or as amides , e . g . acetamides and benzamides . furthermore , hydrates , solvates of compounds of formula ( i ), and physiologically hydrolyzable derivatives ( i . e ., prodrugs ) of compounds of formula ( i ) are included within the scope of the present invention . pharmaceutically acceptable salts of the compounds of formula ( i ) are the acid addition salts with inorganic or organic , e . g . nitric , hydrochloric , hydrobromic , sulphuric , perchloric , phosphoric , acetic , trifluoroacetic , propionic , glycolic , lactic , oxalic , malonic , malic , maleic , tartaric , citric , benzoic , cinnamic , mandelic , methanesulphonic , isethionic and salicylic acid , as well as the salts with inorganic or organic bases , e . g . alkali or alkaline - earth metals , especially sodium , potassium , calcium or magnesium hydroxides , carbonates or bicarbonates , acyclic or cyclic amines , preferably methylamine , ethylamine , diethylamine , triethylamine or piperidine . preferred compounds of formula ( i ) are the compounds wherein r is h , i , br , cl , f , aryl , c 2 - c 6 alkenyl , c 2 - c 6 alkynyl , — b ( or ′″) 2 , — cor ′, — conr ′ r ″, — cn , so 2 r ′, or ′, sr ′, and r 1 is h , c 1 - c 6 alkyl , aryl , — cor ′, — conr ′ r ″, — coor ′, — so 2 r ′, or — so 2 nr ′ r ″, and r 2 is h , — coor ′, — cor ′, — conr ′ r ″, c 1 - c 6 alkyl , — so 2 r ′, or — so 2 nr ′ r ″, ( heterocyclyl ) c 1 - c 6 alkyl group , wherein r ′ and r ″, the same or different , are selected from hydrogen or optionally substituted straight or branched c 1 - c 6 alkyl , aryl or aryl c 1 - c 6 alkyl groups ; r a , r b , r c and r d , the same or different , are selected from hydrogen or straight or branched c 1 - c 3 alkyl or , taken together with the carbon atom to which they are bonded form a c 3 - c 6 cycloalkyl group . other preferred compounds of formula ( i ) are the compounds wherein r is selected from aryl , heterocyclyl , — cor ′, — conr ′ r ″, wherein r ′ and r ″, the same or different , are selected from hydrogen or optionally substituted straight or branched c 1 - c 6 alkyl , aryl or aryl c 1 - c 6 alkyl groups . other preferred compounds of formula ( i ) are the compounds wherein r 1 is selected from h , c 1 - c 6 alkyl , aryl , — cor ′, — conr ′ r ″, coor ′, — so 2 r ′ or — so 2 nr ′ r ″, wherein r ′ and r ″, the same or different , are selected from hydrogen or optionally substituted straight or branched c 1 - c 6 alkyl , aryl or aryl c 1 - c 6 alkyl groups . another preferred class of compounds of formula ( i ) are the compounds wherein r 2 is h , — coor ′, — conr ′ r ″, c 1 - c 6 alkyl , wherein r ′ and r ″, the same or different , are selected from hydrogen or optionally substituted straight or branched c 1 - c 6 alkyl , aryl or aryl c 1 - c 6 alkyl groups . as formerly indicated , it is a further object of the invention a process for preparing the compounds of formula ( i ) and pharmaceutically acceptable salts thereof wherein r 1 is as defined above but not hydrogen , and r a , r b , r c , r d , r 2 , m and n are as defined above , to diazotation and subsequent appropriate quenching , thus obtaining a compound of formula ( i ) wherein r 1 is as defined above but not hydrogen ; r a , r b , r c , r d , r 2 , m and n are as defined above , and r is hydrogen , iodine , bromine , chlorine or fluorine atom or a cn group ; b1 ) converting a thus obtained compound of formula ( i ) wherein r is l br , cl into another compound of formula ( i ) wherein r is an optionally substituted aryl , c 2 - c 6 alkenyl , c 2 - c 6 alkynyl , — sr ′, — or ′ or — cor ′ wherein r ′ is as defined above ; b2 ) converting a compound of formula ( i ) wherein r is hydrogen into another compound of formula ( i ) wherein r is — b ( or ′″) 2 , — snr ″″, — coor ′, — cor ′, c 1 - c 6 alkyl or iodine , wherein r ′, r ′″ and r ″″ are as defined above ; c ) converting a compound of formula ( i ) wherein r is — b ( or ′″) 2 or — snr ″″ as above defined into another compound of formula ( i ) wherein r is an optionally substituted aryl c 2 - c 6 alkenyl , c 2 - c 6 alkynyl ; d ) optionally converting a compound of formula ( i ) into another different compound of formula ( i ), and , if desired , converting a compound of formula ( i ) into a pharmaceutically acceptable salt thereof or converting a salt into the free compound ( i ). the above process can be carried out according to well known methods . it is clear to the person skilled in the art that if a compound of formula ( i ), prepared according to the above process , is obtained as an admixture of isomers , their separation into the single isomers of formula ( i ), carried out according to conventional techniques , is still within the scope of the present invention . likewise , the salification of a compound of formula ( i ) or the conversion of its salt into the free compound ( i ) carried out according to well - known procedures in the art , are still within the scope of the invention . according to a preferred aspect of the process of the invention avoiding the unwanted by - products formation , a compound of formula ( i ), obtained according to step a above , could be first supported onto a suitable solid support , such as resin and then , after the reactions as per steps b1 , b2 , c and d above described , reconverted into a compound of formula ( i ). it is therefore a further object of the invention a process for preparing a compound of formula ( i ) as defined above , which process comprises : b1a ) converting a compound of formula ( i ) into another compound of formula ( i ) wherein r has the above reported meanings resulting from step b1 and r 1 , r a , r b , r c , r d , m and n are as defined above analogously to step b1 above described and pa ) reacting the resultant compound of formula ( i ) wherein r , r a , r b , r c , r d , m and n are as defined above , r 1 is as described above but not hydrogen and r 2 is hydrogen , with a suitable solid support so as to obtain a compound of formula ( iii ) wherein r , r a , r b , r c , r d , m and n are as defined above , r 1 is as defined above but not hydrogen , and q is a solid support , or p ) reacting a compound of formula ( i ) wherein r , r a , r b , r c , r d , m and n are as defined above , r 1 is as defined above but not hydrogen and r 2 is hydrogen , with a suitable solid support so as to obtain a compound of formula ( iii ) as defined above and b ) then , analogously to steps b1 , b2 , c and d above described , optionally converting a thus obtained compound of formula ( iii ) into another compound of formula ( iii ) wherein r has the above reported meanings for steps b1 , b2 , c and d and r 1 , r a , r b , r c , r d , m and n are as defined above ; d ) cleaving the resultant compound of formula ( iii ) so as to eliminate the solid support and to obtain the desired compound of formula ( i ); e ) optionally converting a compound of formula ( i ) into another different compound of formula ( i ), and , if desired , converting a compound of formula ( i ) into a pharmaceutically acceptable salt thereof or converting a salt into the free compound ( i ) as described above . it is a further object of the present invention to provide useful intermediates of formula iii wherein r , r 1 r a , r b , r c , r d , m and n are as defined above , and q is a solid support , more preferably a residue derived from a resin selected from the group consisting of isocyanate polystyrenic resin , 2 - chloro - trityl chloride resin , trityl chloride resin , p - nitrophenyl carbonate wang resin and the bromo - 4 - methoxyphenyl ) methyl polystyrene . a process for the preparation of a compound of formula ( iii ) as defined above is also provided , which process comprises : b1a ) converting a compound of formula ( i ) into another compound of formula ( i ) wherein r has the above reported meanings resulting from step b1 and r 1 , r a , r b , r c , r d , m and n are as defined above , analogously to step b1 above described and pa ) reacting the resultant compound of formula ( i ) wherein r , r a , r b , r c , r d , m and n are as defined above , r 1 is as defined above but not hydrogen and r 2 is hydrogen , with a suitable solid support so as to obtain a compound of formula ( iii ) wherein r , r a , r b , r c , r d , m and n are as defined above , r 1 is as defined above but not hydrogen , and q is a solid support , or p ) reacting a compound of formula ( i ) wherein r , r a , r b , r c , r d , m and n are as defined above , r 1 is as described above but not hydrogen and r 2 is hydrogen , with a suitable solid support so as to obtain a compound of formula ( iii ) as defined above and b ) then , analogously to steps b1 , b2 , c and d above described , optionally converting a thus obtained compound of formula ( iii ) into another compound of formula ( iii ) wherein r has the above reported meanings for steps b1 to d and r 1 , r a , r b , r c , r d , m and n are as defined above . according to step a ) of the process , a compound of formula ( i ) wherein r is hydrogen , i , br , cl , f , cn , and r 1 is as defined above but not hydrogen , and r a , r b , r c , r d , r 2 , m and n are as defined above , may be prepared by reacting a compound of formula ( ii ), wherein r 1 is as defined above but not hydrogen , and r a , r b , r c , r d , r 2 , m and n are as defined above , with organic or inorganic nitrates such as sodium nitrate or isopentylnitrate , in the presence of a suitable hydrogen source , such as hpo 2 , thiophenol , sodium stannite , bu 3 snh , et 3 sih , or of a suitable halogenating or cyanating agent such as tetrabutylamonium iodide and / or iodine , tetrabutylamonium bromide and / or bromine , tetrabutylamonium chloride and / or chlorine , cubr , cucl , cui , cucn , sodium tetrafluoroborate , ammonium tetrafluoroborate , in aqueos acidic solution at various concentrations such as diluted chloridic acid or diluted citric acid , or in organic solvents such as tetrahydrofurane , 1 , 4 - dioxan , dichloromethane , chloroform , toluene , acetonitrile , ethylacetate , acetone , dimethylformamide , ethanol , methanol water at a temperature ranging from about − 78 ° c . to reflux , for a suitable time ranging from 5 min to 72 hours . more preferably , the step a ) is carried out on compounds of the formula ( ii ) wherein r 2 is not hydrogen atom . according to step b1 ) of the process , a compound of formula ( i ) wherein r is an optionally substituted aryl or c 2 - c 6 alkenyl group , and r 1 , r 2 , r a , r b , r c , r d , m and n are as defined above , can be obtained by reacting a compound of formula ( i ), wherein r is halogen atom , and r 1 , r 2 , r a , r b , r c , r d , m and n are as defined above , with a suitable aryl boronic acid or ester , alkenyl boronic acid or ester , arylstannane , in the presence of a suitable catalysing agent such as palladium ( 0 ) tetrakis , bis triphenylphosphine palladium ( ii ) dichloride , bis tricyclohexylphosphine palladium ( ii ) dichloride , bis tri - o - tolylphosphine palladium ( ii ) dichloride , palladium ( ii ) acetate , tris ( dibenzylideneacetone ) dipalladium ( 0 ), [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( ii ), [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloronickel ( ii ), 1 , 4 - bis ( diphenylphosphino ) butane palladium ( ii ), and of a suitable base such as sodium carbonate , cesium carbonate , potassium carbonate , potassium phosphate , triethylamine , sodium hydroxide , cesium fluoride , potassium tert - butylate , sodium ethylate , potassium acetate , in a suitable solvent , such as 1 , 4dioxan , tetrahydrofurane , dmf ( n , n - dimethylformamide ), dimethoxyethane , toluene , methanol , ethanol , water , n - methylpyrrolidone , and , when needed , adding a suitable ligand , such as tributylphosphine , triphenylphosphine , tri - o - tolylphosphine , tricyclohexyl , biphenyl ( dicyclohexyl ) phosphine , biphenyl ( ditert - butyl ) phosphine , diphenylphosphine ferrocene , and / or cu ( i ) salts such as cui , cu ( i ) thiophene - 2 - carboxylate at a temperature ranging from room temperature to reflux , for a suitable time ranging from 15 minutes to 72 hours . according to step b1 ) of the process , a compound of formula ( i ) wherein r is an optionally substituted c 1 - c 6 alkynyl , and r 1 , r 2 , r a , r b , r c , r d , m and n are as defined above , can be obtained by reacting a compound of formula ( i ), wherein r is halogen , and r 1 , r 2 , r a , r b , r c , r d , m and n are as defined above , with a suitable alkyne under the condition of the sonogashira &# 39 ; s reaction , in the presence of a suitable catalysing agent such as bistriphenylphosine palladium ( ii ) dichloride , palladium ( 0 ) tetrakis , palladium ( ii ) acetate , tris ( dibenzylideneacetone ) dipalladium ( 0 ), and of a suitable cu ( i ) salt , such as cui , and in presence of a suitable base such as sodium carbonate , potassium carbonate , cesium carbonate , potassium phosphate , triethylamine , diisopropylamine , pyridine , in a suitable solvent , such as 1 , 4 - dioxan , tetrahydrofurane , dmf , dimethoxyethane , toluene , ethanol , methanol , and , if needed , adding a suitable ligand such as triphenylphosphine , tri - o - tolylphosphine , tricyclohexyl , diphenylphosphineferrocene , at a temperature ranging from room temperature to reflux , for a suitable time ranging from 15 minutes to 72 hours . according to step b1 ) of the process , a compound of formula ( i ) wherein r is sr ′, or ′, and r 1 , r 2 , r a , r b , r c , r d , r ′, m and n are as