HUE028525T2 - 6-cikloamino-3-(1H-pirrolo[2,3-b]piridin-4-il)imidazo[1,2-b]piridazin-származékok, elõállításuk és terápiás alkalmazásuk - Google Patents

Description

^€YCLOAM«P^{ii^FVRROLOC2>3^]PVRIDIN-4-Yf..)IM!DAZO|I,2-/'|~

PYRiîMZINE IMiilYAOTBS, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF

The present invention rollte tm 6~eydoaBim»-'3Tl//-pyn'olo[23~^jpyndm~4« y!)lmkkzo[ 13-*jpyridazine derivatives;, to the préparai« thereoTand to tie tRerapeotle use thereof. In tire treatment or prevention of diseases Involving casein kutasé I epsilon and/or casein kinase 1 delta.

One subject of the present:: indention is the pompcmods;; eenmsppdlni; to; lie: ;|enemi formula HV.

in which: - R2 represents an ary! group optionally substituted wilt; one or more substituents chosen from halogen atone., ad i * <tik\ b C < udk> io\\, C,„t mlh> Ithku C s, tleonolks b C tluoroalkyloxy and ~€N groups or R:> reppsehts aCmralkyí, C,,trfinoroalkyk C3.?« cyeloalkyl or CVrcyeloalkybC; «--alkyl gtoup; - A represents a CTr-alkylene group optionally substituted with one or two R:; groups: -- B represents a CVv-alkylene group optionally substituted with an R|, group;; -. L rppesonú either a alfmgett atom optionally substituted with an R* or; TU group, or a, carbon, atom, substituted with: áh 1C: gronpondAn. Rg group or two R*a groups; the carbon atoms of A and B being optionally substituted with one or more Rr groups, which may be identical to or different from one another; - Rs, 1% and R<. am deinedsneh that: two R;i groups ns ay together form a Cffc-aikykme group;

Es and 1¾ may together förm i homl or a C^mlkylene group; R* and R(; may together ihmt a bond or a Cuteky lene group;

Rpiand R« may together term a bond or a C^odkylene group; > Ra represents a group chosen tom a hydrogen atom add CWaikyl, CP^-eyctoaikyl Cj..7-cyeloatfeyh^s.r^kyk lyärm£y'C^<,‘afei, Ci.6~a|kyioxy»Cä.rÄyi Cs.4-aj|ylthi>~ Cj-^ aikyL Cu^uoroalkyl or henry! groups; - represents at -NR,*Rs go-up or a esche monoamine optioMÜy comprising an oxygon atom, the eye he monoamine being optionally substituted with one or more substituents chosen dons a duorine atom and Cj-^-alkyl, Cj^-aikyloxy and hydroxyl groups; - two groups form,, with the prbop gtom that hears them, a eyelid monoamine optionally comprising an onypn atom, the cyclic monoamine bfiog optionally substituted with ode or more R: groups, which may he identical to or different ten one another: -t? represents a Ch.^-alkyl Q^-eycloaikyi, £Vreycloalkylffff.&amp;miky!, C^y-alkyloxy-Ci.*-alkyb h>dn>xv-Ch **alk>L C^-0nnj^l:ylp^en^#r'ben2^|::irpp^ - II4 and Rs represent, independently of one another, a hydrogen atom ora Cumdkyh CY?- oyeloalkyl #&amp;&amp;r-eychndkyRCn«-alkyl group; and * imd Eg mpreseuit mtmAm, a hjititop* é® or a C^-alkyl group. Çppvn írom the prior art is dbcomept WO 2008/138834, which: discloses 2,3,0-trisubstitated imlttaf l,2«b]pyrida2me derivativ es of the following general formula (1 ) m·. inhibitors of kinases of the PB-kiratse-rektteá proiein kinase family;

Pf 1 low over, mo compounds of formcUt l s possess no n/ao>v5o as R" group

Jrisd known moo? lie: prior art is document WO 2Ö0S/13888.9, which describes 3^ dtaebstituted iraidazoj: 1,2-bjpyridarine derivatives of ihe foUowing general forant!» (2) as inhibitors of kinases of ihe PO-kioase-reisisd protein kinase family*

However, these compounds are not substituted »1 position 2,

The compounds of formula (I) may comprise one or snore asymmetric carbon atumsfThey may thus exist in the form of enantiomers or diastereoisomem These enantiomers sand diastereolsomeoi, and also mixtures thereof including racemic mixtures, Sm part of the invention.

The compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts form part of the invention. These salts ate Mvamaponsly prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, lot put n> ctg and isolation emupoumN of formula il) also form pmt of the invention?.

Known from the prior m is document WO 2008/138834, which diseases trlsuhstitufed imkteo| 1 >2-b]p|^aäri«£ derivatives of the following general formula (I ) as Inhibitors of kinases of the:Pil-ii»ä»iiniÄI $r#Ä ^Ι|ϋ||

Pl

However, the compounds of .formula {1} possess no aaaeyele as R" group.

Also known from the prior at is document WO 2008/.138889» which describes 3,6-disubstituted imitlmo[l ,2-b]pyridaaine derivatives of the following general formula (2) as inhibitors of kinases of the PB^oase^Äedim^^rlcm^ furniiy:

ψ

However, these compoundtÄ not substituted at position. 2, flfo compounds of IVnrmla (!) may Éao ukisI mthe form of hydrates or solvates, le, in the form of associations or combinations with one or mofo molecules of water or with a plveol ioeh hydrates api solvates also form part of the invention.

In the context of the invention, the following ddflniiops apply; - C*. in which t and z may take values f#m ! to 7» a cafoon~h&amp;sed chain possibly containing from t to z carbon atoms, for example C5.? is a carbon-based chain that may contain from 1 to ? carbon atoms; - alkyl, a linear or branched, satumtólnlij|teitc·0mp; for example, a C{.>~alky! group represents a linear or branched carbon-based ebalu of I to 7 carbon atoms, for example a methyl ethyl, propyl, isopropyl butyl isobutyl, tert-butyl pentyl hexyl or heptyl * aikylene, a linear or branched, satufoted divalent alkyl group, for example a CW aikylene group represent a linear or branched divalent carbon-based chain of 1 to 6 carbon atoms, for example a methylene, ethylene, 1 -mefhylethyiene propylene or butylene; • oycioalkyka cyclic älkylpüifi, for ^^fel^.cycioalkyl gtoup represents a cyclic carbon-based group of 3 to ? carbon atoms, for example a cyelopropyi eyclohutyl cyciopentyl, eye-lohexyl or eycloheptyk - hydroxyl an "OB' group; > -CM a nitrile group; ~ cyclic monoamine, a Saturated cyclic or polyeydle carlofobased:: êbain, optlpmdiy bridged or condsmsed, comprising one nitrogen atom;

Ily way of example of a cyclic monoamine formed by N, A. L and 8 optionally comprising an oxygen atom, .mention may in particular be made of aairidiae, asseüdine. pyrrolidine, piperidine, az coins, morpholine, homopiperidine, deeabydnaquinofme, decahydroisoquisoliue, uxabkyoloheptane, axabicyclooetane, awfokyeiononane* azaoxobicycloheptaae and azaoxobkyelooctane: - hydroxyalkyl an alkyl group in winch one hydrogen atom has been substituted with a hydroxyl group;; - aikyioxy, an -O-alkyl group; - idkylthio, an -S'-alkyl group; - tluoroalkyi, an alkyl group in which one or more hydrogen atoms have been substinted with a fluorine atom; - Ilnoroaikyloxy, an aikyioxy group in wifok one or more hydrogen atoms have been substituted with a Icorine atom; c a halogen atom, a fluorine, chlorine, bromine or iodine atom; ~ aryl, a monocyclic or bieyclic aromáié gimp containing between i and |i carbon atoms. By way of example of an aryl group, mention may be made of phenyl or naphthyl groups.

Among the compounds of general formula tit that aa subjects of the .rnenoon, a first snoop of sunnpunnds is constituted bv the eon'.pounds to* which R- i epreset tts a phenyl optionally substituted with one or store halogen atoms or Cy^aikyl or Cl A-fluomalkyl groups; •A,..t, 1, R.-> end Rsbelngihs Äö®i the mmpmmàs «f geaeral formula (Π that are subjects of the invention, a second group of confounds is constituted by the compounds for which R.j represents a phenvi optionally substituted with one Of more fluorine atoms; A. L, B, R? and R* being as denned above.

Among the compounds of genend finnül a (Γ> that ere subtems A the invention, a third group of compounds is constituted by the compounds tor which Re represents: 8 3-üuorophenyl or 4~Huort>phenyl; A, |u B. R? and R$ being as defined above.

Among the compounds of general formula (1 that are subjects of the invention, a fourth group of compounds is constituted by the compounds tor winch R, represents a C*.*.-alkyl; Cs^-iiuoroalkyi, C».?-cyeloaikyl or C^-cyc-Ioaikyl-C}s~âikyl group, A, L, 8, Rr and Rs being as defined above.

Among tire compounds of general formula (1) that are subjects of the invention, l iil group of compounds is constituted by the compounds lor which R2 represents a mpiyj group; A, h:? 8, R? nsîd Rs being as defined above.

Among the compounds of general formula (Î) that are subjects of the invention, a sixth group of compounds is constituted by the compounds for which R·? and R$ represent, independently of each other, a hydrogen mom or a methyl group:

As 1., .8, and R:$ being as defined above..

Among the compounds of general formula t i) that, are subjects of the invention, a seventh group of compounds is constituted by the compounds lor which;. - A represents a €V?»aiky!ene group bponaity substituted with one of two II« groups; " 8 represents a Clmùkykue group optionally substituted with an :¾ tnmp; ~ l represents amtrogen atom optionally substituted with an R« or 1¾ group; the carbon atoms of A and of B being optionally substituted with one or mote Rr groups. which, may he identical to or different from each other; - two R:, groups may together form a Cumdkylene group; - Ra and R» may together form a bond or a i?;.<;-alkyiene group; - R« and Rv may together lotah a bond or a Ch.^-alkylene group; - R*j arid ft- may together form a bond or a €i.<.-alky!ene group;

Ra represents a group chosen from a hydrogen atom and CWalkyl Cso-cyeloaikyl, Cj ?-cycloaikyl-Ci^-alkyl» hydroxy-C j ^-alkyl CW.aikxloxy^C**-aik yl GwikyUhl'-CW alkyl CWiluoroalkyl or benzyl groups; and

Rf represents a Chalky!, Cur-cyemalkyl. C^reyadoaikyi-CM-alkyl Ci^lkyioxy-C j v alkyl hydroxy-Ci^-aikyl Cns-Buoroalkyl or phenyl group; - Ra> R„, Rc, flu R: and R§ being as defined above.

Among the compounds of general, tormuia (1} that are subjects of the invention, an eighth gronp of compotuA Is constituted by the cmnponnds lor which; * the cyclic amine formed by -hl-A-L-B- represents a piperazinyl diazabicydoheptyi, heaahydropymoI<pyns>lyl or oetahydropyrmlppyridinyl gronp optionally substituted wil ope or more methyl Isopropyl iutylene, phenyl benzyl hydroxymethyl hydroxycityl hydroxypropyl hydmxytnethy|?rppyi or hydmxymethyibuiyi groups; - 1¾ Rf and Ég being as defined above.