defined above , can be obtained by reacting a compound of formula ( i ), wherein r is halogen , and r 1 , r 2 , r a , r b , r c , r d , m and n are as defined above , with a suitable alcohol or thiol r ′ oh or r ′ sh wherein r ′ is as above defined , in the presence of a suitable base , such as potassium carbonate , sodium carbonate , cesium carbonate , potassium hydroxide , sodium hydroxide , sodium hydride , sodium methylate , sodium tert - butylate , diisopropylethylamine , pyridine , piperidine , n - methylmorpholine , dimethylaminopyridine , and , if needed , in the presence of catalysing agent , such as bis tricyclohexylphosphine palladium ( ii ) dichloride , bis tri - o - tolylphosphine palladium ( ii ) dichloride , palladium ( ii ) acetate , tris ( dibenzylideneacetone ) dipalladium ( 0 ), [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( ii ), and of a suitable ligand , such as , triphenylphosphine , tri - o - tolylphosphine , tricyclohexyl , diphenylphosphineferrocene , in a suitable solvent , such as dimethylformamide , nmp , dichloromethane , tetrahydrofurane , benzene , toluene , pyridine , dimethylsulfoxide at a temperature ranging from − 20 ° c . to reflux , for a suitable time ranging from 15 minutes to 72 hours . according to step b1 ) of the process , a compound of formula ( i ) wherein r is — cor ′, and r 1 , r 2 ; r a , r b , r c , r d , m and n are as defined above , can be obtained by reacting a compound of formula ( i ) wherein r is halogen and r 1 , r 2 , r a , r b , r c , r d , m and n are as defined above , with a suitable base , such as n - butyl lithium , lda ( lithium diisopropylamide ), sec - butyl lithium , t - butyl lithium , lithium 2 , 2 , 6 , 6 - tetramethylpiperidin amide , phenyl lithium , magnesium , isopropylmagnesium bromide in a suitable solvent , such as diethyl ether , tetrahydrofurane , 1 , 4dioxan , n - hexane , cyclohexane , pentane , toluene , dme ( ethylene glycol dimethyl ether ), dimethylsulfoxide in the presence of a base if needed , such as tmeda ( n , n , n ′, n ′- tetramethylethylenediamine ), at a suitable temperature ranging from − 78 ° c . to room temperature , for a time ranging from 15 minutes to 3 hours ; the resulting lithium derivative can be quenched with a suitable electrophilic agent , such as , trialkylarylstannane / carbon monoxide , acid chlorides , acid fluorides , acid bromides , anhydrides , carbonates , halo carbonates , carbamates , dmf , and if needed , in the presence of a suitable catalysing agent , such as pd ( 0 ) tetrakis , and of a suitable coordinating agent , such as zncl 2 , znbr 2 , cucn . 2licl , cui cubr , cubr . sme 2 at a suitable temperature ranging from about − 78 ° c . to reflux , for a time ranging from 15 minutes to about 72 hours . according to step b2 ) of the process , a compound of formula ( i ) wherein r is iodine , b ( or ′″) 2 , snr ″″, — coor ′, — cor ′, c 1 - c 6 alkyl and r 1 , r 2 , r a , r b , r c , r d , r ′, r ′″, r ″″, m and n are as defined above , can be obtained by reacting a compound of formula ( i ) wherein r is hydrogen and r 1 , r 2 , r a , r b , r c , r d , m and n are as defined above , with a suitable lithiating agent , such as n - butyl lithium , lda , sec - butyl lithium , t - butyl lithium , lithium 2 , 2 , 6 , 6 - tetramethylpiperidinamide , phenyl lithium , in a suitable solvent , such as diethyl ether , tetrahydrofurane , 1 , 4 - dioxan , n - hexane , cyclohexane , toluene , dme , dimethylsulfoxide in the presence of a base if needed , such as tmeda , at a suitable temperature ranging from − 78 ° c . to room temperature , for a time ranging from 15 minutes to 3 hours ; the resulting lithium derivative can be quenched with a suitable electrophilic agent , such as trialkyl boronic esters , trialkylstannyl chloride , acid chlorides , acid fluorides , acid bromides , anhydrides , carbonates , halo carbonates , dmf , iodine , aldehydes , ketones , alkyl halides , in the presence of a suitable coordinating agent , such as zncl 2 , znbr 2 , cucn . 2licl , cui , cubr , cubr . sme 2 when needed , at a suitable temperature ranging from about − 78 ° c . to reflux , for a time ranging from 15 minutes to about 72 hours . according to step c ) of the process , a compound of formula ( i ) wherein r is an optionally substituted aryl or c 1 - c 6 alkenyl group and r 1 , r 2 , r a , r b , r c , r d , m and n are as defined above , can be obtained by reacting a compound of formula ( i ) wherein r is b ( or ′″) 2 , snr ″″, and r 1 , r 2 , r a , r b , r c , r d , r ′″, r ″″, m and n are as defined above , with a suitable aryl halide or halogeno olefine , in the presence of a suitable catalysing agent such as as palladium ( 0 ) tetrakis , bis triphenylphosphine palladium ( ii ) dichloride , bis tricyclohexylphosphine palladium ( ii ) dichloride , bis tri - o - tolylphosphine palladium ( ii ) dichloride , palladium ( ii ) acetate , tris ( dibenzylideneacetone ) dipalladium ( 0 ), [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( ii ), [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloronickel ( ii ), 1 , 4bis ( diphenylphosphino ) butane palladium ( ii ), as sodium carbonate , cesium carbonate , potassium carbonate , potassium phosphate , triethylamine , sodium hydroxide , cesium fluoride , potassium tert - butylate , sodium ethylate , potassium acetate , in a suitable solvent , such as 1 , 4 - dioxan , tetrahydrofurane , dmf , dimethoxyethane , toluene , methanol , ethanol , water , n - methylpyrrolidone and , if needed , adding a suitable ligand , such as tributylphosphine , triphenylphosphine , tri - o - tolylphosphine , tricyclohexyl , biphenyl ( dicyclohexyl ) phosphine , biphenyl ( ditert - butyl ) phosphine , diphenylphosphineferrocene , and / or a suitable cu ( i ) salts , such as cui , cu ( i ) thiophene - 2 - carboxylate at a temperature ranging from room temperature to reflux , for a suitable time ranging from 15 minutes to 72 hours . according to step c ) of the process , a compound of formula ( i ) wherein r is an optionally substituted c 2 - c 6 alkynyl , and r 1 , r 2 , r a , r b , r c , r d , m and n are as defined above , can be obtained by reacting a compound of formula ( i ) wherein r is b ( or ′″) 2 , snr ″″, and r 1 , r 2 , r a , r b , r c , r d , r ′″, r ″″, m and n are as defined above , with a suitable 1 - alkyl ( aryl ) thio - alkyne , 1 - iodo ( bromo ) alkyne , or 1 , 1 - dibromo - 1 - alkene , in the presence of a suitable catalysing agent such as as palladium ( 0 ) tetrakis , bis triphenylphosphine palladium ( ii ) dichloride , bis tricyclohexylphosphine palladium ( ii ) dichloride , bis tri - o - tolylphosphine palladium ( ii ) dichloride , palladium ( ii ) acetate , tris ( dibenzylideneacetone ) dipalladium ( 0 ), [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( ii ), [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloronickel ( e ), 1 , 4 - bis ( diphenylphosphino ) butane palladium ( ii ) in a suitable solvent , such as 1 , 4 - dioxan , tetrahydrofurane , dmf , dimethoxyethane , toluene , methanol , ethanol , water , n - methylpyrrolidone and , if needed , adding a suitable ligand , such as tributylphosphine , triphenylphosphine , tri - o - tolylphosphine , tricyclohexyl , biphenyl ( dicyclohexyl ) phosphine , biphenyl ( ditert - butyl ) phosphine , diphenylphosphineferrocene , and / or a suitable cu ( i ) salts , such as cui , cu ( i ) thiophene - 2 - carboxylate at a temperature ranging from room temperature to reflux , for a suitable time ranging from 15 minutes to 72 hours . according to steps p and pa of the process , a compound of formula ( iii ) wherein r , r a , r b , r c , r d , m and n are as described above , r 1 is as described above but not hydrogen and q is a solid support can be obtained by reacting a compound of formula ( i ) wherein r , r a , r b , r c , r d , m and n are as described above , r 1 is as described above but not hydrogen and r 2 is hydrogen ( step p ) or different from hydrogen ( step pa ), with a suitable solid support such as a polymeric support like isocyanate polystyrenic resin , 2 - chloro - trityl chloride resin , trityl chloride resin , p - nitrophenyl carbonate wang resin , bromo - 4 - methoxyphenyl ) methyl polystyrene or the like , which are all conventionally known in this field , in the presence , when needed , of a suitable base , such as diisopropylethylamine , triethylamine , 1 , 8 - diazabiciclo [ 5 . 4 . 0 ] undec - 7 - ene or 2 - tert - buytlimino - 2 - diethylamino - 1 , 3 - dimethylperhydro - 1 , 3 , 2 - diaza - phosphorine , in a suitable solvent such as dichloromethane , chloroform , tetrahydrofurane , dimethylformamide , dimethylacetamide , 1 - methyl - 2 - pyrrolidinone , dimethylsulfoxide and the like , at a temperature ranging from room temperature to 50 ° c ., for a suitable time ranging from 10 minutes to 90 hours . according to step b1 a ) of the process , a compound of formula ( i ) may be converted into a different compound of formula ( i ) by steps analogous to the steps b1 ) herein described for the conversion of a compound of the formula ( i ) into a different compound of formula ( i ). according to step b of the process , a compound of formula ( iii ) may be converted into a different compound of formula ( iii ) by steps analogous to the steps b1 ), b2 ), c ) and d ) herein described for the conversion of a compound of the formula ( i ) into a different compound of formula ( i ). according to step d of the process , a compound of formula ( i ) wherein r , r a , r b , r c , r d , m and n are as described above , r 1 is as described above and r 2 is hydrogen , can be obtained by cleaving a compound ( iii ) wherein r , r a , r b , r c , r d , m and n are as described above , r 1 is as described above and q is a solid support , according to conventional hydrolytic methods in the presence of a suitable acid , such as hydrochloric acid , acetic acid , trifluoroacetic acid , hydrofluoric acid , or in the presence of a suitable base , such as sodium hydroxide , potassium hydroxide , sodium carbonate , sodium hydrogencarbonate , piperidine , or in the presence of other hydrolytic agents , such as tetrabutyl ammoniumfluoride , trimethyl silylchloride , in a suitable solvent such as dichloromethane , chloroform , methanol , ethanol , trifluoroethanol , dioxan , at a temperature ranging from room temperature to 70 ° c ., for a suitable time ranging from 10 minutes to 90 hours . r 2 is according to step e of the process , a compound of formula ( i ) wherein r , r a , r b , r c , r d , m and n are as described above , r 1 is as described above and r 2 is hydrogen may be converted into another different compound of formula ( i ), the conversion being carried out in several ways , depending on the meanings of the substituents and the presence of other substituents in the molecule . for example , by this conversion a compound of formula ( i ) wherein r 2 is as defined above but not hydrogen may be obtained . according to step d ) of the process , the conversion of a compound of formula ( i ) into another different compound of formula ( i ) may be carried out in several ways , depending on the meanings of the substituents and the presence of other substituents in the molecule . for example , a conversion can be a hydrolysis , a reductive amination , an arylation , an alkylation , an amination , a nucleophilic substitution , a catalytic reduction , an oxidation , a reduction , a condensation with an appropriate reagent or a combination of these reactions . as an example , the compounds of formula ( i ) or ( iii ), wherein r 1 is — coo t bu can be hydrolized to the corresponding compounds of formula ( i ) wherein r 1 is h , by treatment with a suitable acid , for instance trifluoroacetic or hydrochloric acid so far , any of the above compounds of formula ( i ) or ( iii ) wherein r 1 is a hydrogen atom can be easily converted into the corresponding derivatives alkylated , acylated , sulfonated or arylated . the reactions are carried out according to conventional techniques , for instance by properly reacting the amino derivative ( 1 ) or ( iii ) wherein r 1 is hydrogen with alkylating , acylating , sulfonylating or arylating agents and the like . in particular , a compound of formula ( i ) or ( iii ) wherein r 1 is selected from r ′ other than hydrogen , — cor ′, — coor ′, — conr ′ r ″, — so 2 r ′, or — so 2 nr ′ r ″, wherein r ′ and r ″ have the above reported meanings ; r , r 2 and r a , r b , r c , r d , m and n are as above defined , may be prepared by reacting a compound of formula ( i ) or a compound of formula ( iii ), having r 1 equal to hydrogen , with a compound of formula ( iv ) wherein r 1 is as above defined but not hydrogen and x is a suitable leaving group , preferably fluorine , chlorine , bromine or iodine . the above reaction can be carried out according to conventional procedures well known in the art for acylating , sulfonylating , alkylating or arylating amino groups , for instance in the presence of a suitable base , such as potassium carbonate , triethylamine , n , n - diisopropylethylamine or pyridine , in a suitable solvent such as dimethylsulfoxide , toluene , dichloromethane , chloroform , diethyl ether , tetrahydrofurane , acetonitrile , or n , n - dimethylformamide , at a temperature ranging from about − 10 ° c . to reflux and for a time varying from about 30 minutes to about 96 hours . a compound of formula ( i ) or ( iii ) wherein r 1 is an aryl group , r , r 2 and r a , r b , r c , r d , m and n are as above defined , may be prepared by reacting a compound of formula ( i ) or a compound of formula ( iii ), having r 1 equal to hydrogen with a compound of formula ( v ) wherein r 1 is an aryl group and x is as above defined . the above reaction can be carried out according to conventional procedures well known in the art for arylating amino groups , for instance in the presence of a suitable catalyst when needed , such as palladium ( 0 ) tetrakis , bistriphenylphosphinepalladium ( ii ) chloride , bis tricyclohexylphosphine palladium ( ii ) dichloride , bis tri - o - tolylphosphine palladium ( ii ) dichloride , palladium ( ii ) acetate , tris ( dibenzylideneacetone ) dipalladium ( 0 ), [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( ii ), as sodium carbonate , cesium carbonate , potassium carbonate , potassium phosphate , triethylamine , sodium hydroxide , cesium fluoride , potassium tert - butylate , sodium tert - butylate , sodium ethylate , potassium acetate , in a suitable solvent , such as 1 , 4dioxan , tetrahydrofurane , dmf , dimethilsulfoxide , dimethoxyethane , toluene , methanol , ethanol , water , n - methylpyrrolidone and adding a suitable ligand , such as tributylphosphine , triphenylphosphine , tri - o - tolylphosphine , tricyclohexyl , biphenyl ( dicyclohexyl ) phosphine , biphenyl ( ditert - butyl ) phosphine , diphenylphosphineferrocene , binap [( 2 , 2 ′- bis ( diphenylphosphino )- 1 , 1 ′- binaphthyl ], and adding , when needed a phase transfer catalysing agent , such as 18 - crown - 6 , at a temperature ranging from room temperature to reflux , for a suitable time ranging from 15 minutes to 72 hours . from the foregoing it is clear to the person skilled in the art that the preparation of the compounds of formula ( i ) or ( iii ) having r 1 equal to — so 2 nr ′ r ″ can be actually performed as above described or , alternatively , by properly reacting a compound of formula ( i ) or ( iii ) having r 1 equal to — so 2 nhr ′ with any suitable alkylating moiety , according to well known methodologies for preparing di - substituted sulfonamides . a compound of formula ( i ) or ( iii ) wherein r 1 is a — conhr ′ group , r ′ has the above reported meanings other than hydrogen , r , r 2 , and r a , r b , r c , r d , m and n are as above defined , may be prepared by reacting a compound of formula ( i ) or a compound of formula ( iii ) having r 1 equal to hydrogen , with a compound of formula ( vi ) wherein r ′ is as above defined but not hydrogen , so as to obtain a corresponding compound of formula ( i ) or ( iii ) which may be optionally further reacted with a compound of formula ( vii ) wherein r ″ is as above defined other than hydrogen and x is as above defined , so as to obtain a compound of formula ( i ) or ( iii ) wherein r 1 is — conr ′ r ″, wherein r ′ and r ″ are as above defined but not hydrogen atom . the reaction between the above compounds ( i ) or ( iii ) with a compound of formula ( vii ) can be carried out in the presence of a tertiary base , such as triethylamine , n , n - diisopropylethylamine or pyridine , in a suitable solvent , such as toluene , dichloromethane , chloroform , diethyl ether , tetrahydrofurane , acetonitrile , or n , n - dimethylformamide , at a temperature ranging from about − 10 ° c . to reflux and for a time varying from about 30 minutes to about 72 hours . the optional subsequent conversion of a compound of formula ( i ) or ( iii ) having r 1 equal to — conhr ′ into a corresponding derivative having r 1 equal to — conr ′ r ″ is carried out according to conventional methods used to prepare di - substituted ureido derivatives . a compound of formula ( i ) or ( iii ) wherein r 1 is a — conr ′ r ″ group , r ′ and r ″ has the above reported meanings other than hydrogen , r , r 2 and r a , r b , r c , r d , m and n are as above defined , may be prepared by reacting a compound of formula ( i ) or a compound of formula ( iii ) having r 1 equal to hydrogen with 4 - nitrophenylchloroformate and subsequently with a compound of formula ( viii ) wherein r ′ and r ″ are as defined above but not hydrogen . the reaction is carried out according to conventional methods used to prepare di - substituted ureido derivatives . alternatively , a compound of formula ( i ) or a compound of formula ( iii ), having r 1 equal to hydrogen may be reacted under reductive conditions with a compound of formula ( ix ) wherein r ′ is as defined above but not hydrogen , so as to obtain a corresponding compound of formula ( i ) or ( iii ) wherein r 1 is a — ch 2 r ′ group and r ′ being as defined above but not hydrogen . the reaction is carried out in a suitable solvent such as , for instance , n , n - dimethylformamide , n , n - dimethylacetamide , chloroform , dichloromethane , tetrahydrofurane , or acetonitrile , optionally in the presence of acetic acid , ethanol or methanol as co - solvents , at a temperature ranging from about − 10 ° c . to reflux and for a time varying from about 30 min to about 4 days . conventional reducing agents in the reaction medium are , for instance , sodium boron hydride , sodium triacethoxy boron hydride , and the like . in a further example , any of the above compounds of formula ( i ) or of formula ( iii ) wherein one or more of r a , r b , r b and r d is — ch 2 oh may be conveniently prepared by starting from a corresponding protected derivative having one or more of r a , r b , r b and r d as — ch 2 — o — si ( me ) 2 tbu or — ch 2 — o — ph . the reaction is carried according to conventional techniques , for instance in a suitable solvent such as , for instance , n , n - dimethylformamide , chloroform , dichloromethane , tetrahydrofurane , methanol , ethanol or acetonitrile , at a temperature ranging from about − 10 ° c . to reflux and for a time varying from about 30 min to about 72 hours with a suitable fluoride source , for instance tetrabutylamonium fluoride . likewise , the above compounds of formula ( i ) or ( iii ) having one or more r a , r b , r c and r d equal to — ch 2 oh can be reacted with a compound of formula ( vii ′) wherein r ′ is as above defined but not hydrogen and x is as above defined , so as to obtain the corresponding compounds wherein one or more r a , r b , r c and r d are a — ch 2 or ′ group , wherein r ′ is as defined above but not hydrogen . this latter reaction can be carried out in the presence of a base , such as sodium hydride , n , n - diisopropylethylamine or pyridine , in a suitable solvent , such as toluene , dichloromethane , chloroform , diethyl ether , tetrahydrofurane , acetonitrile , or n , n - dimethylformamide , at a temperature ranging from about − 10 ° c . to reflux . in an analogous manner , a compound of the formula i wherein r 2 is hydrogen may be converted into another compound of the formula i wherein r 2 is as defined above but not hydrogen atom . the starting compound of formula ( ii ) are known or can be prepared starting from known compounds using known methods of preparation , for example those described in wo02 / 12242 . as it will be really appreciated by the man skilled in the art , when preparing the compounds of formula ( i ) object of the invention , optional functional groups within both the starting materials or the intermediates thereof , which could give rise to unwanted side reactions , need to be properly protected according to conventional techniques . likewise , the conversion of these latter into the free deprotected compounds may be carried out according to known procedures . the above cited reagents of the process , i . e . arylboronic acids , arylboronic esters , alkenylboronic acids , alkenylboronic esters , triarylstannanes , acid chlorides , acid fluorides , acid bromides , anhydrides , carbonates , halo carbonates , alkynes , aryl halides , halogeno alkenes and the compounds of formula ( iv ), ( v ), ( vi ), ( vii ), ( vii ′), ( viii ) and ( ix ) are known or can be prepared according to known methods . as it will be also really appreciated by the man skilled in the art , when preparing the compounds of formula ( i ) object of the invention , according to steps a )- c ), each of the above cited reactants can be replaced by the corresponding polymer - supported reactant . in addition to the above , it is also clear to the skilled man that the compounds of formula ( i ) of the invention can be advantageously prepared by combining the above described reactions in a combinatorial fashion , for example according to solid - phase - synthesis ( sps ) techniques , so as to get a combinatorial chemical library of compounds of formula ( i ). it is therefore a further object of the invention a library of two or more compounds of formula ( i ): wherein r , r 1 , r 2 r a , r b , r c , r d m and n are as defined above , which can be obtained starting from one or more compound supported onto a solid support of the formula ( iii ) as defined above . the compounds of formula ( i ) are active as protein kinase inhibitors and are therefore useful , for instance , to restrict the unregulated proliferation of tumor cells . in therapy , they may be used in the treatment of various tumors , such as those formerly reported , as well as in the treatment of other cell proliferative disorders such as psoriasis , vascular smooth cell proliferation associated with atherosclerosis and post - surgical stenosis and restenosis and in the treatment of alzheimer &# 39 ; s disease . the inhibiting activity of putative cdk / cyclin inhibitors and the potency of selected compounds is determined through a method of assay based on the use of the spa technology ( amersham pharmacia biotech ). the assay consists of the transfer of radioactivity labelled phosphate moiety by the kinase to a biotinylated substrate . the resulting 33p - labelled biotinylated product is allowed to bind to streptavidin - coated spa beads ( biotin capacity 130 pmol / mg ), and light emitted was measured in a scintillation counter . kinase reaction : 4 μm in house biotinylated histone h1 ( sigma # h - 5505 ) substrate , 10 μm atp ( 0 . 1 microci p 33 γ - atp ), 1 . 1 nm cyclin a / cdk2 complex , inhibitor in a final volume of 30 μl buffer ( tris hcl 10 mm ph 7 . 5 , mgcl 2 10 mm , dtt 7 . 5 mm + 0 . 2 mg / ml bsa ) were added to each well of a 96 u bottom . after incubation for 60 min at room temperature , the reaction was stopped by addition of 100 μl pbs buffer containing 32 mm edta , 500 μm cold atp , 0 . 1 % triton x100 and 10 mg / ml streptavidin coated spa beads . after 20 min incubation , 110 μl of suspension were withdrawn and transferred into 96 - well optiplates containing 100 μl of 5m cscl . after 4 hours , the plates were read for 2 min in a packard top - count radioactivity reader . ic50 determination : inhibitors were tested at different concentrations ranging from 0 . 0015 to 10 μm . experimental data were analyzed by the computer program graphpad prizm using the four parameter logistic equation : where x is the logarithm of the inhibitor concentration , y is the response ; y starts at bottom and goes to top with a sigmoid shape . experimental method : reaction was carried out in buffer ( 10 mm tris , ph 7 . 5 , 10 mm mgcl 2 , 0 . 2 mg / ml bsa , 7 . 5 mm dtt ) containing 3 . 7 nm enzyme , histone and atp ( constant ratio of cold / labeled atp 1 / 3000 ). reaction was stopped with edta and the substrate captured on phosphomembrane ( multiscreen 96 well plates from millipore ). after extensive washing , the multiscreen plates were read on a top counter . control ( time zero ) for each atp and histone concentrations was measured . experimental design : reaction velocities are measured at four atp , substrate ( histone ) and inhibitor concentrations . an 80 - point concentration matrix was designed around the respective atp and substrate km values , and the inhibitor ic50 values ( 0 . 3 , 1 , 3 , 9 fold the km or ic50 values ). a preliminary time course experiment in the absence of inhibitor and at the different atp and substrate concentrations allows the selection of a single endpoint time ( 10 min ) in the linear range of the reaction for the ki determination experiment . kinetic parameter estimates : kinetic parameters were estimated by simultaneous nonlinear least - square regression using [ eq . 1 ] ( competitive inhibitor respect to atp , random mechanism ) using the complete data set ( 80 points ): v = vm · a · b α · ka · kb + α · ka · b + a · kb · a + a · b + α · ka ki · i · ( kb + b β ) [ eq . ⁢ 1 ] where a =[ atp ], b =[ substrate ], i =[ inhibitor ], vm = maximum velocity , ka , kb , ki the dissociation constants of atp , substrate and inhibitor respectively . α and β the cooperativity factor between substrate and atp binding and substrate and inhibitor binding respectively . in addition the selected compounds are characterized on a panel of ser / thre kinases strictly related to cell cycle ( cdk2 / cyclin e , cdk1 / cyclin b1 , cdk5 / p25 , cdk4 / cyclin d1 ), and also for specificity on mapk , pka , egfr , igf1 - r , aurora - 2 and cdc 7 kinase reaction : 10 μm in house biotinylated histone h1 ( sigma # h - 5505 ) substrate , 30 μm atp ( 0 . 3 microci p 33 γ - atp ), 4 ng gst - cyclin e / cdk2 complex , inhibitor in a final volume of 30 μl buffer ( tris hcl 10 mm ph 7 . 5 , mgcl 2 10 mm , dtt 7 . 5 mm + 0 . 2 mg / ml bsa ) were added to each well of a 96 u bottom . after incubation for 60 min at room temperature , the reaction was stopped by addition of 100 μl pbs buffer containing 32 mm edta , 500 μm cold atp , 0 . 