Among the edmpounis of general formula (!) that are suhjefts of the indention, a nipil gronp of eohfpotmda is constituted by the compounds for which: - ite cyclic amine ibnned by -N~A-L~8- fipessuts an (.R}l3unethyip:ipera.xin -1 -yl 3lh dimeihyipipurMn''l'>yl, .(cii}sd,5*àiMÂ^p|piÉÉm*.| *yl d-iaopfihaylpipcruzin-l-yl 6,9·· dIaMspiro[4.5]dee-'9^y! d-pheappipragimi-yl 4-benzylpiperaz.in-t-yl. B~ hydroxymethylpipemxlmisyl 4-(2~hydroxyethyl)piperaain4~yis|l)-4d2~hptroxypn3pyly' piperazin -1 -yl f6)-4-(2-ttydroxypnapyi fpiperazin- l -yl, 4-(1 -hplmxy-2~mediylihyspan~2- yifpipera./in-1-yh do Sfeydroxy· ^nethylpropyi ipipsraatim i -yK 4-< ^h\droxy-.>-meíhy!butyl)pipar«iz:itt- I ~yh {.¾)-3 · phenylpiperar.in- ; ~yk (5;-3 - ph enyipipera;on- l-yk 4~ beswylpipera;rin^ys, !vehr5--methylheushydtoovu*k\ Ά > pvrro, ff 1//)-' ,< s' ''λ 4 hydK>xyethy!)hexahydropwn*lo(.Μ >* Ipyrrol ?0/A~>k (*o£ "«#}' * -«thyloo^ahydsö-b/^ pyrroloj 3,4-b]pyridin-6-yí, (4aS 7aSh l-me!hyk>ct;ü>ydrod>//"pym>kí[3,4--djpyridí.n'-6- yl, orf I ^4d5-6"methyl:-2>5“dia2abícyc!o[2.2.1 ]hopk2~yI gdfup;: - R2> R? and R$ being as defined above.

Among the compounds of general formula (!) feat are subjects of the invention, a tenth group of compounds is constituted by fee compounds tor which; ~ Â represents a£l,?~alkylene group optionally substitited wife one or two 11¾ groups; - .Sr^twtnis#:C5.?^kylene-§rt-Jup optionally substituted with an 1¾¾ group; -1. represents a carbon atom optionally substituted with two R,,? groups; the cate atoms of Ά and of B being optionally substituted with one or more Rt- groups, which may be identical to or different from each other; - two R«2 groups form, with the carbon atom that hears them, a cyclic monoamine optionally comprising, an oxygen atom, this cyclic monoamine being optionally substituted with one or more Rf groups, which may he identical to or different ímm. one another; and - R; represents a CWalkyl group; - E.<, R*» Rs, R? and R» being as de lined above,

Among the compounds ol general formula í I; that an, subjects of the invention, an eleventh group of compcmnds is constituted by the compounds tor which; the cyclic amine formed by -N--A~t~S~ represents a diaapsphoundecyl group; R/.-, R? as id Rs being as defused above.

Among the compounds of gmertr form«!,* sit feat are subjects of the inventh-su a twelfth grotsp of compoustds is eon-lsosted ny the compounds lor whsefe 'ív C'· u isoe > oned iw \A 4 coses* oy e fa/, op > h ^ am ce -, atp R> R ’ ind %:lemg as delidé! shorn

Among the compounds of genera! formula (!) that are subjects of the invention, a thirteenth group of compounds is constituted by the compounds tor which: - A rep;ovent\ a fi) '-ulhUeue group; - B represents a C:.r*alky!ene group; » L represents a carbon atom substituted with an Rsj group dp| an Rggroup; : - R.j represents a hydrogen atom; - rAs represents an -NR4R5 group or a cyclic monoamine optionally comprising an oxygen atom, the cyclic monoamine being optionally. ..substituted, -with one or more Rr groups, winch may be identical to or different from one another; and * Rs represents a Co«-alkyl Corcyeloaiky! or CA.7~eyefoa!kyiAh..6-a!kyl group; - R·?, R? and Rs being as defined above.

Among the compounds of ginem! formula (!) that ire subjects of the invention, a fourteenth group of compounds is constituted by the compounds for winch; - A représenta a -Cdhr group - B represents a - tfoHfo group; - L represents a carbon atom substituted with an Roä group am! an R;$ group, V R,| represents &amp; hydrogen atom; luki - iAs represents a pyrrohdiny! group: - Rn R- and R« borne is defined a xn 0.

Among the compounds of genera! formula (!) that are subjects ot the invention, a Ihdeenth group of compounds Is constituted by the compounds for winch:; - the cyclic amine formed by -N-A-l-B- represents a 4-(pwrohdin~;-yOpiperkua- :-yi; · Rj, R? and 1¾ being as defined above.,

Among foe compounds of general formula (!) that are subjects tw toe -mention, a stxmeoth group of compounds; is constituted by the compounds for which: * Fb represeids s methyl group; - fou cyclic amine formed by -NrA~L~B~ represents a (3Ä)-3-methylpiperazin~l -yi, 3,3- dipMtiyipiperafoiî^l-yij, l~yl d-isöpmpyiplperaäit-l-y! or fodyb5-metiiylhc^:afeydropyjTol0[3:,4-e|pyrrol~2( i//)~yi group; and - R7 and R§ represettt a hydrogen atom.

Among the Compounds of general formula (!) that are subjects of the invention, a seventeenth: group of compounds is constituted by the compounds for which: - Rt represents a 3-flaorephenyl or a 4-jluorophenyl group; ·· the: cyclic amine: formed, by ~N'iA4^B·- represents an (Aj-S-methyipiperaäm-h^l!: dimethylpipera^lm>!--yi;? U/si-hS-dimefoyjpiperadn'-]-yi, d-'isopropyipiperaciim-hbi»: fo9-diaEaspiro{4,SPce-§-yh -yi, AfoeneylpiperazmA-yl, 3-

Itydroxyntefoyfotpe^in-1 -yf 4^p»hyd^yeihyl)p5pera2Ín~ 1 -yl„ /S)-4~12foydfox:ypi'0pyi)'-plperazm-f-yl,, fo)-4.-(2-hydmK:y^?0py^pipe!p^m-· 1 -yi 4-( 1 -hydroxy-2-issefoy3:pfopan-2-yl )piperazin-l -yi, 4-(2“hyiroxÿ“2-m:ethyipropyi)piperîmi3>-l -yi,. 4~t 3-hydroxyfo-

Mefoylhutyljgiperszm- 1 -yi, (/i}-3^«Eÿlps|p^zïn-l-yl, (S)-3-phenyipipera®t-l-yi, 4-henzylpiperaztn-i-yL foiyl-5-methylhexahydropyrrolo(3s4»e]pyrrol-2(lAb-yh icish5-(2-èy^KyQihy^kçx^é^ymîolS^JpyïTôi^tM^yl (4A 7aR)·· i -methylpcfohydro-dff-jayrrolofl,4-hjpyridih-b-yi, (4aS, 7aS)~ 1 -meîhyloetahydfo“ë//-pyrrolo[3<4--hjpyddin-ô-yi, or(15,4%S*i5!eÉ|í^2,5-dia^hípydliP,2J]i^líÍ»yji group; and - R? and Ks represent, independently of each other, a hydrogen atom or a methyl group.

Among; foe compounds df pnerai formula (Í) that am subjects of the invention, an eighteenth group of emnpdunds is constituted by the compounds for which: -1½ represents a 4-fídofophenyl group: - the cyclic amine formed by -N-A-L-B- represents a 2,9-41azasphm[5,5]uvídee~P~yl group; and - Rr ami Kg represent a hydrogen atom.