1 % triton x100 and 10 mg / ml streptavidin coated spa beads . after 20 min incubation , 110 μl of suspension were withdrawn and transferred into 96well optiplates containing 100 μl of 5m cscl . after 4 hours , the plates were read for 2 min in a packard top - count radioactivity reader . kinase reaction : 4 μm in house biotinylated histone h1 ( sigma # h - 5505 ) substrate , 20 μm atp ( 0 . 2 microci p 33 γ - atp ), 3 ng cyclin b / cdk1 complex , inhibitor in a final volume of 30 μl buffer ( tris hcl 10 mm ph 7 . 5 , mgcl 2 10 mm , dtt 7 . 5 mm + 0 . 2 mg / ml bsa ) were added to each well of a 96 u bottom . after 20 min at r . t . incubation , reaction was stopped by 100 μl pbs + 32 mm edta + 0 . 1 % triton x - 100 + 500 μm atp , containing 1 mg spa beads . then a volume of 110 μl is transferred to optiplate . after 20 min . incubation for substrate capture , 100 μl 5m cscl were added to allow statification of beads to the top of the optiplate and let stand 4 hours before radioactivity counting in the top - count instrument . the inhibition assay of cdk5 / p25 activity is performed according to the following protocol . kinase reaction : 10 μm biotinylated histone h1 ( sigma # h - 5505 ) substrate , 30 μm atp ( 0 . 3 microci p33γ - atp ), 15 ng cdk5 / p25 complex , inhibitor in a final volume of 30 μl buffer ( tris hcl 10 mm ph 7 . 5 , mgcl2 10 nm , dtt 7 . 5 mm + 0 . 2 mg / ml bsa ) were added to each well of a 96 u bottom . after incubation for 35 min at room temperature , the reaction was stopped by addition of 100 μl pbs buffer containing 32 mm edta , 500 μm cold atp , 0 . 1 % triton x100 and 10 mg / ml streptavidin coated spa beads . after 20 min incubation , 110 μl of suspension were withdrawn and transferred into 96 - well optiplates containing 100 μl of 5m cscl . after 4 hours , the plates were read for 2 min in a packard top - count radioactivity reader . kinase reaction : 0 , 4 μm μm mouse gst - rb ( 769 - 921 ) (# sc - 4112 from santa cruz ) substrate , 10 μm atp ( 0 . 5 μci p 33 γ - atp ), 100 ng of baculovirus expressed gst - cdk4 / gst - cyclin d1 , suitable concentrations of inhibitor in a final volume of 50 μl buffer ( tris hcl 10 mm ph 7 . 5 , mgcl 2 10 mm , 7 . 5 mm dtt + 0 . 2 mg / ml bsa ) were added to each well of a 96 u bottom well plate . after 40 min at 37 ° c . incubation , reaction was stopped by 20 μl edta 120 mm . capture : 60 μl were transferred from each well to multiscreen plate , to allow substrate binding to phosphocellulose filter . plates were then washed 3 times with 150 μl / well pbs ca ++ / mg ++ free and filtered by multiscreen filtration system . detection : filters were allowed to dry at 37 ° c ., then 100 μl / well scintillant were added and 33 p labeled rb fragment was detected by radioactivity counting in the top - count instrument . kinase reaction : 10 μm in house biotinylated mbp ( sigma # m - 1891 ) substrate , 15 μm atp ( 0 . 15 microci p 33 γ - atp ), 30 ng gst - mapk ( upstate biothecnology # 14 - 173 ), inhibitor in a final volume of 30 μl buffer ( tris hcl 10 mm ph 7 . 5 , mgcl 2 10 mm , dtt 7 . 5 mm + 0 . 2 mg / ml bsa ) were added to each well of a 96 u bottom . after incubation for 35 min at room temperature , the reaction was stopped by addition of 100 μl pbs buffer containing 32 mm edta , 500 μm cold atp , 0 . 1 % triton x100 and 10 mg / ml streptavidin coated spa beads . after 20 min incubation , 110 μl of suspension were withdrawn and transferred into 96 - well optiplates containing 100 μl of 5m cscl . after 4 hours , the plates were read for 2 min in a packard top - count radioactivity reader . kinase reaction : 10 μm in house biotinylated histone h1 ( sigma # h - 5505 ) substrate , 10 μm atp ( 0 . 2 microm p 3 γ - atp ), 0 . 45 u pka ( sigma # 2645 ), inhibitor in a final volume of 30 μl buffer ( tris hcl 10 mm ph 7 . 5 , mgcl 2 10 mm , dtt 7 . 5 mm + 0 . 2 mg / ml bsa ) were added to each well of a 96 u bottom . after incubation for 90 min at room temperature , the reaction was stopped by addition of 100 μl pbs buffer containing 32 mm edta , 500 μm cold atp , 0 . 1 % triton x100 and 10 mg / ml streptavidin coated spa beads . after 20 min incubation , 110 μl of suspension were withdrawn and transferred into 96 - well optlplates containing 100 μl of 5m cscl . after 4 hours , the plates were read for 2 min in a packard top - count radioactivity reader . kinase reaction : 10 μm in house biotinylated mbp ( sigma # m - 1891 ) substrate , 2 μm atp ( 0 . 04 microci p 33 γ - atp ), 36 ng insect cell expressed gst - egfr , inhibitor in a final volume of 30 μl buffer ( hepes 50 mm ph 7 . 5 , mgcl 2 3 mm , mncl 2 3 mm , dtt 1 mm , navo 3 3 μm ,+ 0 . 2 mg / ml bsa ) were added to each well of a 96 u bottom . after incubation for 20 min at room temperature , the reaction was stopped by addition of 100 μl pbs buffer containing 32 mm edta , 500 μm cold atp , 0 . 1 % triton x100 and 10 mg / ml streptavidin coated spa beads . after 20 min incubation , 110 μl of suspension were withdrawn and transferred into 96 - well optiplates containing 100 μl of 5m cscl . after 4 hours , the plates were read for 2 min in a packard top - count radioactivity reader . the inhibition assay of igf1 - r activity is performed according to the following protocol . enzyme activation : igf1 - r must be activated by auto - phosphorylation before starting the experiment . just prior to the assay , a concentrated enzyme solution ( 694 nm ) is incubated for half a hour at 28 ° c . in the presence of 100 μm atp and then brought to the working dilution in the indicated buffer . kinase reaction : 10 μm biotinylated irs1 peptide ( primm ) substrate , 0 - 20 μm inhibitor , 6 μm atp , 1 microci 33 p - atp , and 6 nm gst - igf1 - r ( pre - incubated for 30 min at room temperature with cold 60 μm cold atp ) in a final volume of 30 μl buffer ( 50 mm hepes ph 7 . 9 , 3 mm mncl 2 , 1 mm dtt , 3 μl navo 3 ) were added to each well of a 96 u bottom well plate . after incubation for 35 min at room temperature , the reaction was stopped by addition of 100 μl pbs buffer containing 32 mm edta , 500 μm cold atp , 0 . 1 % triton x100 and 10 mg / ml streptavidin coated spa beads . after 20 min incubation , 110 μl of suspension were withdrawn and transferred into 96 - well optiplates containing 100 μl of 5m cscl . after 4 hours , the plates were read for 2 min in a packard top - count radioactivity reader . kinase reaction : 8 μm biotinylated peptide ( 4 repeats of lrrwslg ), 10 μm atp ( 0 . 5 uci p 33 γ - atp ), 7 . 5 ng aurora 2 , inhibitor in a final volume of 30 μl buffer ( hepes 50 mm ph 7 . 0 , mgcl 2 10 mm , 1 mm dtt , 0 . 2 mg / ml bsa , 3 μm orthovanadate ) were added to each well of a 96 u bottom well plate . after 60 minutes at room temperature incubation , reaction was stopped and biotinylated peptide captured by adding 100 μl of bead suspension . stratification : 100 μl of cscl2 5 m were added to each well and let stand 4 hour before radioactivity was counted in the top - count instrument . the inhibition assay of cdc7 / dbf4 activity is performed according to the following protocol . the biotin - mcm2 substrate is trans - phosphorylated by the cdc7 / dbf4 complex in the presence of atp traced with γ 33 - atp . the phosphorylated biotin - mcm2 substrate is then captured by streptavidin - coated spa beads and the extent of phosphorylation evaluated by β counting . the inhibition assay of cdc7 / dbf4 activity was performed in 96 wells plate according to the following protocol . 10 μl substrate ( biotinylated mcm2 , 6 μm final concentration ) 10 μl enzyme ( cdc7 / dbf4 , 17 . 9 nm final concentration ) 10 μl test compound ( 12 increasing concentrations in the nm to μm range to generate a dose - response curve ) 10 μl of a mixture of cold atp ( 2 μm final concentration ) and radioactive atp ( 1 / 5000 molar ratio with cold atp ) was then used to start the reaction which was allowed to take place at 37 ° c . substrate , enzyme and atp were diluted in 50 mm hepes ph 7 . 9 containing 15 mm mgcl 2 , 2 mm dtt , 3 μm navo 3 , 2 mm glycerophosphate and 0 . 2 mg / ml bsa . the solvent for test compounds also contained 10 % dmso . after incubation for 60 minutes , the reaction was stopped by adding to each well 100 μl of pbs ph 7 . 4 containing 50 mm edta , 1 mm cold atp , 0 . 1 % triton x100 and 10 mg / ml streptavidin coated spa beads . after 20 min incubation , 110 μl of suspension were withdrawn and transferred into 96 - well optiplates containing 100 μl of 5m cscl . after 4 hours , the plates were read for 2 min in a packard top - count radioactivity reader . the compounds of formula ( i ) of the present invention , suitable for administration to a mammal , e . g . to humans , can be administered by the usual routes and the dosage level depends upon the age , weight , conditions of the patient and the administration route . for example , a suitable dosage adopted for oral administration of a compound of formula ( i ) may range from about 10 to about 500 mg pro dose , from 1 to 5 times daily . the compounds of the invention can be administered in a variety of dosage forms , e . g . orally , in the form of tablets , capsules , sugar or film coated tablets , liquid solutions or suspensions ; rectally in the form of suppositories ; parenterally , e . g . intramuscularly , or by intravenous and / or intrathecal and / or intraspinal injection or infusion . in addition , the compounds of the invention can be administered either as single agents or , alternatively , ill combination with known anticancer treatments such as radiation therapy or chemotherapy regimen in combination with cytostatic or cytotoxic agents , antibiotic - type agents , alkylating agents , antimetabolite agents , hormonal agents , immunological agents , interferon - type agents , cyclooxygenase inhibitors ( e . g . cox - 2 inhibitors ), metallomatrixprotease inhibitors , telomerase inhibitors , tyrosine kinase inhibitors , anti - growth factor receptor agents , anti - her agents , anti - egfr agents , anti - angiogenesis agents , farnesyl transferase inhibitors , ras - raf signal transduction pathway inhibitors , cell cycle inhibitors , other cdks inhibitors , tubulin binding agents , topoisomerase i inhibitors , topoisomerase ii inhibitors , and the like . as an example , the compounds of the invention can be administered in combination with one or more chemotherapeutic agents such as , for instance , exemestane , formestane , anastrozole , letrozole , fadrozole , taxane , taxane derivatives , encapsulated taxanes , cpt - 11 , camptothecin derivatives , anthracycline glycosides , e . g ., doxorubicin , idarubicin , epirubicin , etoposide , navelbine , vinblastine , carboplatin , cisplatin , estramustine , celecoxib , tamoxifen , raloxifen , sugen su - 5416 , sugen su - 6668 , herceptin , and the like , optionally within liposomal formulations thereof . if formulated as a fixed dose , such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent within the approved dosage range . compounds of formula ( i ) may be used sequentially with known anticancer agents when a combination formulation is inappropriate . it is therefore a further object of the invention a product or kit comprising the compound of formula ( i ) of the invention and one or more chemotherapeutic agents for simultaneous , separate or sequential use in anticancer therapy or for the treatment of cell proliferative disorders . the present invention also includes pharmaceutical compositions comprising an effective amount of a compound of formula ( i ) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient , carrier or diluent . the pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form . for example , the solid oral forms may contain , together with the active compound , diluents , e . g . lactose , dextrose , saccharose , sucrose , cellulose , corn starch or potato starch ; lubricants , e . g . silica , talc , stearic , magnesium or calcium stearate , and / or polyethylene glycols ; binding agents , e . g . starches , arabic gum , gelatine , methylcellulose , carboxymethylcellulose or polyvinyl pyrrolidone ; disaggregating agents , e . g . a starch , alginic , alginates or sodium starch glycolate ; effervescing mixtures ; dyestuffs ; sweeteners ; wetting agents such as lecithin , polysorbates , laurylsulphates ; and , in general , non - toxic and pharmacologically inactive substances used in pharmaceutical formulations . said pharmaceutical preparations may be manufactured in known manner , for example , by means of mixing , granulating , tabletting , sugar - coating , or film - coating processes . the liquid dispersions for oral administration may be . e . g . syrups , emulsions and suspensions . the syrups may contain as carrier , for example , saccharose or saccharose with glycerine and / or mannitol and / or sorbitol . the suspensions and the emulsions may contain as carrier , for example , a natural gum , agar , sodium alginate , pectin , methylcellulose , carboxymethylcellulose , or polyvinyl alcohol . the suspension or solutions for intramuscular injections may contain , together with the active compound , a pharmaceutically acceptable carrier , e . g . sterile water , olive oil , ethyl oleate , glycols , e . g . propylene glycol , and , if desired , a suitable amount of lidocaine hydrochloride . the solutions for intravenous injections or infusions may contain as carrier , for example , sterile water or preferably they may be in the form of sterile , aqueous , isotonic saline solutions or they may contain as a carrier propylene glycol . the suppositories may contain together with the active compound a pharmaceutically acceptable carrier , e . g . cocoa butter , polyethylene glycol , a polyoxyethylene sorbitan fatty ester surfactant or lecithin . hewlett packard 1312a binary pump gilson 215 autosampler fitted with a 1 ml syringe polymer labs pl1000 evaporative light scattering detector micromass zmd mass spectrometer operating in electrospray positive ionisation mode . the lc eluent is split and approximately 200 μl / min enters the mass spectrometer , 800 μl / min to the els . the instruments are currently controlled using micromass masslynx 3 . 5 software under windows nt4 . 0 mobile phase : aqueous - water + 0 . 1 % trifluoroacetic acid organic - acetonitrile + 0 . 1 % trifluoroacetic acid gradient : time ( mins ) % aqueous % organic 0 . 0 100 0 1 . 8 5 95 2 . 1 5 95 2 . 3 100 0 2 . 4 100 0 run time : 2 . 4 mins flow rate : 1 ml / min injection vol : 3 μl column temperature : ambient ( 20 ° c .) column : 50 × 2 . 0 mm hypersil c18 bds ; 5 μm els detector nebuliser temperature 8 ° c . evaporation temperature 9 ° c . gas flow 1 . 5 l / hr ms detector m / z 150 - 800 @ 0 . 5 secs / scan , 0 . 1 second interscan delay cone voltage 25 v , source temp . 140 ° c . drying gas 350 l / hr as formerly indicated , several compounds of formula ( i ) of the invention have been synthesized in parallel , according to combinatorial chemistry techniques . in this respect , some compounds thus prepared have been conveniently and unambiguously identified , as per the coding system of tables i - iii , together with hplc retention time and mass . each code , which identifies a single specific compound of formula ( i ), consists of three units a - m - b . a represents any substituent r -[ see formula ( i )] and is directly attached to the rest of the pyrrolopyrazole moiety so as to get pyrrolopyrazole derivatives being substituted in position 3 ( a - m - b ); each a radical ( substituent ) is represented in the following table i . b represents any substituent r 1 -[ see formula ( i )] and is attached to the rest of the pyrrolopyrazole moiety through the nitrogen atom so as to get pyrrolopyrazole derivatives being substituted in position 5 ( a - m - b ); each b radical ( substituent ) is represented in the following table ii . m refers to the central core of the divalent pyrrolopyrazole moiety and is substituted by groups a and b . for ease of reference , each a or b groups of tables i and ii has been identified with the proper chemical formula also indicating the point of attachment with the rest of the molecule m . just as an example , the compound a7 - m - b30 of table iii ( see entry 133 ) represents a pyrrolopyrazole m being substituted in position 3 ( direct bond ) by the group a7 and in position 5 ( through the — n — group ) by the group b30 . table i a group code fragment a1 a2 a3 a4 a5 a6 a7 a8 a9 a10 a11 a12 a13 a14 a15 a16 a17 a18 a19 a20 a21 a22 a23 a24 a25 a26 a27 a28 a29 a30 preparation of 5 - tert - butyloxycarbonyl - 1 - ethoxycarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r ═ h , r 1 = t - butyloxycarbonyl ( boc ), r 2 = ethoxycarbonyl ). a solution of 3 - amino - 5 - tert - butyloxycarbonyl - 1 - ethoxycarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( 0 . 4 g , 1 . 35 mmol ) in dry tetrahydrofurane ( 10 ml ) was added drop wise to a solution of isoamylnitrite ( 0 . 32 ml , 2 . 36 mmol ) in dry tetrahydrofurane ( 2 ml ) maintained at reflux . the resulting solution was stirred at reflux for 4 hours , and then cooled to room temperature . after removal of the solvent under vacuum , the crude material was purified by flash chromatography on silica gel using n - hexane ÷ ethyl acetate 90 ÷ 10 ; 70 ÷ 30 . the title compound was obtained as a light yellow oil ( 200 mg , y 53 %). 1 h - nmr ( dmso - d 6 ) δ ppm : 7 . 67 ( s , 1h ); 4 . 54 ( m , 2h ); 4 . 39 ( q , 2h ); 4 . 32 ( m , 2h ); 1 . 43 ( s , 9h ); 1 . 31 ( t , 3h ). operating in an analogous way , the following compound was also obtained 5 - tert - butyloxycarbonyl - 2 - ethoxycarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole 1 h - nmr ( dmso - d 6 ) δ ppm : 8 . 05 ( s , 1h ); 4 . 39 ( q , 2h ); 4 . 37 ( m , 4h ); 1 . 43 ( s , 9h ); 1 . 31 ( t , 3h ). preparation of 5 - tert - butyloxycarbonyl - 1 ( 2 ) h - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r 1 ═ h , r 1 = t - butyloxycarbonyl ( boc ), r 2 ═ h ). 5 - tert - butyloxycarbonyl - 1 - ethoxycarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( 1 . 5 g , 5 . 3 mmol ) was treated with a solution of 10 % triethylamine in methanol ( 74 ml ) at room temperature for about 20 hours . after removal of the solvents under vacuum , the crude material was dissolved with chloroform ( 30 ml ) and washed with water ( 20 ml × 2 ), brine ( 20 ml ), dried over sodium sulphate , filtered and evaporated to dryness . the title compound was obtained as a beige powder ( 1 . 08 g , yield 97 %). 1 h - nmr ( dmso - d 6 ) δ ppm : 12 . 63 ( s , 1h ); 7 . 47 ( s , 1h ); 4 . 31 ( m , 4h ); 1 . 42 ( s , 9h ). 3 - iodo - 5 - t - butyloxycarbonyl - 1 ( 2 ) h - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r ═ i , r 1 = t - butyloxycarbonyl , r 2 ═ h ). 1 h - nmr ( cdcl 3 ) δ ppm : 11 . 00 ( 1h , br . s ), 4 . 60 - 4 . 26 ( 4h , m ), 1 . 46 ( 9h , s ) 3 - iodo - 5 - isopropylaminocarbonyl - 1 ( 2 ) h - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r ═ i , r 1 = 3 - isopropylaminocarbonyl , r 2 ═ h ). 1 h - nmr ( dmso - d 6 ) δ ppm : 13 . 03 ( s , 1h ); 5 . 63 ( s , 1h ); 4 . 18 ( m , 4h ); 3 . 78 ( m , 1h ); 1 . 07 ( d , 6h ). preparation of 5 - tert - butyloxycarbonyl - 1 -( 2 - trimethylsilanyl - ethyloxymethyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole and 5 - tert - butyloxycarbonyl - 2 -( 2 - trimethylsilanyl - ethyloxymethyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r ═ h , r 1 ═ t - butyloxycarbonyl ( boc ), r 2 = trimethylsilanyl - ethoxymethyl ( sem )). a solution of 5 - tert - butyloxycarbonyl - 1 ( 2 ) h - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( 0 . 7 g , 3 . 35 mmol ) in dry tetrahydrofurane ( 3 ml ) was added dropwise to a suspension of 60 % sodium hydride ( 0 . 147 g , 3 . 68 mmol ) in dry tetrahydrofurane ( 2 ml ), maintained at room temperature under an argon atmosphere . after 1 hour , the mixture was cooled to 0 ° c . and added with a solution of trimethylsilylethyloxymethyl chloride ( semcl , 0 . 651 ml , 3 . 68 mmol ) in dry tetrahydrofurane ( 2 ml ). the reaction mixture was then allowed to warm to room temperature and stirring was continued for about 20 hours . after addition of water ( 10 ml ), the mixture was extracted with ethyl acetate ( 15 ml × 4 ). the organic layers were combined , dried over sodium sulphate , filtered and evaporated to dryness under vacuum . the crude material was purified by flash chromatography on silica gel , using cyclohexane : ethyl acetate 80 : 20 as eluent to yield the title compound ( yellow oil , 0 . 85 g , 75 % yield ) as a mixture of 1 - sem and 2 - sem regioisomers ( 30 : 70 ), which were used without being separated . 1 h - nm ( dmso - d 6 ) δ ppm : 7 . 7 ( s , 1h ); 7 . 32 ( s , 1h ); 5 . 34 ( s , 1h ); 5 . 33 ( s , 1h ); 4 . 4 ( m , 4h ); 4 . 29 ( m , 4h ); 3 . 48 ( m , 2 × 2h ); 1 . 42 ( s , 2 × 9h ); 0 . 81 ( m , 2 × 2h ); − 0 . 06 ( m , 2 × 9h ). preparation of 3 - boronic acid - 5 - tert - butyloxycarbonyl - 1 -( 2 - trimethylsilanyl - ethoxymethyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole and 3 - boronic acid - 5 - tert - butyloxycarbonyl - 2 -( 2 - trimethylsilanyl - ethoxymethyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r ═ b ( oh ) 2 , r 1 = t - butyloxycarbonyl ( boc ), r 2 = trimethylsilanyl - ethoxymethyl ( sem )). n - buthyllithium ( 1 . 6m in n - hexane , 0 . 75 ml , 1 . 2 mmol ) was slowly added to a solution of the mixture of 5 - tert - butyloxycarbonyl - 1 -( and 2 )-( 2 - trimethylsilanyl - ethoxymethyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole regioisomers ( 0 . 339 g , 1 mmol ) in dry tetrahydrofurane ( 4 ml ), maintained under stirring at − 7 ° c ., under an argon atmosphere . after 30 minutes , triisopropyl borate ( 1 . 15 ml , 5 mmol ) was added dropwise , while keeping the temperature at − 78 ° c . the reaction mixture was allowed to spontaneously warm to room temperature and stirring was continued for about 4 . 5 hours before quenching with 2n hcl to ph6 ; water ( 5 ml ) was added and the mixture was extracted 15 with ethyl acetate ( 15 ml × 4 ). the organic layers were combined , washed with brine , dried over sodium sulphate , filtered and dried under vacuum to yield the title compound ( light orange oil which solidifies on standing , 350 mg ) as a mixture of 1 - sem and 2 - sem regioisomers , which was used without any further purification . 1 h - nmr ( dmso - d 6 ) δ ppm : 8 . 3 ( m , 2h ); 7 . 65 ( m , 2h ); 5 . 54 ( s , 1h ); 5 . 34 ( s , 1h ); 4 . 4 - 4 . 3 ( m , 2 × 4h ); 3 . 6 - 3 . 4 ( m , 2 × 2h ); 1 . 43 ( s , 2 × 9h ); 0 . 6 ( m , 2 × 2h ); − 0 . 06 -− 0 . 07 ( m , 2 × 9h ). preparation of 5 - tert - butyloxycarbonyl - 3 - phenyl - 1 -( 2 - trimethylsilanyl - ethoxymethyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r = ph , r 1 = t - butyloxycarbonyl ( boc ), r 2 = trimethylsilanyl - ethoxymethyl ( sem )) . a mixture of 3 - boronic acid - 5 - tert - butyloxycarbonyl - 1 -( 2 - trimethylsilanyl - ethoxymethyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( 70 %, 0 . 060 g , 0 . 16 mmol ), iodobenzene ( 0 . 005 ml , 0 . 044 mmol ), sodium carbonate ( 0 . 055 g , 0 . 52 mmol ) and palladium ( 0 ) tetrakis ( 2 mg , 5 %) in water ( 0 . 16 ml )- dimethoxyethane ( 1 ml ) was heated under an argon atmosphere at 80 ° c . for about 6 hours . the mixture was diluted with ethyl acetate ( 5 ml ), washed with water ( 3 ml ), brine ( 3 ml ), dried over sodium sulphate , filtered and evaporated to dryness . the crude material was purified by flash chromatography to yield the title compound as a light yellow solid ( 20 mg ). preparation of 1 - ethoxycarbonyl - 5 -( 3 - methylbutanoyl )- 3 - iodo - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r = iodo , r 1 = 3 - methylbutanoyl , r 2 = 1 - ethoxycarbonyl ). a solution of 5 - tert - butyloxycarbonyl - 1 - ethoxycarbonyl - 3 - iodo - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( 0 . 7 g , 1 . 72 mmol ) in dichloromethane ( 40 ml ) was treated with trifluoroacetic acid ( 9 ml ) at room temperature for about 4 hours . after removal of the solvents , the crude salt was dissolved with dry tetrahydrofurane ( 40 ml ) and added with diisopropyl ethyl amine ( 1 . 47 ml , 8 . 6 mmol ) and isovaleroyl chloride ( 0 . 23 ml , 1 . 89 ml ) diluted with dry tetrahydrofurane ( 2 ml ). the reaction mixture was stirred at room temperature for about 20 hours ; the solvent was evaporated under vacuum and the crude material was dissolved with dichloromethane ( 25 ml ), washed with water ( 15 ml ), brine ( 15 ml ), dried over sodium sulphate , filtered and dried under vacuum to yield the title compound as a light brown solid which was used without any further purification ( 0 . 65 g , yield 96 %). 1 h - nmr ( dmso - d 6 ) δ ppm : 4 . 5 ( m , 2h ); . 4 . 38 ( m , 2h ); 4 . 25 ( m , 2h ); 2 . 18 ( m , 2h ) 1 . 32 ( m , 3h ); 0 . 92 ( m , 6h ). operating in an analogous way , the following compounds are also obtained : 1 - ethoxycarbonyl - 3 - iodo - 5 - isopropylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole 1 h - nmr ( dmso - d 6 ) δ ppm : 6 . 07 ( m , 1h ); 4 . 59 ( m , 2h ); 4 . 38 ( m , 2h ); 4 . 21 ( m , 2h ); 3 . 78 ( m , 1h ); 1 . 32 ( m , 3h ); 1 . 08 ( m , 6h ). preparation of 5 - isopropylaminocarbonyl - 3 -( pyrrol - 2 - yl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r = pyrrol - 2 - yl , r 1 = 3 - isopropylaminocarbonyl , r 2 ═ h ). a mixture of 3 - iodo - 5 - isopropylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( 0 . 15 g , 0 . 38 mmol ), 1 - tert - butyloxycarbonyl - pyrrole - 2 - boronic acid ( 0 . 191 g , 0 . 95 mmol ), 2m potassium phosphate in water ( 1 ml ) and palladium ( 0 ) tetrakis ( 22 mg , 5 %) in dimethoxyethane ( 4 ml ) was heated under an argon atmosphere at 80 ° c . for about 7 hours . the mixture was diluted with ethyl acetate ( 8 ml ), washed with water ( 5 ml ), brine ( 5 ml ), dried over sodium sulphate , filtered and evaporated to dryness . the crude material was purified by flash chromatography , using dichloromethane : methanol 95 : 5 as eluent to yield the title compound as a light yellow solid ( 17 mg ). 1 h - nmr ( dmso - d 6 ) δ ppm : 6 . 82 - 6 . 10 ( m , 3h ); 5 . 86 ( d , 1h ); 4 . 42 ( m , 4h ); 3 . 79 ( m , 1h ); 1 . 10 ( m , 6h ). operating in an analogous way , the following compounds were also obtained : using 2m caesium carbonate as a base : 5 - tert - butyloxycarbonyl - 3 -( 1 - tert - butyloxycarbonyl - pyrrol - 2 - yl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r = 1 - tert - butyloxycarbonyl - pyrrol - 2 - yl , r 1 = tert - butyloxycarbonyl r 2 ═ h ). 5 - tert - butyloxycarbonyl - 3 -( 1 - tert - butyloxycarbonyl - indol - 2 - yl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r = 1 - tert - butyloxycarbonyl - indol - 2 - yl , r 1 = tert - butyloxycarbonyl , r 2 ═ h ); 3 -( 1 - tert - butyloxycarbonyl - indol - 2 - yl )- 5 ( 3 - methylbutanoyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r = 1 - tert - butyloxycarbonyl - indol - 2 - yl , r 1 = 3 - methylbutanoyl , r 2 h ). 1 h - nmr ( dmso - d 6 ) δ ppm : 12 . 94 ( s , 1h ); 7 . 47 ( m , 4h ); 6 . 91 ( s , 1h ); 4 . 61 ( m , 4h ); 2 . 18 ( m , 2h ); 2 . 