Among the compounds of general formula ID that are subjects of the invention, a ftiöstäsöäti grupp of compiiiöis is etmst&amp;ited by Ae compounds: tbrwhich: - R.> represents a d-tiunropheoyl group; ~ the cyclic amine formed by »M-A-L-B- represents â;4opyrroiimo-l-y!Vpipendin-l-yl group; - ft? mid %fepbrsehi a hydrogen atom, \romig the eon wound of general formula (1} that are subjects of the intention, tnemion may especially be made of the following compounds; L 2*Methyi*64(^b3-m«thylplpera2iö4:*'yl3'-3-'{!ji/«pym)to{'2,3~fe}pyri<liä#- yf }inhdazo( i ,2~b]pyridazme: :|, 6u3 J-Dimethylpip^razin-1 -yiV2-methyb3 ( i//-pym>k>í2,3-b3pyrtdm-4~ yt}imidazo( 1,2-/>]pyridazme and the trihydrochíoríde thereof! 3. Íbf(e/^)'3,5d3inmthytpiperaídn~l~yl|~2~methyl~3~(i//-psmxl0[2,3“b]p>aidin-4ryl}-' imidazo[ L2 ó]pyrídazinc and the trihydtochtoride thereof; 4 6a a bopropUpiperaziw Idddandhxh wJ/opYwolod^dJpyridin-d-yOinudaaoj: 1.2~6}pyridmdne and the trihydroeMoride thereof; 5 2-Metbyl~6~[foft}-5onethyihexahydro:pyrrol<>[3,4-e)pyyr,oi-2(í//}-yíj-3-(i//·' p>m>)0F2,3“bjpyridin-4~yl}imidazo[ I ^-blpyndazhte and the trihydrochloride thereof; 6, 2^4.r,uot**phonyiM>-x,3 medTd,npom/m 1·>Γ '4|//-pyrtplo(2J~ö]pyddin-4~ yffmidazoî 1d-bjpyrídnz Ine: I, {4-(2-{4-Fluorophenyl)-3-( I tf-pyrroloj2,3»è]ppidtn.-4-yl}tmidazo[ 1,2- h\ pyndazin~6~y I j p loeraz i n-2-y I} rneth and ; t, 6-(3,3-Dimethylpiperaztn-1 -yi)-2-(4«f!uorophenyl}· 3 -( 1 iV-pym>lo[2,3~b)pyridin-4-yl}imidazo( 1 Jwlpyridazine; S< 6-( 3>3-Dimethylptperazin- 1 -yl)~2d3-iluorophenyl}-8~methyl -3-( t #-pynv>ioi'2.3- b)pyridm-4-yi)lmidazoi L2-6]pyridazine; 10, 6-(3,3«Dimeöíylpipera2Ín«l-yl)-2-<'4-fluorophenyl)-H~methyl--3-(l//-pym>lo[2,3- ippyridi n-4-y I ) un idazoi h 2-6jpyridazine; 11., 1 * vi]-2 44~fíuoropkenyi>3--(1 M-\\\ ? ? ob[23~ iï!pyndm-4--ÿl)imidsa;}{ ! ,2'/>]pyfidaziöe: 12,2-44'-[2-'(3--lr4ííSorö|dieúyl)-'S''meth)4'-3'-(1/4%pym)lo(2v3'öjpvridía-4~yl)imldazo(lv2~ èjpyridmfï'-ô'yQpipem^m-1 ~yl} ethanol: !3. 2--{4~|2'44"Fluoröpheayl)-3'-meth>4'-3-‘(l2f--pwmlo(2v3'P]pv«dbb~vi)imiiiazo|L2~ 1:(]p)bdaidti--6--yí|p5perasuv 1 -y! 1 ethanol: 14, 2-':(4~Fluorophm)44~6~(4~isopmpy4plpsræiü-'1-'yl)-\vd1i2--p>Trolo[2,3-ôjpyridIn--4.- yöimidazof 1,24%nbdazbe; 15, :2-(4~f luoTOphea:)4Vd-'(4~isopropylpspsr8zm-' 1 ~ylp8~meihyl-'3-{ W»pymde{2.3-á|p.yridio.-4.Tyl)imid.am( 12 ~b}pyúáíxúm; !6. (R)-1 - H~| 244~FíuorophenylFB-methyl-34 1 //^yrrolö[2J-£]pyiidÍ8-4- yl)imidszo[ 1 f2-h]pyrída?.m4í~yl]pipemzm~ 1 ~yl}pmpm~2·<A; 17. {.S>t-14-{244d:1«0iOpher»yl}-S-me1hyl-3-(1//-pyrrf3lo(2x3~/?jpyridin4~ yl.)imidazo[ ! *2-h)pyridaam-d-y13pîper»zm-1 -yl}propan-2-ot; 18, 6~{6,9-Díam«pm>{4.5]dőc~9<'yl)~2:~(4«íl'uoíophenyl}»8'-methyl-3~{1^’i5ym)l.o(2>.3~ .èlpyTi.dm-^y^jmulaxoli^-^pyîidazmec 19, 2- {4~[244-Buorophenyl)~3~(li7-pyrrol.o{2x3~é3pyrídín~4~yljííí»Edazö| t,2-élpyrldazk^€“:yl|pipeimía«l-yl| ^l-methyipmpa«-1 -oh 20. I- {4-434'4''Fluoropheay!)~3-( l-//-^ymdö(2.3'~é]pyndl»~4~yí)tmií.teo| 1 >2 -^pyridazin-6-yl jpiper&amp;zin- i -y!} -2-rnethylpropan-2“OÍ; 21.. 1 - 14424'3-Fl:uoropheoyl)~8-methyl-.H 1 ^p>woío|2,3~^]pyridin“4-yl )?mtdazo[ 1,2-dJpyndtón-6-yl jpipefróa- ! -yl. ! -2 -meíhy lpropan-2-o l; 22, - l·|44244·'-flîιor0phe«y!)«8·'nîethyl"^'‘{-iÄ-pym)lo{2,3'*^|ρyridk}-4-yl)iTOdâ¾o[l.i2~ ^]pyrida2áa»6“yl)p.ipefa2í«* í-yt)· -2-methylpmpa»«2«ol: 23, 4-14~[2-44«Fl«oropheEyl)-3“C 1i/-pyjTolo(23~^]pyrídín»4“yl>i.nüdaxo[.l ,2~ 1> jpynäozm-6-yl jpiperazw-1 -yl | -2-methyibutaa -2 -ol; 24. ()9}--2--(4 -FUK^ropher!yl}-'6-i3-'pru\niylpiperu:?ln-l -)4j -3 -(1/f-pym4:o!2,3'P)pyí4dk^4-yl)imidazo[ i. 2-d]pyridazme and the tríhydrochloride thereof; 25. {5>-2“(4-Fluotophenyl)-é~f3-pheay{p1peíazifí· l»yl|-3~(-l-i7~pyfrol0('23-ih|pyridin-4-yl)itmdazo[l,2-h]pyridazme and the trihydrochloride thereof; 20.2- .4·*· tuorophenviVs-metint-H *'pb^>Ipipera/m-1-yI'-3-x !iï-p^méPltS· f>)pyridm-4-yí)íroida20{ I,2'&amp;jpyridaxise; 27, ö-pfSenzvipiperatán- I -yI)-2<441uort^hm^i}-3<li/^ym>b[2v3-%y!|ííW-^·' umdazoj' 1 2-b)pynŐ2zim; 21, ^>-2-(4~Fíuoít>ph«® yl}-6MS^methyÍteaáyáropymfbí3^c]pym>I~2{ I Η}~γψ'$-(lf/-pym>Io[2,3-ft)pyndÍB4-yi)hiddöH>|L2~/y|pyrída/íT,no; 29 {as > 2 -{4 -Heorophens lt-S-mcíh) l-o-(5-sueth> ihex^yÄp>W)i.o[3,4<'jpym>l~ 2(:^yt}J.{i//vpyra*íoí2,3^)py«din^yl)Umd«>(IJí*ájp><ndazí»«; 30. (m}-2··|5·Γ2-{4·F!uoropheöyI>-3«( 1 //-pym>!o[2J-b]pyridm-4-yipmidas:o| K2-b)pyrida;dn--4-> \ ÍUexahydmpymdof 3„4~</jp\πό!~2( l//)->4 k-riumoh 3 ! , 0.75)-2- {5-[2-{4>Fluoroph^yI)sl*mtHhyl^(i/Opyrmk^2.3-/>J|>yridm-4- y!)imidazop,2-b)pyrida£in--6~yl]hexakydropytToM3,4~e]pyr5-oi~2t IJ/oyi) ethanol; 72 2~k~l^mopLen\i>~8~tm4h>i-ri-tA4-i?. '2í^4-methytoetahydm“fí/3-pyr--okH3.4- ^jpyridtn-6-yi>3-(l2/-pyTrolo[23-h]pyndin-4-y|)imidsxo[1.2-Ä'jpyndaziöe; 33.2- (4-14 uor«phenyl)-S-me%l-6-{{4«S, 7«$)- I -methylocîahÿ<'i©-^pyptlf [1^4-bjpyridiîv~4>-l}-3 -( l//-pym>k>[2t.^/>]pyrkHr,-4-yi)im ids*o[ L2-&amp;]pyrídazune; 34,2 - (4-FI uorophenyl )-6-(( I SAS)-5-melhyl-2,5-di^abtcyc!o[2J, ipepr2~5d)-3 -( W~ pynx4.o(2;.F2>]pyrKlin'-4-y!)iintdMo|'!,2-h!|midajikay 35, 9-[2~(%Flyorp|h«pyi-3-|| /ppyrroioi 2 J -hjpyridm-4-yl hmidazo( l,2-^jp>Ttdaxin-^yl]-2.^#8#^jro|!v5|iiid^ap; 34 2-(4- F! uoropheit5yl}-6-(4^pyrroii:fc-1 -ylpiperidln- I -)4)-3-( I f^pyrnslepj-Fsp\ndtn 4-yFmmhooli.2-o'psmUane, yypother sobfpf of tip ipypripp isdprpopss Iff preparing compounds pf the Ipven&amp;on of formula (I). ln accordance with the invention it is possible to prepare the eompppsil of paaral formula (I) according to the general process described in Scheme I below, 'úfe?rehalÍy,;.Plá: ns illustrated in Scheine t, the 6«o>vk';troino-3-(1 ft-pyrroloj 2,3-&amp;]pyridia* 4-yí}hni<teo[}derivatives of general formula (1) in which R2. A, L 8, R? •Md Ri are m defined afe may be prepared rom a ',// o^ ,\fio ? 3-^ρνΓ«,«ι-4~ yi)hnidaa:o[l^Tfipyridazlue derivative of general formula 1 Ü), in which R> R? and R* are as defined above and 5½ «^reseats a leaving group such as a halogen, by treatrnent using an amine of general formula (III) in which A, L and B are as defined previously. This risadfioh may be carried out by healing the reactants in a fdlaf solvent such as peotanot m ditpefity Isdlpibslde,

The 11 //pyrrolo[23"bjpyridin-4-y!)imidazo[ L2-ó)pyridaaine derivatives of general formula (Π) ns defined above may be obtained from dot twelves of general tonmua (IV) in which R.u X.v R? and R* are as defined above and PCI represents a protecting group 1er protecting an amine Rmodon such as a sulphonate, for example losykneor any other group normally used for the prmeehon of mncaorio, pyrrole or todole (" Protective groups in organic chemistry’*, T, W. Greene mû P, G. M. Wats, 2!!<i Edition, Wiley fnter$eléncev í3É$~39?k The conversion of the derivatives of genetal formula (IV) is then camed dnt via a deproteetioa reaction, for example by treatment using a base such as sodium hydroxide when PC represents a benzene or toluenesulphonyl group.

SCHEME I

m

Alternatively,· the 6~cyc!m«ii«o-3-{ 1 //-pym>Io[2,3"è)pyfid?n.»4«yl)îmida2:o[ 1,2- b}pyrk!azine derivatives of geoeral formols (I) may also be prepared by deproteeling a {i/^pyrîolo[23"^}pynàin-4~yl>xrnnJnj^^jpyrid3me èiivia of general formula x'O in ohioh IT, A, L, lb R , Rs and PG are as defined âi«; llg iæœm of Ihe derivatives of general formula tVl is dien carded out via a deprotection reaction, 1er example by treatment- using a base suck as sodium hydroxide when PG represents a benzene or toiuencsuipKonyi group.

The derivatives of general tbnnula (V) may fie pepafed Imiwatitf formula (iVi as defined above by treahnent using ah alnine of general iormula fill) In which A. i.· and B are as defined previously, heating me reactants in a polar so hem snob as pemaned or dimeifeyisulphoxide,.

The í i//-pym>io[2í3"^]pyriíiin~4->la'núda2o[i,2oy|pyrkia2ine derivatives of general formula (IV c in which R;, X*, R-. Rx an| PG are as defined above, may be prepared by mutabeatalysed coupling according to Suzuki confit lions between a 3-haknmidazo(l,2* tfipyridazlne derivative of general formula (V!) in which Rw X«, R> aodlRy are asieined above whilst ΧΛ represents a bromine or iodine atom and a derivative of general formula (VU) in Which PG is as defined above and M represents a dlhydrosyhoryl or dialkyloxyboryi .ppttp, most iRea a 4,4,5, SdetrptethylG ,3,3,2-dioxaboro ! an~2 -y I group,

The couplings according to the Suzuki method are, for example, carried out by heating in the presence of a catalyst such m ff :1.,1¾ bis(dinhen>îpnosphuîo)iérrocefteldieitiompaHadium and of a mirtefil base such as caesium carbonate, in a mixture of solvents such as dioxane and water.

The 3-ha!o-{ ii/4ayrrokti2J3-b]pyridin-'4-yl)itnidazo[ 1,2-ólpyridazíne derivatives of genesnl formula (Vi| and the derivatives of general Imnula (VII) as defined above ate known or may fee prepared according to methods known to a person skilled In the rat.

In certain eases, He b-eyeioarninu-3-(IGpytyoin|.|^ blpyridaxine derivatives ofgeneral formula (1} for which the amine formed by M, L. A arid B comprises a second secondary of tertiary amine iuay he prepared respect;vdy (Vorn the corresponding primary or secondary amine by alkylation or reductive amination according to methods customary for a person skilled in the art.