05 ( m , 1h ); 1 . 42 ( s , 9h ); 0 . 91 ( m , 6h ). using potassium carbonate as a base and a mixture of toluene : ethanol : water 2 : 1 : 1 as solvent : 5 - tert - butyloxycarbonyl - 3 -( 4 - methoxyphenyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r = 4 - methoxyphenyl , r 1 = t - buthoxycarbonyl , r 2 ═ h ). 1 h nmr ( cdcl 3 ) δ ppm : 7 . 4 - 7 . 31 ( 2h , m ), 6 . 95 - 6 . 89 ( 2h , m ), 4 . 50 - 4 . 31 ( 4h , m ), 3 . 78 ( 3br . s ), 1 . 48 ( 9h , br . s ) preparation of 3 -( indol - 2 - yl )- 5 -( 3 - methylbutanoyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r = indol - 2 - yl , r 1 = 3 - methylbutanoyl , r 2 ═ h ). a solution of 3 -( 1 - tert - butyloxycarbonyl - indol - 2 - yl )- 5 -( 3 - methylbutanoyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( 0 . 2 g , 0 . 49 mmol ) in dichloromethane ( 3 . 5 ml ) was treated with trifluoroacetic acid ( 0 . 74 ml ), at room temperature for about 24 hours . after removal of the solvents under vacuum , the mixture was diluted with dichloromethane ( 15 ml ), washed with saturated sodium bicarbonate , dried over sodium sulphate , filtered and evaporated to dryness . the crude material was purified by flash chromatography , using dichloromethane : methanol 95 : 5 , 90 : 10 to yield the title compound as beige solid ( 0 . 1 g , 65 %). 1 h - nmr ( dmso - d 6 ) δ ppm : 13 . 05 ( s , 1h ); 11 . 22 ( bs , 1h ); 7 . 47 ( m , 2h ); 6 . 99 ( m , 2h ); 6 . 72 ( bs , 1h ); 4 . 80 ( m , 4h ); 2 . 27 ( m , 2h ); 2 . 1 1 ( m , 1h ); 0 . 95 ( m , 6h ). operating in an analogous way , the following compound was also obtained 3 -( 1 - h - indol - 2 - yl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r = indol - 2 - yl , r 1 ═ h , r 2 ═ h ). 1 h - nmr ( dmso - d 6 ) δ ppm : 12 . 71 ( bs , 1h ); 11 . 08 ( bs , 1h ); 6 . 97 ( m , 2h ); 6 . 72 ( s , 1h ); 6 . 60 ( bs , 1h ); 6 . 72 ( bs , 1h ); 4 . 07 - 3 . 89 ( m , 4h ). preparation of 5 - tert - butyloxycarbonyl - 1 - ethoxycarbonyl - 3 - iodo - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r = iodo , r 1 = t - butyloxycarbonyl ( boc ), r 2 = ethoxycarbonyl ). isoamyl nitrite ( 18 . 2 ml , 135 . 2 mmol ) was slowly added to a mixture of iodine ( 20 . 58 g , 81 . 11 mmol ) in 145 ml of anhydrous dichloromethane , at + 22 ° c . to this dark mixture a solution of 5 - tert - butyloxycarbonyl - 1 - ethoxycarbonyl - 3 - amino - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( 20 . 03 g , 67 . 6 mmol ) in 140 ml of dichloromethane was added dropwise over 100 min at + 22 ° c . the internal temperature rose to + 28 ° c . and gas evolved during the addition . after 1 hour stirring at room temperature , the reaction mixture was slowly poured in 800 ml of 10 % sodium metabisulfite . the phases were separated and the aqueous was extracted twice with 300 ml dichloromethane . the combined extracts were dried over anhydrous sodium sulfate and the solvent evaporated 25 under vacuum . this raw material was purified by flash chromatography eluting with 20 : 80 etoac / cyclohexane . a light yellow product ( 25 . 5 g ) was obtained which was finally purified with mtbe ( 60 ml ) and n - hexane ( 60 ml ): 21 . 8 g of high purity , white product was isolated ( 79 % yield ). m . p . 166 - 168 ° c . 1 h - nm ( dmso - d 6 ) δ ppm : 4 . 58 ( m , 2h ); 4 . 38 ( q , 2h ); 4 . 24 ( m , 2h ); 1 . 43 ( s , 9h ); 1 . 32 ( t , 3h ). preparation of 5 - tert - butyloxycarbonyl - 3 - iodo - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h . r = iodo , r 1 = t - butyloxycarbonyl ( boc ), r 2 ═ h ). 1 - ethoxycarbonyl - 3 - iodo - 5 - tert - butyloxycarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( 270 mg , 0 . 66 mmol ) was stirred with a mixture of meoh ( 2 ml ) and triethylamine ( 0 . 5 ml ) at room temperature for about 30 min . the solvents were evaporated and the compound was dried under vacuum . white solid ( 220 mg ). preparation of 5 - tert - butyloxycarbonyl - 3 - phenyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r = phenyl , r 1 = t - butyloxycarbonyl ( boc ), r 2 ═ h ). a mixture of 5 - tert - butyloxycarbonyl - 1 - ethoxycarbonyl - 3 - iodo - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( 60 mg , 0 . 15 mmol ), phenylboronic acid ( 22 mg , 0 . 18 mmol ), potassium carbonate ( 31 mg , 0 . 22 mmol ), triethylamine ( ml 0 . 03 , 0 . 22 mmol ) and palladiumdichloride - diphenylphosphine ( 8 mg , 7 %) in dioxan / water 10 / 1 ( 2 ml ) was heated under argon atmosphere at 80 ° c . for about 3 hours . the mixture was diluted with ethyl acetate ( 8 ml ), washed with water ( 5 ml ), brine ( 5 ml ), dried over sodium sulphate , filtered and evaporated to dryness . the crude material was purified by flash chromatography , using ethylacetate / hexane as eluent to yield the title compound as a light yellow solid ( 27 mg 63 %). preparation of 5 - acetyl - 3 - phenyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r = phenyl , r 1 = acetyl , r 2 ═ h ). a solution of 5 - tert - butyloxycarbonyl - 3 - phenyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( 90 mg , 0 . 31 mmol ) in dichloromethane ( 3 . 5 ml ) was treated with trifluoroacetic acid ( 0 . 5 ml ), at room temperature for about 4 hours . after removal of the solvents , the crude salt was dissolved with dry dichloromethane ( 5 ml ) and diisopropylethylamine ( 0 . 32 ml , 1 . 86 mmol ) and acetyl chloride ( 0 . 07 ml , 0 . 9 mmol ) were added . the reaction mixture was stirred at room temperature for about 2 hours ; the crude material was diluted with dichloromethane ( 25 ml ), washed with water ( 15 ml ), brine ( 15 ml ), dried over sodium sulphate , filtered and dried under vacuum . the crude was suspended in a solution of sodium bicarbonate and stirred at room temperature for about 3 hours , then extracted with ethylacetate to yield the title compound as a light brown solid ( 40 mg ). preparation of 5 - tert - butyloxycarbonyl - 3 - iodo - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = iodo , r 1 = t - butyloxycarbonyl ( boc ), q = polystyrenemethylaminocarbonyl ). the isocyanate methylpolystyrene resin ( 1 . 14 g , 1 , 71 mmol ) was swelled with 15 ml of dichloromethane , and a solution of 5 - tert - butyloxycarbonyl - 3 - iodo - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( 410 mg , 1 . 22 mmol ) in 3 ml of dimethylformamide was added . the mixture was stirred at room temperature for about 24 hours ; after filtration ; the resin was washed with dichloromethane ( 2 × 20 ml ), meoh ( 2 × 20 ml ), dimethylformamide ( 2 × 20 ml ) and dichloromethane ( 3 × 20 ml ). operating in an analogous way , the following compound was also obtained 5 - tert - butyloxycarbonyl - 3 -( 4methoxyphenyl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii r a ═ r b ═ r c ═ r d ═ h , r = 4 - methoxyphenyl , r 1 = t - butyloxycarbonyl ( boc ), q = polystyrenemethylaminocarbonyl ). preparation of 5 - tert - butyloxycarbonyl - 3 - phenyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = phenyl , r 1 = t - butyloxycarbonyl ( boc ), q = polystyrenemethylaminocarbonyl ). to a suspension of 5 - tert - butyloxycarbonyl - 3 - iodo - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( 117 mg , 0 . 17 mmol ) in dioxan / water 10 / 1 ( 3 ml ), phenylboronic acid ( 108 mg , 0 . 88 mmol ), potassium carbonate ( 171 mg , 0 . 8 mmol ), triethylamine ( 0 . 18 ml , 0 . 8 mmol ) and palladiumdichloride diphenylphosphine ( 25 mg , 20 %) were added . the mixture was stirred at 80 ° c . for about 8 hours ; after filtration , the resin was washed with dichloromethane ( 2 × 20 ml ), meoh ( 2 × 20 ml ), dimethylformamide ( 2 × 20 ml ) and dichloromethane ( 3 × 20 ml ). operating in an analogous way , using a suitable boronic acid , the following compounds were also obtained : 5 - tert - butyloxycarbonyl - 3 -( 4 - phenoxy - phenyl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 4 - phenoxy - phenyl , r 1 = t - butyloxycarbonyl ( boc ), q = polystyrenemethylaminocarbonyl ); 3 -( 4benzyloxy - phenyl )- 5 - tert - butyloxycarbonyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( m , r a ═ r b ═ r c ═ r d ═ h , r = 4 - benzyloxy - phenyl , r 1 = t - butyloxycarbonyl ( boc ), q = polystyrenemethylaminocarbonyl ); 5 - tert - butyloxycarbonyl - 3 -( 5 - chloro - thiophen - 2 - yl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 5 - chloro - thiophen - 2 - yl , r 1 - t - butyloxycarbonyl ( boc ), q = polystyrenemethylaminocarbonyl ); 5 - tert - butyloxycarbonyl - 3 -( 4 - methoxy - phenyl ) 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 4 - methoxy - phenyl , r 1 = t - butyloxycarbonyl ( boc ), q = polystyrenemethylaminocarbonyl ) and 5 - tert - butyloxycarbonyl - 3 -( 4 - dimethylamino - phenyl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 4 - dimethylamino - phenyl , r 1 = t - butyloxycarbonyl ( boc ), q = polystyrenemethylaminocarbonyl ). preparation of 5 - tert - butyloxycarbonyl - 3 - phenylethynyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r = phenylethynyl , r 1 = t - butyloxycarbonyl ( boc ), q = polystyrenemethylaminocarbonyl ). to a suspension of 5 - tert - butyloxycarbonyl - 3 - iodo - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( 200 mg , 0 . 21 mmol ) in dioxan ( 2 ml ), phenylethyne ( 0 . 23 ml , 2 mmol ), cui ( 20 mg , 50 %), triethylamine ( 0 . 12 ml , 1 . 5 mmol ) and palladiumdichloride diphenylphosphine ( 29 mg , 20 %) were added . the mixture was stirred at 80 ° c . for about 8 hours ; after filtration , the resin was washed with dichlorometane ( 2 × 20 ml ), meoh ( 2 × 20 ml ), dimethylformamide ( 2 × 20 ml ) and with dichloromethane ( 3 × 20 ml ). preparation of 3 - phenyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = phenyl , r 1 ═ h , q = polystyrenemethylaminocarbonyl ). to 5 - tert - butyloxycarbonyl - 3 - phenyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole swelled in dichloromethane ( 5 ml ) trifluoroacetic acid ( 1 ml ) was added . the mixture was stirred at room temperature for about 4 hours , after filtration , the resin was washed with dichlorometane ( 2 × 20 ml ), meoh ( 2 × 20 ml ), dimethylformamide ( 2 × 20 ml ) and dichloromethane ( 3 × 20 ml ). operating in an analogous way , the following compounds were also obtained : 3 -( 4 - phenoxy - phenyl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = phenyl , r 1 ═ h , q = polystyrenemethylaminocarbonyl ); 3 -( 4 - benzyloxy - phenyl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 4 - benzyloxyphenyl , r 1 ═ h , q = polystyrenemethylaminocarbonyl ); 3 -( 5 - chloro - thiophen - 2 - yl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydro - pyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 5 - chloro - thiophen - 2 - yl , r 1 ═ h , q = polystyrenemethylaminocarbonyl ); 3 -( 4 - methoxy - phenyl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 4 - methoxyphenyl , r 1 ═ h , q = polystyrenemethylaminocarbonyl ); 3 -( 4dimethylamino - phenyl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 4 - dimethylaminophenyl , r 1 ═ h , q = polystyrenemethylaminocarbonyl ); 3 - phenylethynyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = phenylethynyl , r 1 ═ h , q = polystyrenemethylaminocarbonyl ) and 3 -( 4 - methoxyphenyl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 4 - methoxyphenyl , r 1 ═ h , q = polystyrenemethylaminocarbonyl ). preparation of 5 - acetyl - 3 - phenyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = phenyl , r 1 = acetyl , q = polystyrenemethylaminocarbonyl ). to 3 - phenyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole swelled in dichloromethane ( 5 ml ) diisopropylethylamine ( 0 . 21 ml , 1 . 24 mmol ) and acetylchloride ( 0 . 06 ml . 0 . 88 mmol ) were added . the mixture was stirred at room temperature for about 24 hours ; after filtration , the resin was washed with dichlorometane ( 2 × 20 ml ), meoh ( 2 × 20 ml ), dimethylformamide ( 2 × 20 ml ) and dichloromethane ( 3 × 20 ml ). the resin was dried under vacuum . operating in an analogous way , the following compounds were also obtained : 5 - acetyl - 3 -( 4 - phenoxy - phenyl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 4 - phenoxyphenyl , r 1 = acetyl , q = polystyrenemethylaminocarbonyl ); 5 - acetyl - 3 -( 4 - benzyloxy - phenyl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 4 - benzyloxyphenyl , r 1 = acetyl , q = polystyrenemethylaminocarbonyl ); 5 - acetyl - 3 -( 5 - chloro - thiophen - 2 - yl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 5 - chloro - thiophen - 2 - yl , r 1 = acetyl , q = polystyrenemethylaminocarbonyl ); 5 - acetyl - 3 -( 4 - methoxy - phenyl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii r a ═ r b ═ r c ═ r d ═ h , r = 4 - methoxyoxyphenyl , r 1 = acetyl , q = polystyrenemethylaminocarbonyl ); 5 - acetyl - 3 -( 4 - dimethylamino - phenyl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 4 - dimethylamino - phenyl r 1 = acetyl , q = polystyrenemethylaminocarbonyl ); 5 - acetyl - 3 - phenylethynyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = phenylethynyl , r 1 = acetyl q = polystyrenemethylaminocarbonyl ) and 3 -( 4 - t - butylphenyl - 5 -( 2 - phenoxypropionyl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h = 4 - t - butylyphenyl , r 1 - 2 - phenoxypropionyl , q = polystyrenemethylaminocarbonyl ). preparation of 5 - isopropylaminocarbonyl - 3 - phenyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = phenyl , r 1 = isopropylaminocarbonyl , q = polystyrenemethylaminocarbonyl ). to 3 - phenyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole swelled in dichloromethane ( 5 ml ) isopropylisocyanate ( 0 . 09 ml . 0 . 88 mmol ) was added . the mixture was stirred at room temperature for about 24 hours ; after filtration , the resin was washed with dichloromethane ( 2 × 20 ml ), meoh ( 2 × 20 ml ), dimethylformamide ( 2 × 20 ml ) and dichloromethane ( 3 × 20 ml ). the resin was dried under vacuum . operating in an analogous way , the following compounds were also obtained : 5 - isopropylaminocarbonyl - 3 -( 4 - phenoxy - phenyl )- 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 4 - phenoxyphenyl , r 1 = isopropylaminocarbonyl , q = polystyrenemethylaminocarbonyl ); 3 -( 4 - benzyloxy - phenyl )- 5 - isopropylaminocarbonyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 4 - benzyloxyphenyl , r 1 = isopropylaminocarbonyl , q = polystyrenemethylaminocarbonyl ); 3 -( 5 - chloro - thiophen - 2 - yl )- 5 - isopropylaminocarbonyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 5 - chloro - thiophen - 2 - yl , r 1 = isopropylaminocarbonyl , q = polystyrenemethylaminocarbonyl ); 5 - isopropylaminocarbonyl - 3 -( 4 - methoxy - phenyl )- 1 - polystyrenemethylamino carbonyl - 4 , 6 - dihydro - pyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 4methoxy - phenyl , r 1 = isopropylaminocarbonyl , q = polystyrenemethylaminocarbonyl ); 3 -( 4 - dimethylamino - phenyl )- 5 - isopropylaminocarbonyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = dimethylamino - phenyl , r 1 = isopropylaminocarbonyl , q = polystyrenemethylaminocarbonyl ); 5 - isopropylaminocarbonyl - 3 - phenylethynyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = phenylethynyl , r 1 = isopropylaminocarbonyl , q = polystyrenemethylaminocarbonyl ) and 3 -( 2 , 5 - dimethylphenyl )- 5 - n - propylaminocarbonyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( iii , r a ═ r b ═ r c ═ r d ═ h , r = 4 -( 2 , 5 - dimethylphenyl ), r 1 = n - propylaminocarbonyl , q = polystyrenemethylaminocarbonyl ). preparation of 5 - acetyl - 3 - phenyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( r a ═ r b ═ r c ═ r d ═ h , r = phenyl , r 1 = acetyl , r 2 ═ h ). to 5 - acetyl - 3 - phenyl - 1 - polystyrenemethylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( 200 mg ) swelled in dioxan ( 3 ml ), sodium hydroxide ( 35 % in water ) was added ( 0 . 4 ml ) and the mixture was stirred at 40 ° c . for about 90 hours . after neutralization of the solution , the mixture was filtered and the desired product was dried under vacuum : a white solid ( 40 mg ) was obtained . operating in an analogous way , the following compounds were also obtained . 5 - isopropylaminocarbonyl - 3 - phenyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( r a ═ r b ═ r c ═ r d ═ h , r = phenyl , r 1 = isopropylaminocarbonyl , r 2 ═ h ). 1 h - nmr ( dmso - d 6 ) δ ppm : 13 . 12 ( s , 1h ); 7 . 58 - 7 . 32 ( m , 5h ); 5 . 97 ( d , 1h ); 4 . 53 ( m , 4h ); 3 . 38 ( m , 1h ); 1 . 10 ( m , 6h ); 5acetyl - 3 -( 4 - phenoxy - phenyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( r a ═ r b ═ r c ═ r d ═ h , r = 4 - phenoxy - phenyl , r 1 = acetyl , r 2 ═ h ). 1 h - nmr ( dmso - d 6 ) δ ppm : 13 . 11 ( s , 1h ); 7 . 62 - 7 . 05 ( m , 9h ); 4 . 78 ( m , 4h ); 2 . 06 ( s , 3h ) 5 - isopropylaminocarbonyl - 3 -( 4 - phenoxy - phenyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( r a ═ r b ═ r c ═ r d ═ h , r = phenoxy - phenyl , r 1 = isopropylaminocarbonyl , r 2 ═ h ). 1 h - nmr ( dmso - d 6 ) δ ppm : 13 . 06 ( s , 1h ); 7 . 59 - 7 . 04 ( m , 9h ); 5 . 93 ( d , 1h ); 4 . 51 - 4 . 42 ( m , 4h ); 3 . 80 ( m , 1h ); 1 . 09 ( m , 6h ). 5 - acetyl - 3 -( 4 - benzyloxy - phenyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( r a ═ r b ═ r c ═ r d ═ h , r = 4 - benzyloxy - phenyl , r 1 = acetyl , r 2 ═ h ): 3 -( 4 - benzyloxy - phenyl )- 5 - isopropylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( r a ═ r b ═ r c ═ r d ═ h , r = 4 - benzyloxy - phenyl , r 1 = isopropylaminocarbonyl , r 2 ═ h ). 5 - acetyl - 3 -( 5 - chloro - thiophen - 2 - yl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( r a ═ r b ═ r c ═ r d ═ h , r = 5 - chloro - thiophen - 2 - yl , r 1 = acetyl , r 2 ═ h ). 1 h - nmr ( dmso - d 6 ) δ ppm : 13 . 07 ( s , 1h ); 7 . 14 ( m , 2h ); 4 . 69 ( m , 4h ); 2 . 04 ( s , 3h ). 3 -( 5 - chloro - thiophen - 2 - yl )- 5 - isopropylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( r a ═ r b ═ r c ═ r d ═ h , r = 5 - chloro - thiophen - 2 - yl , r 1 = isopropylaminocarbonyl , r 2 ═ h ). 1 h - nmr ( dmso - d 6 ) δ ppm : 13 . 13 ( s , 1h ); 7 . 14 ( m , 2h ); 5 . 94 ( d , 1h ); 4 . 41 ( m , 4h ); 3 . 79 ( m , 1h ); 1 . 10 ( m , 6h ). 5 - acetyl - 3 -( 4 - methoxy - phenyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( r a ═ r b ═ r c ═ r d ═ h , r = 4 - methoxy - phenyl , r 1 = acetyl , r 2 ═ h ); 5 - isopropylaminocarbonyl - 3 -( 4 - methoxy - phenyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( r a ═ r b ═ r c 50 r d ═ h , r = 4 - methoxy - phenyl , r 1 = isopropylaminocarbonyl , r 2 ═ h ); 5 - acetyl - 3 -( 4 - dimethylamino - phenyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( r a ═ r b ═ r c ═ r d ═ h , r = 4 - dimethylamino - phenyl , r 1 = acetyl , r 2 ═ h ). 1 h - nmr ( dmso - d 6 ) δ ppm : 7 . 44 - 7 . 41 ( dd , 2h ); 6 . 75 - 6 . 77 ( d , 2h ); 4 . 74 - 4 . 21 ( m , 4h ); 2 . 87 ( s , 6h ); 2 . 00 ( s , 3h ). 3 -( 4 - dimethylamino - phenyl )- 5 - isopropylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( r a ═ r b ═ r c ═ r d ═ h , r = 4 - dimethylamino - phenyl , r 1 = isopropylaminocarbonyl , r 2 ═ h ). 1 h - nmr ( dmso - d 6 ) δ ppm : 7 . 40 ( m , 2h ); 6 . 77 ( m , 2h ); 4 . 18 ( m , 4h ); 3 . 78 ( m , 1h ); 2 . 92 ( s , 6h ); 1 . 11 ( m , 6h ). 5 - acetyl - 3 - phenylethynyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( r a ═ r b ═ r c ═ r d ═ h , r = phenylethynyl , r 1 = acetyl , r 2 ═ h ). 1 h - nmr ( dmso - d 6 ) δ ppm : 7 . 53 - 7 . 42 ( m , 5h ); 4 . 35 ( m , 4h ); 3 . 80 ( m , 1h ); 1 . 03 ( m , 6h ) 5 - isopropylaminocarbonyl - 3 - phenylethynyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( r a ═ r b ═ r c ═ r d ═ h , r = phenylethynyl , r 1 = isopropylaminocarbonyl , r 2 ═ h ) 3 -( 2 , 5 - dimethylphenyl )- 5 - n - propylaminocarbonyl - 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r = 4 -( 2 , 5 - dimethylphenyl ), r 1 = n - propylaminocarbonyl , r2 = h ). lcms : m / z 299 [ m + h ] + @ r t 1 : 21 min ( 81 % by els detection ). 3 -( 4 - t - butylphenyl )- 5 -( 2 - phenoxypropionyl )- 4 , 6 - dihydropyrrolo [ 3 , 4 - c ] pyrazole ( i , r a ═ r b ═ r c ═ r d ═ h , r = t - butylphenyl , r 1 = 2 - phenoxypropionyl , r2 = h ). 1 h nmr ( dmso - d 6 ) δ ppm : 7 . 61 - 7 . 53 ( 2h , m ), 7 . 52 - 7 . 45 ( 2h , m ), 7 . 30 - 7 . 22 ( 2h , m ), 6 . 96 - 6 . 87 ( 3h , m ), 5 . 22 - 5 . 12 ( 1h , m ), 4 . 97 - 4 . 84 ( 1h , m ), 4 . 72 - 4 . 62 ( 2h , m ), 4 . 51 - 4 . 47 ( 1h , m ), 1 . 60 - 1 . 50 ( 3h , m ), 1 . 32 ( 9h , br . s ), pyrazole nh not observed ; lcms : m / z 390 [ m + h ] + @ r t 1 . 57 min ( 88 % by els detection ). by proceeding in the same way as described in examples 7 , 13 , 16 , 17 , 18 and 19 , 1048 products were synthesized in parallel and coded in table iii , as formerly indicated ; related hplc retention time together with experimentally found [ m + h ]+ are reported . table iii r . t . entry compound ( min ) [ m + h ]+ 1 a1 - m - b1 1 . 24 304 . 1 2 a2 - m - b1 1 . 26 304 . 1 3 a3 - m - b1 1 . 1 280 . 1 4 a4 - m - b1 1 . 22 350 . 1 5 a5 - m - b1 1 . 24 310 . 1 6 a1 - m - b2 1 . 3 318 . 2 7 a2 - m - b2 1 . 33 318 . 2 8 a5 - m - b2 1 . 31 324 . 1 9 a1 - m - b3 1 . 38 310 . 2 10 a2 - m - b3 1 . 4 310 . 2 11 a6 - m - b3 1 . 29 302 . 1 12 a3 - m - b3 1 . 24 286 . 1 13 a4 - m - b3 1 . 35 356 . 2 14 a5 - m - b3 1 . 38 316 . 1 15 a1 - m - b4 1 . 02 242 . 1 16 a2 - m - b4 1 . 06 242 . 1 17 a7 - m - b4 0 . 98 258 . 1 18 a3 - m - b4 0 . 88 218 . 1 19 a1 - m - b5 1 . 5 324 . 2 20 a8 - m - b5 1 . 48 370 . 2 21 a3 - m - b5 1 . 37 300 . 2 22 a5 - m - b5 1 . 52 330 . 2 23 a1 - m - b6 1 . 35 338 . 1 24 a2 - m - b6 1 . 37 338 . 1 25 a6 - m - b6 1 . 27 330 . 0 26 a8 - m - b6 1 . 34 384 . 1 27 a3 - m - b6 1 . 22 314 . 1 28 a5 - m - b6 1 . 36 344 . 1 29 a1 - m - b7 1 . 29 348 . 2 30 a9 - m - b7 1 . 32 348 . 2 31 a2 - m - b7 1 . 32 348 . 2 32 a3 - m - b7 1 . 17 324 . 1 33 a4 - m - b7 1 . 27 394 . 2 34 a1 - m - b8 1 . 24 348 . 1 35 a9 - m - b8 1 . 26 348 . 1 36 a2 - m - b8 1 . 26 348 . 1 37 a8 - m - b8 1 . 22 394 . 1 38 a3 - m - b8 1 . 1 324 . 1 39 a5 - m - b8 1 . 24 354 . 1 40 a1 - m - b9 1 . 31 334 . 1 41 a3 - m - b9 1 . 2 310 . 1 42 a4 - m - b9 1 . 3 380 . 2 43 a1 - m - b10 1 . 36 298 . 2 44 a8 - m - b10 1 . 34 344 . 2 45 a3 - m - b10 1 . 23 274 . 1 46 a5 - m - b10 1 . 37 304 . 1 47 a1 - m - b11 1 . 27 322 . 1 48 a9 - m - b11 1 . 3 322 . 1 49 a2 - m - b11 1 . 3 322 . 1 50 a6 - m - b11 1 . 2 314 . 1 51 a8 - m - b11 1 . 27 368 . 1 52 a3 - m - b11 1 . 15 298 . 1 53 a5 - m - b11 1 . 28 328 . 1 54 a9 - m - b12 1 . 27 339 . 1 55 a1 - m - b13 1 . 24 310 . 1 56 a3 - m - b13 1 . 11 286 . 1 57 a5 - m - b13 1 . 25 316 . 1 58 a1 - m - b14 1 . 18 364 . 2 59 a2 - m - b14 1 . 21 364 . 2 60 a6 - m - b14 1 . 11 356 . 1 61 a3 - m - b14 1 . 06 340 . 1 62 a5 - m - b14 1 . 18 370 . 1 63 a1 - m - b15 1 . 14 268 . 1 64 a3 - m - b15 1 . 01 244 . 1 65 a5 - m - b15 1 . 17 274 . 1 66 a1 - m - b16 1 . 25 334 . 1 67 a9 - m - b16 1 . 28 334 . 1 68 a2 - m - b16 1 . 28 334 . 1 69 a3 - m - b16 1 . 13 310 . 1 70 a5 - m - b16 1 . 25 340 . 1 71 a1 - m - b17 1 . 2 256 . 1 72 a4 - m - b17 1 . 12 302 . 1 73 a1 - m - b18 1 . 33 340 . 1 74 a6 - m - b18 1 . 26 332 . 1 75 a8 - m - b18 1 . 32 386 . 1 76 a3 - m - b18 1 . 21 316 . 1 77 a5 - m - b18 1 . 33 346 . 1 78 a1 - m - b19 1 . 25 334 . 1 79 a9 - m - b19 1 . 27 334 . 1 80 a2 - m - b19 1 . 27 334 . 1 81 a6 - m - b19 1 . 17 326 . 1 82 a3 - m - b19 1 . 12 310 . 1 83 a5 - m - b19 1 . 25 340 . 1 84 a1 - m - b20 1 . 14 323 . 1 85 a9 - m - b20 1 . 18 323 . 1 86 a2 - m - b20 1 . 17 323 . 1 87 a6 - m - b20 1 . 07 315 . 1 88 a8 - m - b20 1 . 14 369 . 1 89 a7 - m - b20 1 . 1 339 . 1 90 a3 - m - b20 1 . 01 299 . 1 91 a5 - m - b20 1 . 15 329 . 1 92 a1 - m - b21 1 . 27 322 . 1 93 a9 - m - b21 1 . 29 322 . 1 94 a2 - m - b21 1 . 29 322 . 1 95 a6 - m - b21 1 . 19 314 . 1 96 a8 - m - b21 1 . 25 368 . 1 97 a7 - m - b21 1 . 21 338 . 1 98 a3 - m - b21 1 . 14 298 . 1 99 a5 - m - b21 1 . 3 328 . 1 100 a1 - m - b22 1 . 32 296 . 2 101 a9 - m - b22 1 . 38 296 . 2 102 a2 - m - b22 1 . 35 296 . 2 103 a6 - m - b22 1 . 23 288 . 1 104 a8 - m - b22 1 . 31 342 . 2 105 a3 - m - b22 1 . 18 272 . 1 106 a5 - m - b22 1 . 32 302 . 1 107 a1 - m - b23 1 . 36 332 . 2 108 a8 - m - b23 1 . 35 378 . 2 109 a3 - m - b23 1 . 25 308 . 1 110 a1 - m - b24 1 . 34 348 . 2 111 a9 - m - b24 1 . 37 348 . 2 112 a7 - m - b24 1 . 29 364 . 2 113 a3 - m - b24 1 . 22 324 . 1 114 a1 - m - b25 1 . 32 338 . 1 115 a9 - m - b25 1 . 33 338 . 1 116 a2 - m - b25 1 . 33 338 . 1 117 a8 - m - b25 1 . 29 384 . 1 118 a7 - m - b25 1 . 25 354 . 1 119 a3 - m - b25 1 . 18 314 . 1 120 a8 - m - b26 1 . 22 375 . 1 121 a1 - m - b27 1 . 24 282 . 2 122 a2 - m - b27 1 . 28 282 . 2 123 a3 - m - b27 1 . 11 258 . 1 124 a1 - m - b28 1 . 32 340 . 1 125 a2 - m - b28 1 . 37 340 . 1 126 a8 - m - b28 1 . 31 386 . 1 127 a3 - m - b28 1 . 2 316 . 1 128 a1 - m - b29 1 . 04 272 . 1 129 a1 - m - b30 1 . 21 394 . 2 130 a9 - m - b30 1 . 24 394 . 2 131 a2 - m - b30 1 . 24 394 . 2 132 a6 - m - b30 1 . 24 386 . 1 133 a7 - m - b30 1 . 17 410 . 2 134 a4 - m - b30 1 . 21 440 . 2 135 a1 - m - b31 1 . 31 340 . 1 136 a9 - m - b31 1 . 33 340 . 1 137 a2 - m - b31 1 . 33 340 . 1 138 a6 - m - b31 1 . 23 332 . 1 139 a8 - m - b31 1 . 29 386 . 1 140 a7 - m - b31 1 . 26 356 . 1 141 a3 - m - b31 1 . 18 316 . 1 142 a1 - m - b32 1 . 28 322 . 1 143 a2 - m - b32 1 . 3 322 . 1 144 a6 - m - b32 1 . 21 314 . 1 145 a3 - m - b32 1 . 16 298 . 1 146 a1 - m - b33 1 . 3 284 . 2 147 a2 - m - b33 1 . 33 284 . 2 148 a8 - m - b33 1 . 29 330 . 2 149 a3 - m - b33 1 . 17 260 . 1 150 a1 - m - b34 1 . 51 326 . 2 151 a9 - m - b34 1 . 54 326 . 2 152 a2 - m - b34 1 . 53 326 . 2 153 a6 - m - b34 1 . 42 318 . 2 154 a8 - m - b34 1 . 48 372 . 2 155 a7 - m - b34 1 . 44 342 . 2 156 a3 - m - b34 1 . 38 302 . 2 157 a1 - m - b35 1 . 33 382 . 0 158 a9 - m - b35 1 . 34 382 . 0 159 a2 - m - b35 1 . 34 382 . 0 160 a6 - m - b35 1 . 24 374 . 0 161 a7 - m - b35 1 . 26 398 . 0 162 a3 - m - b35 1 . 19 358 . 0 163 a1 - m - b36 1 . 28 324 . 1 164 a2 - m - b36 1 . 31 324 . 1 165 a3 - m - b36 1 . 16 300 . 1 166 a1 - m - b37 1 . 44 346 . 2 167 a2 - m - b37 1 . 47 346 . 2 168 a6 - m - b37 1 . 51 338 . 1 169 a8 - m - b37 1 . 43 392 . 2 170 a3 - m - b37 1 . 32 322 . 1 171 a1 - m - b38 1 . 52 376 . 2 172 a9 - m - b38 1 . 55 376 . 2 173 a1 - m - b39 1 . 29 397 . 2 174 a8 - m - b39 1 . 28 443 . 2 175 a7 - m - b39 1 . 25 413 . 2 176 a1 - m - b40 1 . 28 340 . 1 177 a9 - m - b40 1 . 3 340 . 1 178 a2 - m - b40 1 . 3 340 . 1 179 a6 - m - b40 1 . 2 332 . 1 180 a8 - m - b40 1 . 27 386 . 1 181 a7 - m - b40 1 . 23 356 . 1 182 a3 - m - b40 1 . 15 316 . 1 183 a1 - m - b41 1 . 38 382 . 0 184 a8 - m - b41 1 . 37 428 . 1 185 a3 - m - b41 1 . 25 358 . 0 186 a1 - m - b42 1 . 32 318 . 2 187 a2 - m - b42 1 . 34 318 . 2 188 a8 - m - b42 1 . 31 364 . 2 189 a3 - m - b42 1 . 19 294 . 1 190 a1 - m - b43 1 . 21 302 . 1 191 a2 - m - b43 1 . 24 302 . 1 192 a8 - m - b43 1 . 21 348 . 1 193 a1 - m - b44 1 . 33 336 . 1 194 a9 - m - b44 1 . 36 336 . 1 195 a3 - m - b44 1 . 21 312 . 1 196 a1 - m - b45 1 . 4 352 . 1 197 a8 - m - b45 1 . 39 398 . 1 198 a3 - m - b45 1 . 29 328 . 1 199 a1 - m - b46 1 . 39 310 . 2 200 a8 - m - b46 1 . 38 356 . 2 201 a3 - m - b46 1 . 27 286 . 1 202 a1 - m - b47 1 . 