In certain cases., the derivatives: of general formulae (1} or (V) as defined above with m IN* A-L-B group comprising a primary or secondary amine function, may be protected during the. spfeis; at this, primary m secondary amine fonction by a protecting group* tor example a benzyl or a. tfoutylnxyeafoonyL

The: products of general structure f|| as defined above are then obtained: according to the processes described, after a supplementary step of deprotection of the protecting group according: to the usual conditions known to· the person skilled in the art. fs^ytög..gi:öMis

In the foregoing, the: expression "leaving group" is understood to mean a group which may be easily cleaved ftom a molecule by breaking a heteolysis bond, with the departure of a pair of electrons, This; group may, for example, thus be readily replaced with another group during a substitution reaction. Such leaving groups are, for exempte halogens or an activated hydroxy! group such as a mesyl. tosyi, trilláié, acetyl, etc.. Examples of leaving groups and also references for the preparation thereof are given in "Advances in Organic Chemistry”, J. March. 3!0 Edition, Wilev Interscience, p. 31.0-316.

The following examples describe foe peparation. of eeftaln compounds in accordance with the invention. These examples are not limiting and setw only to llkstrafo the Invention, The numbers of the compounds exemplified refer to those given in Table 1, hereinafter, which illustrates the chemical structures and the physical, properties, respectively, of a number of compounds according to the invention.

Example I (compomtd No. 29); {Os>2-(44Ί«0rnpheny 1 >-8~mel:hyi-é-(S-i0gt&amp;¥i- !iexíUivdmpyrsoloP,4'<|pyrroI-2(l//}-yi^341//-pvrrol<>i2,3--(?||>yridlE'4- yï }imid a m f 1 ,2-éi py rtd a due

Step 1.1: 6>~C'hl0m~4“.meihyipyTi4a25in~5“ylamtee mâ é<Mare"S-methylpyíidaxtm3'· ylatnine

A mixture of 50,0 g <307 mmoi) al3,6*dicMoîO«4.methyipyrida2:be in 170 mi of aqueous ammonia (30%) is heated ai 12(Ρ€ for !6 h in a steel reactor at an internal pressure of 10 bar.

The reactor is cooled and the reaction mixture ts poured into 200 mi of water. The aohd fanned is isolated by filtration and dried under vacuum to give 38.7 g of a mixture containing around 45% of 6-chloro~4mtethylpynda£m--3--ylamifte (CAS 64008-00-4) and 55% of 6-cMoro~5~methyipyrida:Ae~3~yiamine (CAS 06346-87-0), *H NMR (CDC1A o; 7.20 and 6,75 (2s, IB); 01 0.55H); 4.9 (si 2H): 2,40 and 2.25 (2s, 3H) ppm.

Step ! ,2 6-Chloro-2-(4.tluorophenyiVS»methylimitiu2:o[ 1,2-6]pyxidazine and 6- cbioro-2-(4~.Ouorophenyl|-7-mrrthyliffikfetm[ L2-6]pvri.danine

1h« mixture aí76 gphO mmol| M ÏCÂ&amp;ÆÈ’M-W} with 38.7 g (269 mmolt of Ute mixture of 0<h!cn\>--4--nun1tyipyTt4azxn~3-vlan^ne and oi b* chlaro-5-moths hsyndarin·) \Umine obtained in stop Li m 500 ml ot n-butanoi is heated at I20c€ for 18 hours.

The solvent is removal by evaporation under reduced pressure and the solid is triturated in acetone; After chilling, the solid is separated by nitration. The filtrate is concentrated $3É@r .reduced. pressure- :a»d the residue is triturated in dtethvl drier After ehtlUng, the solvent is again separated by filtration. The two batches of solid (75 g) are combined and dissolved: In 1 I of water- The solution is hasi fi ed by addition of aqueous am.mo.ma and the product is exti-eted wm ehlototbrm. The organic phase .s dried over sodium sulphate má the solvent is ex aporafcd under reduced ptessure to give a red-brow solid. 1 he separation of the two Isomers is carried out by chromatography on a silica gel column (2 x 800 gt by elating with; dichlaromethane, 2 U g of 6-00101-0-2-(4-11 uoropbenyl)-8-rpefhyiimtdaxop,2"%^ in the form of a beige solid after trituration, hi isopropyl ether, chilling, filtration and drying,

MIA 210-212eC hi NMR (tΙΧΊο 6; 8 29 fjD, g,0t) (d4 2Hi; 7,25 <pft 2H); 6.95 (s. 1H); 2.75 (s, 3H) ppm, iloutinumg the:elation:: with a mixture of 2% methanol ii dichloromethane gives 32.0 g of 6-chioro-2-(4~ftuomphenyi}-7mmthylimidsxo[L27>]pyridarine In the form df a belgt solid after trituration in isopropyl ether, chilling* filtration and drying,

MP; 1.96-m°C 41 N MR (CDClj) o; 8.15 (s. 1H): 8.00 (44 21 la 7,80 (s, .1 H>: 7.20 (pt. 2HL 2.55 ts. 3H) ppm.

Step fj

Âifigsà to &amp; »pÄSO» of il;!.t) :g; ::(13,7 JHÄll imida?o£ I -2-/>jpvTt<Jaxír«e m $Λ im! of cldqoafono are 2(14 :g ||:20 mmol) pi Iodine monochloríde m sp|:»tío«. in 40 to SO mi of moihnpol. Älter sdmhg Èît:-2 ocpifs r4 antbiont letrperalurm 5.0 g (31 onno!) of iodine mmpsftlori#? m solution in tárnod 10 mi of rnelh&amp;rml are again, added. Äef birring lor a Äther 2; loom, the solddon is pouppi: mm S0Û ml # mi aqueous sqiqtion of sodium hydrogen oatAmde mad;the mixtme is Iremed, with eigemns stirpng,: wild sodium ihmsulpkue wined is added jq popoqs tmtithe mixture lrdesÂmeé(red 1© pllow):. !fbd organic phase m separated, dried deer sodium sulphate &amp;$ eeaporadon under redoeed pressure. I'he solid obtained is then trilutsfod in aeetoditfihx the suspensioti. iS ebided and the solid is isolated by filtrálón to give 30:.21 '#. (d-lluorophenyll^S-iodo-'S-melhylirnidaaoil ,|>’bjpyriiaa:ine in fc iarprot a Jbeige; powder,

MF: i 40-192°C ]H NMR (CDCb) 4: .8.05 idd, 2Hn 740 (pi. 2.11): 6,00 (s. 1H); 2.65 is, 3H> ppm.

Step 1.4 P>Ch!oro'2-(4-il!aompfeeny|--S »methyl M-p ^hs^lhö^N3d5dM.//- pyrrole! 2,3-rïjpyriolî152

Adçki te a Mixtim which has Ipgp and is under argon, of 5.00 g ( 12.$ mmol) of 6-ohioro-2-(4- tiuorophenyi}-3-iodo-8Hmethyiimid?i£o( i J-blpyrtdadne, 195 g {15.5 mmol) of 1 -(phoriy Isulphonyl }-4-{4,4,5<5-ietmoie?hyi-1 ,3,2-dionsbor-o!un-2-yi). 1 f/“pyrroloF2.3-fcjpyridiuc (CAS 942019-24-6) and 12,6 g (38.7 mmol) of caesium carbonate in 50 mi of o mixture of nttrahydmfumn and water (9.-1) are 0,05 g (1.2 mmol) of a leompiex of [hr-biSidiphenylphoaphincOfenOceneipailadiumiu} and diehtoromethane. fho mixture a. heated. under roihrx for )9 hour«, then poured over 300 ml of water. The product is extruded with diddoromethane. The organic phase is separated dries! over sodium sulphate and the solvent is removed by evaporation under rcdticod pmssurs. The chestnut brown solid obtained is then chromatographed over a silica gel eblartmf200 g) by clining with a mixture of dichioromethane, methanol and aqueous ammonia (07/3/0.3) in order to give 55/0 g of 6-düom-2-{4-nuotophenyi)-S-methyb3-[l~(phenyisulptony!)·· ii/pyrîOlo|7 * "htyndni'4.)|htmlu'mhC/ùp}s uh-onc hi the loun of i icl'ow powder after trituration hi isopropyl ether, dulling, fibration and drying.

MP: 226-228 C T-l NMR (CDCt.o ô: 8.6S (il iHi; 8,30 (d. 2H); 7.9 im. 7H>; 7.05 (m. 3H): 6.10 (d, IH); 2,30 is, 311) ppm.

Stop IIS 6-Chlom-2'(4-fiuorxrphcnyl)-8-methyl-3-( l/fipyrroio[2,3'b]pyridin-4* yl)imidpo{‘ 1,2-/>]pyiidaxine

\cu oo vO λ suspension of ί> N μ dl nmol' ot ο ο»' η\>2 χ- ' χηορηοηΦ 5 wednl '· {i^phenylsuiphonyl}'-1 &amp;-ρ>ττο1ο[2.3^]pyridin^^ilimi4a2o{ \J~bjpyrid&amp;úne in 10 mi of a mixture of methanol and a few ml of teimhydmforan is 032 mi (1,9 mmol) of a 6N aqueous aohmon of s>\in.ra hxdroxtde Ihe mixture gradually become homogeneous and the reaction is átírod tic 20 mmoies. t he reaction medium i$ diluted n ith 100 ml of nmer and the product is extracted vuth dichmromethane, The organic phase is separated, dried ewer sodium sulphate and the solvent is removed by evaporation ander reduced pressure, The orange solid obtained is then chromatographed over a silica gel column (35 g) by «luting with a mixture of diehloromethane, methanol and aqueous ammonia (95/5/0.5) in order to give 0.293 g of 6-ehloro-2-(441uomphefiyl)-8~methyl3~(i/f-pyrroioj;2,3~ /.f|pyridin*4-yl)imidae.oi i3b>]pyridaaine in the form of a yellow powder after trituration in isopropyl ether, dulling, filtration and drying,

MF: 226~228°C

Hi NMR (CDCld 8: 9.5 (si, 1H); 8.40 id, 1H): 7.55 (d. 2H): 7.30 (d, ΙΗ,κ 7,2 (m, IBs: 6,9 (m. 3H>: 5.90 (m. 1H); 2.70 is. 3H) ppm.

Step 1.6 ίί λ> 2 :4 lue s pi >„ nil h met ed o OîO 9 methylhexah>bmpyrrolo|3,4-dpyrml.-2( 1 f/)-y!p3-(i H- pyrmlo(2!a-5jp\|tdlm4·-yi)imidmïo| 1,2-/>lpyftdaxinc

In a sealed tubs the mixture of 0.2b g (0.77 mmol) of 6-ehtotm2-(4"fiuoropheny(y)0 methyl-3-0 /7qy>moio[2.37>jpyTldim4-yi}tmidazof H2"hjpynda:rme, 0.. K? g 10.02 mmol) of (eômoeîahydro-6//-2oneihyipyrmiop,4»c]pyrre>!e (CAS 172730-03-6) and 0.11 ml 1037 mmol5 of trietbvl nmue m 4 mi of pmr.anoi m heated ai !5t>'0 tor ?t> hours.

After; eobtiog* tbs reaction;mixture Is poured into 00 ml öf a Tff aqueous solution of hvdrdcldorio acid; and ilso solulioit Is washed with .etftfl. acetate, The aqueous phase is then hasiíkd by addition of aqueous ammonia and the product is exiwhsd with dichloromsthane, 1 ne organic phase ts separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The cheHaot brown oil, obtained: is then ehmntatdgfaphed over a bilisa gel column (II g) by eluting with a mixture of dichloromeihane, methanol and aqueous ammonia (9()/10/1) in ruder to give U >e t g d 2-(4 tluoropK op ^ oetb" lb , v ** *> r u v K'\ whopxnolo M so 2(i.i/)->li“.Mi//“pymdo(2.3^ pyridn^4->Ouuidrtzo(i.2-hlpyndaaine in the form of a beige powder after Irlturadon hi diethyl ether, chilling, fi Und ton and drying, MP: 25577 (decomposition} lH NMR (D.MSO-d<;) §: 11.7 (S> IB): 8.35 (d, IH); 7.50 dm 211); 7.40 (d, ill); 730 (d, IB); 7,1 ipt. 2H); 0.90 (ms IHi; 5.90 (d, IH); 3.50 (m, 2H); 3,20 idd, 2H); 2.85 (m, 2H); 2 JO (ss 3H); 2.45 (m, 2H); 2.4« (m. ./Hi; 2,20 (s, 3ff) ppm.- pyrrolof2dt-l|pyrtdiu-4-yi)imidami|.1,2-bipyridat:pe

Stop .2v.L

0~Chioro· 3 -iodo~2 -methyl imidazoi 1, 2 -&amp;)pyridazine

Added to a solution of 7.00 g (4|,B mmol) of 6-chlo:4K2onethyf inddarof1k-o]pyrid;edne {CAS id/934)0-1} In 300 mi of chloroform» cooled to 0°C are 10.2 g (62.7 mmol) of iodine monocldorlde in oolntiod m 20 mi of methanol; The reactiOnls than tót at aruhient iemg#ttt«re for 16 hourathen poured over a aliwfa 5% and of sodium hydrogen carbonate. The produet is extracted #ith dlehloromeihune, the otpnk phase is dried over sodium sulphate and the solvent is evaporated under reduced pressure..

The solid1 reildde 1$ triturated with acetonitrile,, then isolated he iltralion in order to give, aller drying». 8.5 g of 6-eliknx>30odo-2-metliyUmidazofk.2-ô]pyridaalne iu the form of a yellow solid. *H.HR (CDCh) δ; 7.80 (d, !H);7.i0{d, Ml); 2,55 is. )H) ppm>

Stop 2.2. f-C'feoC-methyMH^ h}pyTidiâî-4-yl} imidaro[ 1,2--n1pyddmne

Added to a mixture. mkkkhm 15¾ previously degassed and is under argon, of 0.470 g iLou unnod of n<h!om-ModoOnneih\imnda/o! 1,ΤΗθ> Marine, 0,765 g * 1A2 mmol) of 1 -(* 4-meth> Iphutydsulphonyl | •4»(4*4<5v5~tetram«tbv 1-1 J,2ulioxaboroiarn2-yl}- 1/A pyrrok>[2.3djpyridine {CAS 916176-50-6} and 1.56 g (4 JO mmol) of caesium carbonate: in m ml of a :Äahydidft» and; water (9/i)» is 0,12 g (0.14 mmol) of a ««duplex -ff (l«lC^(di§jbf4|l^l^^ii^)fmo#4^^idHadium(!!) dtchloride and pf die!|orotdedtaae. Ihp .üftire is fe«at##ßäÄ;ÄÄ^ for 18 hours, then poured into 100 ml of water. The product is extracted with dichioromethane. The organic phase is separated, dried over sodium sulphate and the solvent is: removed by evaporation mater reduced presume, The chestnut brown solid obtained is then chromatographed over an: aminopropyl-grafted silica gel column (SiS’H:: 30 g) by eluting with a mixture of die kkmmw thane and petroleum ether (70/30) in order to give 0,42 g of ó-ehíorö-2-methyl· 3- {f-iX4-ntethyiphenyi(s«iphonyi]· 1 //••pyrrcdoid.J-hjpyrtdittA-yl lkmdazo(l,2-o)pyfiia2Éw in the form of a white powder,

M!>: l .18·· 14ööC lU NMR (CDCh) Ő: 8.50 (d, LH>; 8,10 (d, 2hi); 7.85 (d, ill); 7.75 (d, IH); 7,25 (d 2H.K 7.05 g, IHg 6.30 td> 1H); 2.45 (s, 3H); 2.35 (s, 3H) ppny

Stop 2 J, 1 -yi)-3-{l -[(4- méihÿlph^l)MÎ|teh|lj4Âpy«ôloC23~%^din-4-yl} imidaso[ 1,2-ólpyridaaiue

A mixturp: of 0.325 g (0,97 mmol) ot o-ehloto^ mvdhvl-3- ( I -[* 4. mcth> Iphcny I tsulphons ! )- Í //~ps rrolo[22-h)p\ ; idio-4~} ! : inndc ·< *.1,2- HpyritWine. 0. 15 g i I .5 mmol) of (2ITr2-meihyipipmsdne and d,10 ml «0.74 mano!) of trieihylamiMah 1M of pentaool is heated under relias for 3 days at 130°C. The reaction medium is diluted with 100 ml ;.d a IN aqueous solution oi'bsdrochlorie acid and the solo non. is v. ashed with ethyl acetate. The aqueous phase is then basified by addition of aqueous ammonia and the product is extracted with dichloromethane, The organic phase is separated, dried over sodium sulphate and the solvent. Is removed by evaporation under reduced pressure. The chestnut brown o.U obtained is then chromatographed over a silica gel column (33 g) by ehnmgwnh a tmMure of dichloromethane; methanol and aqueous ammonia (90/10/1) in order to give 0293 g. of 2ouethylT>-ii3//)2~msthyl.p.iperarin~i-yij~3~ll.~[f4~ meth>tphcrísitsulphonvif'Í/-/-pv noT;2.3~b]p>ririin~4~yl (inridaao) 1<2“/.dpyndmdne in the form of a yellow oil alter drying. 1B NMR (CDCb) $: 8.60 (d, !H); 8.20 (d. 2H): 7.80 { d, 1H): 725 id, !H>; 7,40 (a, !B§;: 7.35 (d. 2B); 6.90 (d, iii); 6.55 (d( IB); 3.8 <m, 2H): 2.9 (m, 1H.K 2.7 (m, 3H); 2.40 (s. 3H): 7Λ5 (nr Bh, 2.25 (ri, IB); 0.95 id, 3H) ppm.

Step 2.4, 2~hlethy 1-6-((R)~3-methy Iplper&amp;dn-1 -> 1)-3-( I //-pyrrolof 2,3~b jpyridin-4- y i)hmdaro[ 1,2-6 jpyddaaáne

Added to a solution of 0.300 g ίθ.60 mmol) of 2-meihyT64(3iB-3'Umthyipiperaasn-l-y!)>-3-{ Î -[(44tíeihyiphenyí)sulphrmyl]-l/TpyrrdÍoi2,3~6]pyridm-4~yl}ipúdasA>[ 1,2~ 6)pyridaiàne in 5 ml of methanol is 0,20 ml Ü.6 mmol) of a 6N aqueous solution of sodi urn hydrox ide, 'The mixture is heated at 60°C tor I hour then poured into löd ml of water. The product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The -residue obtained is then elnmnatographed over a silica gel column -(15 g) by eluting with a mixtum of clichlororaethane, methanol and aqueous ammonia tWiö/l) in order to give 0,195 g of 2-methyjr6-[0^}“-3«methyipiperasiir~ 1 -yi)--3-(J i:b-pyrrfik>|2.3dylpyridhi-4->d)imidaeo|Lv2-'ó]pwidaaine ater trituration in düsopropyt ether, chilling, filtration and drying. MF: 202-20441 [alpha]·} - + 29.0° (ClhOIL c- 0,683 g/lOOml) ‘H NMR (CDClj) 4 S.35 id, IH); 7.80 (4 1H); 7.50 hi ÎH>; 430 (4 1H>; 7.20 (d, 1H.K 6.30 td. Ill); 3.85 (m, 2H); 2,9 On, IH); 2.7 (rn, 3H); 2.40 (s, 3H); 2.35 tug IH); 2.2 (si, I Hg 0.95 id, 3.H) ppm.

Example 3 (eomeeund No, bp 2-(4~F1unrnptK>n>1)~6~{<3Ä)~3~methylpiperaxi»~l«yll->3-' {i//“pyrrol0|2«.3~if|p>'riclin"4-yl)imidstx©ri.,2''61pyndäxine

Step 3.1, b-'Chioro~2~i4~0uôrpp|îenyiE3'âodoimidaeo[ls2'gj]ps4dMtne A solution of 6.6 i g 140.9 mmol) of iodine monochloridu in 40 ml of chloroform is added in a rapid dropwise manner to a solution, cooled to 1FC, of 3.20 g {21.0 tntnoi) of 6- chloro-2-t4-Hmm^hemllutù&amp;uofL2-4i|nrUfctf me iCAS number; 24408 S-7CI-7) M !3ö mi of elbomiomt. After tidpftng m atobtest temperature and after stirring tor 4 ;Ji«ÄÄe mixture m heated with -t Bi aqueous solution of sodium thiosulphate. 'Πιο product Is extracted with di#Iotomothá»ó, the organic pdas® is died by filtration over a hydrophobie filtration cartridge and concentrated undor redbeed pressure. The residue is triturated p aceibnitÄ the solid is isolated niter filpiod nil riding with diisopropyt; ether. 52? g of Mid;:powder aie isolated alter drying under Vaeount,

MP; 215CC "MíI.IüIMR íDMSOd,} b: 8,20 (m; 3H>, 7.40 (m, 3ΙΊ) ppm, fiep 3,d> iAlhloro-2-(4- îluorophenvl)-3- {I -[(4-methyiphen)4|plftbonyl]”lÄ pymolopjddpyridm-i-yl Ï tmidazo« 1,2Tjpyrl<üwmc

Added to a mixture, which has hep previously degassed and is under argon, of 0.732 g |2,09 mmol) of 6-ehiom-2«(4-fî«oK>phenyl)*3·iodoimidazof 1>2>b}pyrid&amp;rine, 1.00 g pJt mmol) of l~[(4-metíty1phenyi)sujphonylj-4-í4.4,S,5'ietrametftylri JJ-dioxafeomMw l»|l)xl:H"Pyrroío(23«-ójpyridine (CAS 910176-5196} aed 2.05 g (6.28 mmol) of caesium carbonate m 15 ml o! a unsure of tetrulndíoíuruu and water p) Π is 0.13 g 10,19 mmol) of a complex of [MMriridiphen>lphosp]dno)ierroccne}pulladtmn<f!) dichloride and of dichloromethand. Tho nnvmre is beded under reiux tor 11 hours, then poured into 100 oft of water. The promtet is extracted with dichlomtnethmtefThe organic phase is separated, dried over iodfunt sulphate and the Solvent is removed by evaporation under reduced pressure. The chestnut brown solid obtained is thou chromatographed over an aminopropyl-graded silica gel column (5730¾ 30 g) by eluting with a mixture of dîcMÂÂÈÂ: and petroleum ether 170/30} m order to give 0.62 g of 6-chlon>2-(4-tluorophenyl V Tqbp 4- meth\ iphenyltsuipkony I j- lib pyrrole! 2.3 -A lp\ f >din-4-yll'ímid^ol U2»b]pyúá&amp;zmc in the form of a white powder. MP: 244-246^:: NMR (CDCI,) 6; 8.50#, IH); 8.05 Id, 2H); 7.9$ {<1, IB); 7.55 (d, IH); 7.4 Cm. 31# 7,25 (m, 2H); 7.10 (d, iH); 6.30 (t, 2H); 5.95 (4 Iff); 2.35 (4 3H> ppm.