28 282 . 2 203 a2 - m - b47 1 . 28 282 . 2 204 a8 - m - b47 1 . 25 328 . 2 205 a3 - m - b47 1 . 12 258 . 1 206 a1 - m - b48 1 . 27 284 . 2 207 a9 - m - b48 1 . 3 284 . 2 208 a2 - m - b48 1 . 3 284 . 2 209 a6 - m - b48 1 . 19 276 . 1 210 a8 - m - b48 1 . 26 330 . 2 211 a7 - m - b48 1 . 22 300 . 2 212 a3 - m - b48 1 . 14 260 . 1 213 a1 - m - b49 1 . 39 362 . 2 214 a2 - m - b49 1 . 42 362 . 2 215 a8 - m - b49 1 . 38 408 . 2 216 a3 - m - b49 1 . 28 338 . 1 217 a1 - m - b50 1 . 13 285 . 2 218 a9 - m - b50 1 . 34 285 . 2 219 a2 - m - b50 1 . 18 285 . 2 220 a6 - m - b50 1 . 05 277 . 1 221 a7 - m - b50 1 . 1 301 . 2 222 a3 - m - b50 1 261 . 1 223 a1 - m - b51 1 . 33 333 . 2 224 a2 - m - b51 1 . 37 333 . 2 225 a1 - m - b52 1 . 41 397 . 1 226 a9 - m - b52 1 . 44 397 . 1 227 a2 - m - b52 1 . 45 397 . 1 228 a6 - m - b52 1 . 35 389 . 0 229 a8 - m - b52 1 . 42 443 . 1 230 a1 - m - b53 1 . 31 349 . 2 231 a9 - m - b53 1 . 31 349 . 2 232 a2 - m - b53 1 . 31 349 . 2 233 a6 - m - b53 1 . 21 341 . 1 234 a10 - m - b54 1 . 26 392 . 1 235 a11 - m - b55 1 . 41 374 . 1 236 a1 - m - b56 1 . 05 271 . 1 237 a9 - m - b56 1 . 09 271 . 1 238 a2 - m - b56 1 . 09 271 . 1 239 a6 - m - b56 0 . 97 263 . 1 240 a8 - m - b56 1 . 08 317 . 2 241 a1 - m - b57 1 . 4 325 . 2 242 a9 - m - b57 1 . 33 325 . 2 243 a2 - m - b57 1 . 33 325 . 2 244 a6 - m - b57 1 . 23 317 . 1 245 a8 - m - b57 1 . 31 371 . 2 246 a1 - m - b58 1 . 28 355 . 1 247 a2 - m - b58 1 . 31 355 . 1 248 a1 - m - b59 1 . 28 337 . 1 249 a9 - m - b59 1 . 32 337 . 1 250 a2 - m - b59 1 . 32 337 . 1 251 a6 - m - b59 1 . 22 329 . 1 252 a1 - m - b60 1 . 39 353 . 1 253 a2 - m - b60 1 . 43 353 . 1 254 a6 - m - b60 1 . 33 345 . 0 255 a1 - m - b61 1 . 24 349 . 2 256 a9 - m - b61 1 . 27 349 . 2 257 a2 - m - b61 1 . 27 349 . 2 258 a6 - m - b61 1 . 17 341 . 1 259 a8 - m - b61 1 . 25 395 . 2 260 a1 - m - b62 1 . 47 361 . 2 261 a9 - m - b62 1 . 5 361 . 2 262 a2 - m - b62 1 . 5 361 . 2 263 a6 - m - b62 1 . 41 353 . 1 264 a8 - m - b62 1 . 48 407 . 2 265 a1 - m - b63 1 . 27 347 . 2 266 a9 - m - b63 1 . 3 347 . 2 267 a2 - m - b63 1 . 3 347 . 2 268 a6 - m - b63 1 . 35 339 . 1 269 a8 - m - b63 1 . 29 393 . 2 270 a1 - m - b64 1 . 36 353 . 1 271 a12 - m - b64 1 . 34 369 . 1 272 a1 - m - b65 1 . 38 353 . 1 273 a12 - m - b65 1 . 38 369 . 1 274 a8 - m - b65 1 . 4 399 . 1 275 a1 - m - b66 1 . 32 337 . 1 276 a12 - m - b66 1 . 32 353 . 1 277 a2 - m - b66 1 . 49 337 . 1 278 a6 - m - b66 1 . 26 329 . 1 279 a1 - m - b67 1 . 3 313 . 2 280 a12 - m - b67 1 . 29 329 . 2 281 a2 - m - b67 1 . 34 313 . 2 282 a6 - m - b67 1 . 23 305 . 1 283 a8 - m - b67 1 . 32 359 . 2 284 a1 - m - b68 1 . 23 361 . 2 285 a12 - m - b68 1 . 22 377 . 2 286 a2 - m - b68 1 . 27 361 . 2 287 a1 - m - b69 1 . 33 347 . 2 288 a12 - m - b69 1 . 32 363 . 2 289 a2 - m - b69 1 . 36 347 . 2 290 a8 - m - b69 1 . 34 393 . 2 291 a1 - m - b70 1 . 33 351 . 2 292 a12 - m - b70 1 . 31 367 . 1 293 a1 - m - b71 1 . 57 347 . 2 294 a12 - m - b71 1 . 38 363 . 2 295 a2 - m - b71 1 . 41 347 . 2 296 a6 - m - b71 1 . 31 339 . 1 297 a8 - m - b71 1 . 39 393 . 2 298 a1 - m - b72 1 . 35 355 . 1 299 a12 - m - b72 1 . 35 371 . 1 300 a1 - m - b73 1 . 22 361 . 2 301 a12 - m - b73 1 . 21 377 . 2 302 a2 - m - b73 1 . 26 361 . 2 303 a1 - m - b74 1 . 52 392 . 1 304 a12 - m - b74 1 . 49 408 . 1 305 a2 - m - b74 1 . 54 392 . 1 306 a1 - m - b75 1 . 37 359 . 1 307 a12 - m - b75 1 . 35 375 . 1 308 a2 - m - b75 1 . 4 359 . 1 309 a1 - m - b76 1 . 36 400 . 1 310 a12 - m - b76 1 . 35 416 . 1 311 a2 - m - b76 1 . 4 400 . 1 312 a1 - m - b77 1 . 49 374 . 1 313 a12 - m - b77 1 . 46 390 . 1 314 a2 - m - b77 1 . 52 374 . 1 315 a1 - m - b78 1 . 43 374 . 1 316 a12 - m - b78 1 . 41 390 . 1 317 a2 - m - b78 1 . 46 374 . 1 318 a1 - m - b79 1 . 28 306 . 1 319 a12 - m - b79 1 . 27 322 . 1 320 a2 - m - b79 1 . 32 306 . 1 321 a1 - m - b80 1 . 51 380 . 0 322 a12 - m - b80 1 . 49 396 . 0 323 a2 - m - b80 1 . 55 380 . 0 324 a1 - m - b81 1 . 18 382 . 2 325 a1 - m - b82 1 . 37 365 . 1 326 a1 - m - b83 1 . 23 311 . 2 327 a2 - m - b83 1 . 27 311 . 2 328 a2 - m - b84 1 . 19 278 . 1 329 a12 - m - b85 1 . 42 370 . 1 330 a2 - m - b85 1 . 47 354 . 1 331 a12 - m - b86 1 . 47 390 . 1 332 a1 - m - b87 1 . 51 418 . 0 333 a12 - m - b87 1 . 75 434 . 0 334 a1 - m - b88 1 . 2 292 . 1 335 a2 - m - b88 1 . 24 292 . 1 336 a1 - m - b89 1 . 39 358 . 1 337 a12 - m - b89 1 . 37 374 . 1 338 a2 - m - b89 1 . 42 358 . 1 339 a1 - m - b54 1 . 36 346 . 1 340 a12 - m - b54 1 . 34 362 . 1 341 a2 - m - b54 1 . 4 346 . 1 342 a1 - m - b55 1 . 41 358 . 1 343 a12 - m - b55 1 . 39 374 . 1 344 a2 - m - b55 1 . 44 358 . 1 345 a1 - m - b90 1 . 52 424 . 0 346 a1 - m - b91 1 . 32 400 . 1 347 a2 - m - b91 1 . 36 400 . 1 348 a1 - m - b92 1 . 42 358 . 1 349 a12 - m - b92 1 . 4 374 . 1 350 a2 - m - b92 1 . 45 358 . 1 351 a1 - m - b93 1 . 44 354 . 1 352 a12 - m - b93 1 . 42 370 . 1 353 a2 - m - b93 1 . 47 354 . 1 354 a1 - m - b94 1 . 49 448 . 0 355 a12 - m - b94 1 . 46 464 . 0 356 a2 - m - b94 1 . 52 448 . 0 357 a13 - m - b1 1 . 24 336 . 1 358 a14 - m - b1 1 . 3 318 . 2 359 a13 - m - b2 1 . 3 350 . 1 360 a14 - m - b2 1 . 41 332 . 2 361 a15 - m - b3 1 . 44 324 . 2 362 a13 - m - b3 1 . 38 342 . 2 363 a16 - m - b3 1 . 42 340 . 2 364 a15 - m - b5 1 . 58 338 . 2 365 a17 - m - b5 1 . 35 360 . 0 366 a13 - m - b5 1 . 48 356 . 2 367 a18 - m - b5 1 . 28 300 . 2 368 a11 - m - b5 1 . 47 340 . 2 369 a17 - m - b6 1 . 21 373 . 9 370 a13 - m - b6 1 . 36 370 . 1 371 a13 - m - b7 1 . 29 380 . 1 372 a16 - m - b7 1 . 34 378 . 2 373 a17 - m - b8 1 . 08 384 . 0 374 a15 - m - b10 1 . 43 312 . 2 375 a10 - m - b10 1 . 22 344 . 2 376 a17 - m - b10 1 . 19 334 . 0 377 a13 - m - b10 1 . 36 330 . 2 378 a11 - m - b10 1 . 33 314 . 2 379 a16 - m - b10 1 . 41 328 . 2 380 a15 - m - b11 1 . 35 336 . 1 381 a17 - m - b11 1 . 12 358 . 0 382 a13 - m - b11 1 . 28 354 . 1 383 a14 - m - b11 1 . 38 336 . 1 384 a15 - m - b12 1 . 29 353 . 1 385 a13 - m - b12 1 . 22 371 . 1 386 a19 - m - b12 1 . 15 369 . 1 387 a20 - m - b12 1 . 29 377 . 0 388 a15 - m - b13 1 . 32 324 . 1 389 a17 - m - b13 1 . 07 345 . 9 390 a13 - m - b13 1 . 25 342 . 1 391 a15 - m - b14 1 . 25 378 . 2 392 a17 - m - b14 1 . 02 400 . 0 393 a13 - m - b14 1 . 18 396 . 1 394 a15 - m - b15 1 . 24 282 . 2 395 a13 - m - b15 1 . 16 300 . 1 396 a11 - m - b15 1 . 14 284 . 1 397 a15 - m - b16 1 . 32 348 . 2 398 a17 - m - b16 1 . 09 370 . 0 399 a14 - m - b16 1 . 35 348 . 2 400 a13 - m - b17 1 . 14 288 . 1 401 a17 - m - b18 1 . 18 376 . 0 402 a13 - m - b18 1 . 34 372 . 1 403 a17 - m - b19 1 . 1 370 . 0 404 a13 - m - b19 1 . 25 366 . 1 405 a11 - m - b19 1 . 23 350 . 1 406 a16 - m - b19 1 . 3 364 . 2 407 a15 - m - b20 1 . 23 337 . 2 408 a17 - m - b20 0 . 95 359 . 0 409 a13 - m - b20 1 . 15 355 . 1 410 a11 - m - b20 1 . 14 339 . 1 411 a14 - m - b20 1 . 26 337 . 2 412 a13 - m - b21 1 . 27 354 . 1 413 a11 - m - b21 1 . 25 338 . 1 414 a14 - m - b21 1 . 38 336 . 1 415 a17 - m - b23 1 . 23 368 . 0 416 a13 - m - b23 1 . 36 364 . 1 417 a15 - m - b25 1 . 4 352 . 1 418 a13 - m - b25 1 . 3 370 . 1 419 a19 - m - b25 1 . 24 368 . 1 420 a17 - m - b26 1 . 04 365 . 0 421 a13 - m - b26 1 . 22 361 . 1 422 a17 - m - b27 1 . 07 318 . 0 423 a13 - m - b27 1 . 26 314 . 1 424 a16 - m - b27 1 . 31 312 . 2 425 a17 - m - b28 1 . 2 376 . 0 426 a13 - m - b28 1 . 33 372 . 1 427 a11 - m - b29 1 . 02 288 . 1 428 a14 - m - b29 1 . 16 286 . 1 429 a19 - m - b29 0 . 99 302 . 1 430 a16 - m - b29 1 . 1 302 . 1 431 a17 - m - b95 1 . 22 373 . 9 432 a13 - m - b95 1 . 37 370 . 1 433 a17 - m - b31 1 . 16 376 . 0 434 a13 - m - b31 1 . 32 372 . 1 435 a14 - m - b31 1 . 41 354 . 1 436 a19 - m - b31 1 . 25 370 . 1 437 a15 - m - b32 1 . 37 336 . 1 438 a17 - m - b32 1 . 12 358 . 0 439 a13 - m - b32 1 . 29 354 . 1 440 a11 - m - b32 1 . 26 338 . 1 441 a14 - m - b34 1 . 6 340 . 2 442 a19 - m - b34 1 . 42 356 . 2 443 a20 - m - b34 1 . 58 364 . 2 444 a16 - m - b34 1 . 54 356 . 2 445 a14 - m - b90 1 . 62 438 . 0 446 a15 - m - b96 1 . 6 404 . 1 447 a14 - m - b35 1 . 42 396 . 1 448 a13 - m - b36 1 . 29 356 . 1 449 a15 - m - b37 1 . 52 360 . 2 450 a17 - m - b37 1 . 31 382 . 0 451 a13 - m - b37 1 . 44 378 . 2 452 a11 - m - b37 1 . 42 362 . 2 453 a17 - m - b38 1 . 4 412 . 0 454 a13 - m - b38 1 . 52 408 . 2 455 a17 - m - b97 1 . 36 416 . 0 456 a13 - m - b97 1 . 47 412 . 1 457 a15 - m - b40 1 . 37 354 . 1 458 a17 - m - b40 1 . 12 376 . 0 459 a13 - m - b40 1 . 28 372 . 1 460 a14 - m - b40 1 . 38 354 . 1 461 a16 - m - b40 1 . 33 370 . 1 462 a17 - m - b41 1 . 23 417 . 9 463 a13 - m - b41 1 . 37 414 . 0 464 a13 - m - b42 1 . 32 350 . 1 465 a20 - m - b45 1 . 48 390 . 0 466 a17 - m - b46 1 . 25 346 . 0 467 a13 - m - b46 1 . 4 342 . 2 468 a15 - m - b47 1 . 33 296 . 2 469 a17 - m - b47 1 . 08 318 . 0 470 a13 - m - b47 1 . 27 314 . 1 471 a15 - m - b48 1 . 35 298 . 2 472 a10 - m - b48 1 . 14 330 . 2 473 a17 - m - b48 1 . 1 320 . 0 474 a13 - m - b48 1 . 28 316 . 1 475 a11 - m - b48 1 . 26 300 . 2 476 a14 - m - b48 1 . 39 298 . 2 477 a19 - m - b48 1 . 21 314 . 1 478 a20 - m - b48 1 . 36 322 . 1 479 a15 - m - b50 1 . 21 299 . 2 480 a10 - m - b50 1 . 04 331 . 2 481 a17 - m - b50 0 . 94 321 . 0 482 a14 - m - b50 1 . 25 299 . 2 483 a15 - m - b51 1 . 4 347 . 2 484 a17 - m - b51 1 . 19 369 . 0 485 a13 - m - b51 1 . 34 365 . 1 486 a11 - m - b51 1 . 33 349 . 2 487 a20 - m - b51 1 . 43 371 . 1 488 a17 - m - b52 1 . 29 432 . 9 489 a13 - m - b52 1 . 42 429 . 0 490 a11 - m - b52 1 . 42 413 . 1 491 a20 - m - b52 1 . 51 435 . 0 492 a15 - m - b53 1 . 35 363 . 2 493 a17 - m - b53 1 . 13 385 . 0 494 a13 - m - b53 1 . 29 381 . 1 495 a14 - m - b53 1 . 39 363 . 2 496 a10 - m - b56 0 . 97 317 . 2 497 a14 - m - b56 1 . 18 285 . 2 498 a19 - m - b56 1 . 02 301 . 1 499 a10 - m - b57 1 . 21 371 . 2 500 a17 - m - b57 1 . 16 361 . 0 501 a13 - m - b57 1 . 31 357 . 2 502 a14 - m - b57 1 . 41 339 . 2 503 a19 - m - b57 1 . 27 355 . 2 504 a20 - m - b57 1 . 41 363 . 1 505 a10 - m - b58 1 . 2 401 . 1 506 a17 - m - b58 1 . 13 391 . 0 507 a13 - m - b58 1 . 3 387 . 1 508 a10 - m - b59 1 . 22 383 . 1 509 a17 - m - b59 1 . 14 373 . 0 510 a13 - m - b59 1 . 31 369 . 1 511 a20 - m - b59 1 . 4 375 . 1 512 a13 - m - b60 1 . 41 385 . 1 513 a19 - m - b60 1 . 37 383 . 1 514 a20 - m - b60 1 . 5 391 . 0 515 a20 - m - b62 1 . 57 399 . 1 516 a15 - m - b63 1 . 36 361 . 2 517 a10 - m - b63 1 . 19 393 . 2 518 a17 - m - b63 1 . 13 383 . 0 519 a13 - m - b63 1 . 29 379 . 2 520 a11 - m - b63 1 . 28 363 . 2 521 a14 - 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m - b87 1 . 51 450 . 0 952 a13 - m - b143 1 . 37 386 . 1 953 a19 - m - b143 1 . 32 384 . 1 954 a11 - m - b88 1 . 19 308 . 1 955 a15 - m - b74 1 . 59 406 . 1 956 a13 - m - b74 1 . 51 424 . 0 957 a14 - m - b99 1 . 72 410 . 2 958 a15 - m - b79 1 . 37 320 . 1 959 a13 - m - b79 1 . 29 338 . 1 960 a14 - m - b79 1 . 4 320 . 1 961 a9 - m - b1 1 . 26 304 . 1 962 a8 - m - b1 1 . 23 350 . 1 963 a9 - m - b2 1 . 34 318 . 2 964 a8 - m - b2 1 . 29 364 . 2 965 a7 - m - b2 1 . 25 334 . 1 966 a9 - m - b3 1 . 41 310 . 2 967 a23 - m - b85 1 . 68 396 . 2 968 a6 - m - b4 0 . 94 234 . 1 969 a6 - m - b7 1 . 22 340 . 1 970 a7 - m - b7 1 . 24 364 . 2 971 a6 - m - b15 1 . 07 260 . 1 972 a7 - m - b15 1 . 1 284 . 1 973 a7 - m - b22 1 . 26 312 . 2 974 a2 - m - b24 1 . 39 348 . 2 975 a6 - m - b24 1 . 29 340 . 1 976 a8 - m - b24 1 . 37 394 . 2 977 a9 - m - b27 1 . 31 282 . 2 978 a6 - m - b27 1 . 19 274 . 1 979 a8 - m - b27 1 . 27 328 . 2 980 a2 - m - b29 1 . 09 272 . 1 981 a7 - m - b29 1 . 01 288 . 1 982 a8 - m - b30 1 . 24 440 . 2 983 a9 - m - b33 1 . 33 284 . 2 984 a7 - m - b33 1 . 25 300 . 2 985 a24 - m - b88 1 . 31 334 . 1 986 a2 - m - b144 1 . 31 364 . 2 987 a8 - m - b144 1 . 28 410 . 2 988 a3 - m - b144 1 . 17 340 . 1 989 a8 - m - b44 1 . 34 382 . 1 990 a7 - m - b46 1 . 37 326 . 2 991 a9 - m - b47 1 . 31 282 . 2 992 a7 - m - b47 1 . 23 298 . 1 993 a7 - m - b49 1 . 38 378 . 2 994 a8 - m - b50 1 . 18 331 . 2 995 a9 - m - b51 1 . 36 333 . 2 996 a8 - m - b59 1 . 3 383 . 1 997 a8 - m - b60 1 . 4 399 . 1 998 a8 - m - b64 1 . 37 399 . 1 999 a8 - m - b66 1 . 34 383 . 1 1000 a8 - m - b68 1 . 24 407 . 2 1001 a6 - m - b72 1 . 28 347 . 1 1002 a8 - m - b72 1 . 37 401 . 1 1003 a17 - m - b1 1 . 09 340 . 0 1004 a15 - m - b2 1 . 39 332 . 2 1005 a16 - m - b14 1 . 23 394 . 2 1006 a14 - m - b15 1 . 27 282 . 2 1007 a11 - m - b23 1 . 36 348 . 2 1008 a13 - m - b24 1 . 34 380 . 1 1009 a17 - m - b25 1 . 15 373 . 9 1010 a17 - m - b42 1 . 17 354 . 0 1011 a16 - m - b43 1 . 27 332 . 1 1012 a19 - m - b52 1 . 39 427 . 0 1013 a13 - m - b122 1 . 26 331 . 2 1014 a13 - m - b61 1 . 25 381 . 1 1015 a14 - m - b61 1 . 36 363 . 2 1016 a19 - m - b66 1 . 3 367 . 1 1017 a11 - m - b98 1 . 27 360 . 1 1018 a17 - m - b68 1 . 06 397 . 0 1019 a14 - m - b68 1 . 34 375 . 2 1020 a19 - m - b87 1 . 45 448 . 0 1021 a14 - m - b75 1 . 47 373 . 1 1022 a11 - m - b99 1 . 61 412 . 2 1023 a13 - m - b77 1 . 48 406 . 0 1024 a11 - m - b77 1 . 47 390 . 1 1025 a14 - m - b77 1 . 58 388 . 1 1026 a14 - m - b78 1 . 53 388 . 1 1027 a10 - m - b90 1 . 41 470 . 0 1028 a14 - m - b101 1 . 71 422 . 0 1029 a10 - m - b102 1 . 44 470 . 1 1030 a17 - m - b103 1 . 46 443 . 9 1031 a10 - m - b104 1 . 42 454 . 0 1032 a13 - m - b104 1 . 52 440 . 0 1033 a21 - m - b1 1 . 23 308 . 1 1034 a21 - m - b108 1 . 52 364 . 2 1035 a21 - m - b109 1 . 31 322 . 1 1036 a21 - m - b10 1 . 36 302 . 2 1037 a22 - m - b1 1 . 19 290 . 1 1038 a22 - m - b3 1 . 34 296 . 2 1039 a22 - m - b4 0 . 99 228 . 1 1040 a22 - m - b7 1 . 27 334 . 1 1041 a23 - m - b8 1 . 47 390 . 2 1042 a21 - m - b15 1 . 16 272 . 1 1043 a23 - m - b110 1 . 77 448 . 1 1044 a21 - m - b36 1 . 27 328 . 1 1045 a22 - m - b46 1 . 36 296 . 2 1046 a23 - m - b121 1 . 49 361 . 2 1047 a23 - m - b126 1 . 54 375 . 2 1048 a22 - m - b85 1 . 4 340 . 1