Step 3.3, 2-{4-Iduorophenyi}--6-{(3c?}--3'-methyi|hperemti-i#j-'3-2idC4-· methyiphenyl)su!pkmyl )-1 iï-pymïoi 23 -61pyriblm4~yn mndazo{ i .2 #py úám ne

A mixture of 0.330 g (0,58 mmol) of 6-ehk>i»-2-44-fluor«phetiyl}-3-{ i-(*4-5rmthylphseyl)xulphon>4]-l//#>Trr4o[2,39:dpyodin-4«y!)lmkiaxo[L2-/)]p>Tkkzitte, 0.Í 16 g {1.16 mmol) of (2/#2-inethyipiperaAe |pd 0.08 mi {9,6 mmoiiof trtethylmhine in $ m! of pentauol 1¾ bested under reflux for 24 hours. The reaction medium is diluted with .100 mi of an aqueous solution of hydrochloric acid and the solution is washed with ethyl acetate. The aqueous phase is then basiiied by addition of aqueous ammonia and the product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The •chestnut brown solid obtained is then purified by chromatography on a silica gel column PS g) by eluting with a mixture of diehlorotnethane, methanol and aqueous ammonia (95/5/0.5) in order to give 9.232 g of 2-(4- jflnorophenyi}-6-|(3^)-3-metiyipipq^Â%>î)4 3- {1 "i(4-methylphettyl)sulphonyl}· 1 Af-pyrrolo(2,3-Ajpyddia-4-yl ) imidazoi i ,2-Afpyridazine in the form of a yellow powder after drying,:

.MF: 2$3"256*C H NMR ·Λ"ΐ>0.) à, 3 N"· (d, ÎÜV 8.20 uf 2 H). ' » t d, IHk 7.65 ui !H); 7.5 On. 3H,K 135 (m, 2B)\ 7il («b 3H); 6.20 <d, 11% 3.9 |m. 211 κ ' 1 pu, lli\ 2 A* rn. TU' 2 ^ im 11·!); 2.50 (s, 3TI); IJ (si); 1.10 (d 3H) ppm.

Step 3.4. 244%lanrs4dieeyl)-6-[(3(?)-3-methyîpiperazm-1 -y! ;-3-{ ! //-pyrroiojdLV 0]pYn0in-4'-y! )!mld aM|l J-I>]pyridaa!»e

Added to a solution of 0,230 g (0.40 romol! of 2d4~fiaotop0eeyl)-<!4(3/?)--3-methylpiperazin·- ! -yl] '3 - * 1 yl.· modo tîî ! Jvfpy \lvme obtained >n step 3 J m 5 ml of methanol. s\ on ml ¢0 "6 pnnoii of a 6N aqueous solation of l|ditin ept|<|e, The mlbtdre Is heated at iö% lor 30 minutes then poured into 100 ml of water. The product is mkm^á with diehknomethane, The organic phase is s%arated< dried over sodium sulphate and the solvent is removed: by evaporation under reduced pressure. The residue obtained is recryslailissed in acetonitrile in order to give 0.136 g of 2-(4-'ß.Uorophenyl>6>((3i(h3-·· methylpiperazhu! i ,2~o]pyrMaxine aber drying.

Mf : 285-18743 [alpha]:> « e 4,8^ tdichloromethane, c ™ 0.998 g/IOOml): *H NMR iVlh hi 3 Jj ,4. Ht\ J % Hit, ' ^ % HB " (m. 2H); 7.30 id. 1H); 7.13 {d, IH); 0.085 tm, 4Hh 6.0 (s. !H); 3 80 cm, 2H); 3.45 IHi; 2,95 ($, I H); 2J0 (m. 3H): 2.40 pn. 2H); 1.00 id. 5H) ppm. ilsnmqfé ;4______(eomimnad .No, 13); 2-|4~(2-(4~Ι^οηψ&amp;ν?η I}'S~m<uhyK?»{f//- p> rr»N|2»3~è|p>Ti<li«~4»yi)!isil:da2<>|i»2-élpyrida*ia“it“yi||>lper8xî»-' 1 ~yi)ethafedi

Step 4. !.. 2~ (4~[2-(4~Fíuorophmyl)-S-methy!-3-{ I Hphenybuiphonyl]-UI~ pyrroiof 2,3-b)pyridm-4-yl} imiduzop.2-/>JpyndaxÍK~6-y1jpíperaaá»-1 -y!} ethanol

A -üAtoo of 0 ν'Ά μ 0 02 mmol) of 6«ch!ooOO't1iK>ropheftyr*S-jocthyl-^[l· (phenyls«lphoayl)»yY"pym)!o{2,3-4|pynáin-4-yl}imiduío[L2-/>jpyrtda/ine% prepared according to the method described hi step 1.4 hum Example 1, 0.266 g (2.05 mmol) of 1-so h y droxyet h y 1) piperaz i ne (CAS 103-76-4) and 0.14 ml (|.{) -nmol} of trieihylamine m 5 ml of pentane! is stirred for 2 days at 15045 The inaction «tedium is diluted with 20 ml of an aqueous solution of .hydrochloric acid and the solution is washed with ethyl acetate. The aqueous phase is then hasi tied by addition of aqueous ammonia and the product is extracted with dkhiororoethane, The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. 'The brown oil obtained is then purified by chromatography on a silica gel column (40 g) by eluting with a mixture of diehloromethane, methanol and aqueous ammonia (95/5/().5} in order to give 0.22(1 g of 2' ; 4-(2 -(4-tlues opheso d-f methyi-3- ( 1 -fphenylsulphonyll-1 ftf-pym>inf2.3~ />jpynvnn-4~\ 1 ) mcdaxo( bdmipvride/ m~6q npipermdn-l-yik^dianoi in the form of an amnrp tas p»kr which x$ «sed k the hsliowing step

Hi NMR iCDCb) 6: 8.40 (d, IHy 8.15 (d„ 2H): 7.6-7.3 on, 7H); 6.85 fpt, 2B): 6.65 (s, 114); 6.05 pi IB); 3.6 (m, 214); 3,3 (m. 4H); 2.6 (s. 3fi); 2.5 tm. 614) ppm.

Step 4,2, 2- |4..[2--{4-Fluorüpheïwi|*8-migt|iR|'|!|f-pÿ^0lo|23-7î]p^kk-4'· yilmidazol 1 ,2d?)pyriä4ein--6-y! jpmerakn- l~yl) ethanol

Added to a solution of 0,22 g (036 mmol) of 2« |4«(2*(4«f!uoropheny!)-8*.melhy}~3·-(.1 -[phenylsulphonyfj -1 /Apynoloi 23-é]pyrklin-4-yi} inndplöf1,2*6]pyndaain"6-yI]piperazio-Hyllethanol in S ml *n' a mixture of tetnihydrofhran and methanol 0/1)» k 0.12 ml (0.72 rnrnoü of a 6N aqueous solution of sodium hydroxide, $0¾ tor 1 bom', then poured into 20 mil of water, The product k extracted mth dichloromclhane. The organic phase is separated, dried oxer sodium sulphate and the solvent in remoxed Hx ex tpo'uKon under "educed pressure, ihe yellowish residue obtained is then purified by chromatography on a silica gel column (40 g) by eluting with a mixture of diehloromcthane, methanol and aqueous ammonia (95/5/0.5) in order to give 1).110 g of 2-14~[2~(4~ί]uorophen víV s -me?hyi~3-( I //-pyrrolo[2,3-6]pyridin~4~yi)imKÍax.o! l ,2· èjpyrids7in~6-yi jpipörastin-1 -y! ! ethanol öfter crystal lkadon m 10 mi oi acetonitrile, nitration and drying, MF: 239-2423."

Hi NMR (CDCij) 6: 8.35 id, IH); 7.55 (2d, 2H); 7,40 id, 1H); 7.30 (d, I Hit 7.20 ( s, ÎH); 7,10 fpt, 2Ü); 5.90 (d.. Hip 4.40 q. i fig V50 on, .34), 3 3 ,m. dH ^ 60 «> 3Η: ^ V (m. 4M); 2,40 (t, IE) ppm. JO?* 351,- 9»f2^”i!iiir^pfemyt^4!4llj~pyrmioi2 3~k\pynám*4*

Itæp 5,1, 9^f 1^Φ0»|ίΙ^#)τ1)-3·>[ ! ~{4~t»e&amp;yIp|myb\iIpho»yl)~ 1 //- p^imbpj^è|p^i|||^^|iwîd^||>2'i^|s>Âte^in~6~yi}~2.9;*dia2Îa<5pm>[5.5J«ndec^ïe“2- egthmylate

A mixture of 0,15 g (0.29 mmol) of 6-ch!oro-.2-i4-'Î1uorophtiïjy1)'3>[ i 44~ mtíthylphenylsulpbooyiV I 1/-ρ>ττοΙο[2.3 J]pyndm-4-% l }imidaæo[ i ,2-0 ;pyrida?ine; f'eruaod i^vOKiaui \> A \soJk\I Jcsué'vd m ata,'· î * ot Fsamph \ 0 '/ " |(USmmc-l} of kat-butyl 2 -0-dias?aepi ro{ 5.5]u«decane-2-carboxy hfct hydrochloride {1:1} (CAS Í023301--88-3} .mâ 0,224 g (LT tmBoi} of diisopropyloüiylamkssí mt nàipf pealpKî! Is heated «?«fer'reftny ifbr 402àooo -at 14CI'C. 1 fee solvent is tnen ev^s^Mt^isá^Wiucbcl· pjtmm and the reside k puátled by dhroeiogfaply on a silica gel coluam hy eMi«g with a gradient of dichbromethaae, methanol and aqueous ammonia (of mm M 00/10.1} lh orfe to give 0,190 mg of terhbutyi 9.pH4Ao^heaylVH1#l~ mcthytphenyts.ulphonylV1/f->pyn-olo[2.3“^)pyr5^ta~4->1jimid3xo[L2~^}pyrida«in^yli?

jk-dmssp i roi S. 5] un dee ane J^arhosy late; e^stndkation *h methanoL imp 5,4 "IFèrt-buivi 9-j N» 4Hluorophon>h» H l/i-p>^r<dop,3'b)p>ridm~4~

Mhmuhwt I^Y^rulíuán o-yl]·-’* ^.w^pm^5.5'u^d«ct»e^vaTK>\>Ut«

The ten-butyl *->- pud dlumopheny0-3 q l-M-mothsifhom Oulpheus 1)-'.0/-pymolo ' 5 Mp>Tkhn--4-yl]imidaxoi t .2-bjpyrtdamn-b-yt b-2,9~diaaaapirol 5.5 jtotdecane--2-earboxylate obtained in step 5.1 is dissolved m 3 nil of it mixture of methanol and tetrahydrofuran (2/1 ; and is treated using 0,09 ml (0.54 mmob of a ON aqueous solution of sodium hydroxide at (?(0€ for 1 and a half hours. The solvent is evaporated under reduced pressure and the residue taken up m 5 ml of water. 1 he product ts oxtrscteo 3 times v- ith 3 ml of dlehioromethane. The organic phase is dried over sodium sulphate and the solvent is rerno'- ed by m apooanou under reduced pressure, The residue obtained es thon penned by €Ítromsíogp|?hy m a silica gel column (4 g) bf elming Äh a gradîidtt of diehloromethane, methanol arid aqueous ammonia (of 95/5/05 ίο 90/10/1) In order to give 0.06 g of iert-hutyt 942-(4'Ouorophenyl)~3d l/f~p>Trolo[2,3-b!|ppi.di«f4-yi).tmidaíí<>fU2;« /qpyridamndhyl i--2,9-dln^aspiro[5,5]undecano^2--carboxylate after crystallisation in .1.0 ml of acetonitrile, filtration and drying,

MF: 192-193aC M4H-1S2 Ή NMR tDMbO-4) b: S.35 td. i H>; "'T'i bi IHi 2.50 (na 2Hi. 7,40 (d, 1H): 7.30 (m, 211); 7. H) (pt, 2H); 5.85 tri IM); 3.55 (si): 3,40-3,10 tnt); L2-15 (m) ppm.

Step 5 J. 'Vlllmidaxof IJv );/]pyridmtlmő-yl]-2d2-dia;íaapiro|5.5]nndecane

0 JÉ mg <0,34 ÜB# of lett-butyl 9-[2-<4-fluoropheuyl).3-(]i¥-pym>io{;2,3-è]pyridi»-4*' yl)imldm:o< 1,2 -^Jpyridaxin-b-yll-^O-diazaspind5.5 jmidec<me~2<-arboxyutts; are treated with 5 mi of aqueous 3N hydrochloric acid over ISimOrs at ambient temperature, the reaction medium if pbre# into |0 p! if wáter pid is neutralized by addition of concentrated sodium hplmxido, The product is then extracted with dichloromctae, then the organic phase is dried over sodium sulphate and the selyem Is removed by evaporation under reduced pressure.

The residue c?fetalied;Is then padded by ehmmntp|mphy on a silica gel column by eluting with a mixture of didhlorontethaue, methanol and aqueous ammonia *90 10- Π in order to give 0,07 g of î f/-pyTO!d|2*lsê}pyndin-4-yl)imida2<>[ ! ,2-

MIT 270-2S0°C di NMR (DMSO-diO d: Π.7 (s. Ui); S.35 id. Ui); 73)5 {d. Hh; 7.50 im, Ml); 7,40 pi, 1 Hi: 7.30 im, 2lip 7,10 (pt„ 2H): 5,00 (d, IH), 3.4-3,25 t2m, 4H); 2.0 im, 411); 1.6-1,35 î2ni. SHi ppm. .Example 6 icmnouuttd No, jfe 2^(4#iuuropimnyi)-6-(4-uyer6ltdhu.t. >i}-ddl^iTvrmÍ0|T3^1i>>frídIm4wl)itmdarofI>2-dlpynd8a:ine

Step C L 2T4~nuo^phenyi}--644~p>m>lidin-\-yjpjpendin-!-yit~3d l-(4- meilyipheuy siphons M f/pvmMoJ \* fc(p\rdir~i x* Muw 0 < :-hipyridazine

* of Ili g (0,29 öí â:-chloro-2 -t ddluoropheny 1}· 3 [ 1 « 4- mcthyiphenylsulphojiyl)--i//-pyn’Olo{;2,3--f>)pyridia.4-yi jimidazoj; 1.2-%>?idazji«e. prepared according to the method described m step 3j uf xampte 3. und 0A"ù g (did ramoi) of 4-pyrrolidm-l-ylpiperuiine is heated under rcdlux for 40 hours at J40°C. The reaction medium is cooled. The crystalline solid which ionos on cooling is triturated in I ml of diisopropyl ether and is isolated by centrifugation and removal of the supematant m order lo give 0.144 g of 2'(4-tinorophe!tyl)»6“(4-pym>Iidin~i(ylpipeddinal~ylV3~|;I:d4“ ?net.hyiphenyisuipho.tyvl)-l/^pyrroio[2.3»ó}pyriüin“4-yl)iuúdazoii,2-.djpyridazine, a,séd without additional purification in the remainder of the synthesis, ΜΉΙ ~~ ($36

Step 6.2. 2d4~FttmrophmyfHb(4-p>s^ èlpyriâm-4-yl )imkiazof Í .2 \6]pyrida/me

The 2 i » ιορηοηφ e (4 n-ol du-1 *p (vodt ~I~y!V3~f 1-t4- methylpheny IstdphonylM/T-pymdop J“h]pyrtdin-4'-yt jimidazoj1T-6jpyt.du.-dne obtained in step 6.1 is dissolved in 3 ml of a mixture et medumol and tenabydonumn td I y then treated using 0,09 ml 91.54 mmol) of ® aqueous solution of sodium hydroxide ai 60°C for 1 and a half hours·? ThiÄle« is evaporated and the residue falért up in 3 mi of water. The product is extracted 2 times wnd i mi of uknuorommnane tve @pii phase is dried over sodium sulphate and the solvent is rvrhoved by evapomhorr :&amp;®sdei lidueetf The sessdue obtained xs then purified by chromatography over a silica gel column (4 g) by eluting with a. gradient of dleMoremetimie; methanol mé aqueous ammonia (of95/5/05 to 98/IÔ/Î) in order to give 0,064 g of 244“nuorophenyl)-0-i 4~pym>iid«vd -yiprperidin- I-y;V3-{1 /Apvrroloi 2,3"6]pyridin~4~yl}imidaao[ 1, 2~ hlpyridaeme after eryrtalhration in 10 ml of ueetormr.de, fib ration and drone. MP; 261-264" C NHH - 582 Ή NMR (DNfSO-^) 5; Π.7 is. iU)\ 8.35 (d, 1H); 7.9$ (d, III}; 7.SÖ (gcÄ 7.40 fii 1H): 7-30 (m, 2Rk 7.10 tpt, 2HV. S.8S fd5 W); 2.9 (m, 4I|f:t-If 1¾ iff 1.05 ( m, 3 Hi; ',.7 no, -lib, 1 9 «m, 2.H0 ppm.

Example 7 frammmud No, 16): (^)~|s|4-P-f4~Ffuotaípberíyl)-8“t0ófhyl-3“{ll^ pyrroio|2id-è|pyridin^~yI}ldddaae(ip-.6Jpyodaxm~é~yi|ptF^mU''l~yl}pr6pa»”2-of

Step 7.1, (/1)-1 »(4-Beaaylpmcrazin- i ~yl }-2-hydroxypropan-1 -one

A mixture, of 10,3 g (87.2 mmol) of ethyl. (Rplaetate (CAS 7699-00-5} tnul tS.e g ot beneylpiperaeine (CAS 2759-28-6) la heated at. 150*€ in a microwave oven for 2 hours.

The reaction medium is cooled and is chromatographed over a silica gd cartridge by eliding with a tpthanol (99 Π then 98-2) in order to lead to 10 g of (Ry 1 -i4~hetx?.> (piperéin-1 ~yi h2-hydrt>xypropan- i -one in the term of a brown oil ^dnha]p ! '2 + (rrctkaml c ; Ig-lOOml) ΊΙ d.VIR tHMSCMm 5' (m, d-h; a.45 <m, IHi; 3Λ5 on, IBI 3.7 im. 2H>: 185 is. 2H>; 3.45 (m. 2H>: 2.5 (m. 4Bk 1.35 (<h 3Hi ppm.

Step 7.2. C^HM^~tawy!pipm^

Added dropwise. over 20 minutes, to a suspension of 31 g (103 mmol) of lithium aluminium hydride in 200 mi of tetrahydrofuran. at 2 OX and with stirring, are 12.8 g (51,7 mmol) of il' lu ) wnmipevr n ,mt \W > mdioxxpm'.n.u 1 one .c - Oution in I'd mi of tetrahydrofirram An increase in the temperálom of the reaction medium was observed up to 35"'C and the temperature of the reaction was lett to drop hack down, to ambient temperature, After 30 murines, the excess of hsdnde is hydrolysed by addition of hydrated sodium sulphate, the mixture is then filtered and the solid residue is washed with tetrahydrofura«. The filtrate is concentrated under reduced pressure in order to give 11 g of a yellow oil which is ehromulograpled over a silica gel cartridge by eluting with a mixtum ol ethyl acetate. methanol and aqueous ammonia (95/5/0.5) in order to result in 6.4"g of (i?)-1 ~(4-ben';iylp tpera2ih"i -yl)propan -2 - oi in the form of a yellow oil. (alphajo = «20.5°(methanole = 111 g/lüöml) JH NMR tODClri d; 7.25 pn. 511): 4.20 (d, HI), 3.70 un. ÍH): 5.45 is, 31Π; 2.4 and 2.2 (m, 10H)i l.u pi. HI) ppm. htgp 7,3. (R)~ 1 -(piperééin- ! *yl}pmpimAimf

A solution of 6.2 g (26.5 mmol» of {/?Hd4-ben/ylpiperaznv ! ~yi>peopam2-ôi in 60 ml o( methanol b hydrogenated under a hydrogen pressure of 60 psi al ambient temperature lot 2 hours in tbc pt Csenve m'2 !-!5 g o*'palladium hydroxide-cm-yutrlxm K'AS 12135--22-7), The mixture is then filtered through a Büchner tunnel and the nitrate is concentrated under a reduced pressure to give 3,8 g of yellow oil. The oil is diluted in around 60 mi of isopropanol and the solution is aeidined by addition of 5-6N hydrochloric acid in solution in Isopropanol. The precipitate is stirred for 15 minutes and is isolated by tiltration in order to give, after drying, 4.97 g of (/0-i-(pipsrasdu-i -vl)prop&amp;ri-2-ol dihydroehlorkia in the form of a. white powder Mit :2:22--224^(1 [alpha]»™: -29.2e (methanol, e ~ 1 g/100 mi) Ή NMR (CÖCi.o bt 3.8 (m, 1H); 2,9 ím, 3H); 2.65 (m, 4H)t 235 an4 22 {m and m. 3ld)y 1.1:5 (vf 3H) ppm.

Stop 7,4. t M-i - pl - [2 (4-Fluoropheayi) - 8 - methyl -3 -t i7/--pynx>lo[2.3-h]pyTidin-4-yi)- imidaeoj' 1,2-hJpyridrrdn-d-y I [ni parsain- i - yl |propan-2-o!

Λ solution of 0.450 g Ü.19 mmol) of (>c.hk>ro-2-t4-iluomphertyl)~8-methyl-3-t[//'· pyrrcdof2,3-hjpyTidin-4-yi)imldaîi:o( i ,2-rVipyddaaine, prepared according to the method described in step 1.5 of Example 1.0.517 g (2.38 mmol) of (if)-i-(piperaaln~l-yl)propan-2-o! dihydrochloride and 0.98 ml of diisopropylethylammc in 5 ml of dimethylsulphoxide is heated at 85°C for ? clays. After cooling, the reaction mixture is poured Into water and the paxhk't m extracted with ethyl acetate Vhe organic phase is then daied oxer sodium sulphate, then concentrated under reduced pressure. The brown, residue obtained is then purified by ehromafd||Tdphy over Jtltca gel % eluting with a: mixture of dleilofmnethano, mÈmeà and mmmîà (95/5--0.¾) ^ îo «ε ® ®Afa- y.npiÂm^-yîïppopan-2-d Mer recrÿSîM«ion in 40 mi of acetönin-nn. Simmon and drying,

MF: >4 SCrC

[alpha]*·;. «a -12.6s (methanol. c:::: 0.09 g/if!0 *nl) \H MME (DylÔ-#} 6: 11.7 (broad .s, 1 Hr; 835 <&amp; u% 730 («*, m>: 7AQ <*»♦ ]l|b 7.30 (dd, 1B); 2.20 (s, IH); ?.10tm. 2H'* ^ bnu ä^): 4 **«· ^ (***. **3-Ν <m> 4H+HiO); 2.60 (% 3H); 2.40 |m, 4ir^öMS(Ms); |f25 fm. 2H); COS (d. 3B).

Ksmnmle 0 Ccomnonnd No. 1.7):. (SH»14«Ä4#iii:oröphenyip8-«methyE3HlIf* pyrrölof:2,3-61p>Tid0^4»yi}inüdaao|i,2-'.*!Fyr^i«7^^"yMF^^«^«-l^llpröpJrn-3-nl

Step Ml. (3|4E4~Bengyppbb:in-1 A^diydmaypmpsn- \-one

A anintnm of 6Ä g; ψΜ tnmol) of ethyl (SVdaciati (CAS 687*47-8) and I.I6 | (SO J mmol) of beniylpIpnTJnino (CAS 2759-28-6) is healed at J40°C in a hlibiowaye: ovm(300W) for Iliden fhe:*^öm;p^äi;Ä ipcoókd, then it is ehmmaîograpbëd :ener a sdu'a gel cartridge b> ehduu' o ah a mixture of diehlnrometiiano. methanol and aqueous ammonia (95/5/4§)»ippteJo-p^e 3 g of yellow oil. This oh is diluted in acetone and die (M--i'dT*henKylpiporazin-d-'yl|-#-hydroxypropn-l-one hydrochloride is formed by addition ot a solution of hydmeMoria acid in isopmpsnof tip while ppelFitato formed is isolated by filtration. Chen, It is taken up in water am! treated using aqueous ammonia. lie product is then extracted using dichioromethane* the solution is dried over sodium sulphate and the solvent evaporated under reduced pressure in order to result in 3,7 g of ®^~(4d5epzy!i3Íperaxin-!“yn'i"hydroxypriipau^1--pneín the form of a colourl ess oil. Iblpia]»:® -2,2° (methanol, c ::: 1.56 g/100 ml) 5ff WM tCDCIifo 7.25 (öl, 514435 (m, IH); 3.75 tot, 1H>: 3.6 (m. 2H)t 3J$ p, 21}: 3.35 Cm. 3H); 2.4 (m, 4H)t 1.25 (d. 3H) ppm.

Step i;|, (<S> 1 ~t4~B(.n^ylpiperazin-d-y!}pmpatb2-'Ol;

Added dropwise to a suspension of 1.13 g (26.8 mmol) of lithnnnaluminium hydride in 20 mi of tetraeydrofurau. at 20*C and with stirring, are 3.70 g <14,9 mmf!) of (.5)-1-(4--hensíyNpipemsíin-i-yf)~2*hy<iroxypn>pao-1-one in solution in 100 mi of tetrahydrofuraq. The temperature of the reaction is left to drop back down to ambient temperature. After 2 hours, the excess hydride is hydrolysed by addition ofhydratedisodimn sulphate, then the mixture is theo filtered and the filtrate is concentrated under reduced pressure. The oil obtained is chromatographed over a sdiea gel cartridge by eluting with a mixture of methanol and aqueous ammoma in diehloromethaue (100/0/0 to 95/5/0,5) in order to result in 1.2 gof ifo-l r4“beua>-oipcracin-l-sd)pmpan^oi ln theformofayellowol.

[alpha]» « +23,2* (methanol, c - 1 g/100 mi| *H MMR (CDCi.O &amp; 7,3 im. 5H): 3.8$ (tm Itt); 5#5 |4 2% 2J--2jfm, TOffî 1.15 (d, 311) ppm.

Step 8.3.; (S)~ 1 -(piperaAn- ! -yi)propan-2-ol

A solution of 1,2 g (5.1 mmol) of (5Vl-(4-beruylpiperaxin-i-yl)propans2~ol in 50 f|| of methanol is hydrogenated under a hydrogen pressure of 50 pi at ambiont tempéfofurb for 21 löurs in the präg!*** M 0.6 g of palladium hydroxide. 1¼ mixture b then liereä through a Büchner funnel and the iiUnne is concentrated under reduced procure to give 0J igrif yellow oil. ialpha)n ~ -rdü.S*' (methanol,, c::: i g/100 mi) lH NMR (CDCb)ö: 3.8 (m, 1H); 2.8 (m, 4Hk 2.05 -2.05 (re. 8H) ; i.05 (d. 3H) ppm.

Step 8.4. (5)-1- 14-i2-(4-F!mrophenyi)~S-meitybS-t lif#yrroiopÿ3-û]p>ixdtm4-yâi- hnidazof 1.2 -5 ]pyridaxin~ó~y í jptperaxin-1 -y 1 ) propaa-2-oi

A solution of 0.300 g (O.'-to mmol) of 6chtoto-2-(4..rioompiienyi}-8-·^ pyn'oloilJ-ólpyridi.u-d-yOimidaxoíi,2~6jpyndaxme, prepared according to the method described in step 1,5 of Example 1. 0,345 g ( 1.5$ mmol) of (5M-(piperazin-i -yOpropan-2-ol and 0,45 ml (3.18 mmol) of diisoprop>lethyhuotne in 5 ml of pentánul is heated at I50"C ford daya. Alter cm mag. ihe reaction mixture is pouted into a 15 aqueous solution of hydrochloric acid and the aqueous phase is washed w ith ethyl acetate. The aqueous phase is then hasi tied using an aqueous solution of momenta and the prháüet ia extracted with dicMpt^metham Xhe organic phase i| then: dried; over sodium sulphate, then cotteoutrited under reduced ptissum Ute brown residue obtained is then purified by Ohromatography over a silica get cartridge by eluting with a mixture of dtchioromethane. methanol and aqueous ammonia (9$/$/0.5) in order to result in 0.05 g of (S)-l -|4~i:2'(4-fSuorí>phens-l)“8-methyi-3-(í//~pyrroio[2,3-b|pyridin-4-yl)itn?dazo[S,2~bjpsíndaxin-6” yllpiperazin-1 -vl 1 propan-2-Όΐ after recrvstallbutton in acetonitrile* filtration and drying. MP: >35(r'C

[Alphajo:::: -13.9° (methanol. c - 0,2 g. 100 .mi)

Ti NMR U>MSO-dj N UN R-sroad a, lût: 505 (ti ill); ?.5u (m. 21Π; N4ü pu, I!Π; ?Jb (dd. U-ln 7,20 (St \B); ?.È0 <m, 2H); 5,85 ím; 1H); 4JO (m, 1H): 3.80 im, Iil); 3.35 (m, 41 h; 2 60 j. m\ 2 40 (ni, 4H); 2 25 un, 3H); !.u5 {0, 5 H).

Table ! which follows illustrates the chemical strtphres add the physical properties of a number of compounds according ίο the invention, i'u this table; - in the column bSalff represents a compound in free base form, whereas "HCT represents a compound In the hydrochlonde form and the ratio between parentheses is the acid;base ratio; * the column "MPC* reports the melting points of thPipfodnsts in degress Celsius, "N.D" means that the melting point is ttot determined; -- the column in] ,·> reports the result of the „-.\,ι'λμν ot îhc opta ,tl. rotation of the compounds from the table at a wavelength of 5E9 am; die: solvent indicated between paiimtheses corresponds to the solvent used to carry out the· measurement of the optical, rotation in degrees and the letter "cK Indicates the concentration of the solvent in gtiOO ml. “RAN signifies that the optical rotation measurement is not applicable, - the coinmu "mfe" reports the molecular ion {Muff) or (ΜΊ observed by analysis of the products by mass spectrometry, either by I...CAMS (Liquid Chromatography coupled to Mass Spectroscopy) canted out on an Agilent LC-MSD Trap instrument in positive ESI node, or by direct introduction by MS (Mass Spectroscopy) mio an Autospec M (EBF) Instrument using the DChNHU technique or by using the electron impact technique on a Waters: 8CT Instntmm The values that have; aa asterisk >y*Ceom^pond to the: detection of the ion (M*); - ,!CI:I.r* stands for methyl; - !!CT1 .Of Γ stands tor methanol; - ’'CHA'b” stands tor dichioromeihanc; and - iSDMSO" stands ibr dimethyisulpboxide. ΐιΜα

MmíisáLmffito

The capacity of the· compounds of the invention to inhibit, the phosphorylation of casein by casein kbia.se l epsilon and delta may be evaluated according to the procedure described in US 2005/0ΒΙΟΙ2, I be eîVeet *u me co.npoueos on nf o bon ot tbc pho\M as ,m m et ca-uo K toe en \0 v casein kinase I. epsilon tU&amp;J epsilon}: is measured, using a casein assay with fidmuon of ATP-'VP ín vitro.

Casein kinase ! epsilon (0.58 mg/ml) is obtained via fermentation and purification: |Ä^s::pedF«e4:-^eÄgrf^:::Ähod$ thatane weiÉpDWnl© those skilled in the art, or may also be obtained Horn Invitrogen Corporation™ ( human CK I epsilon).

The compounds are tested at rive dilièrent eoneenimtions so as to generate 1¾ values, ijk the concentration at which a compound is capable of inhibiting the ennymafic activity by 50%, or alternat ively the percentage of inhibition at a concentration of 10 niieromolan "IT-bottomed Falcon plates are préparât by placing 5 μΐ, oi solutions of the compounds according to the invention at concentrations of 10, I, 0. t. {).01 or 0,001 μ M in various '.veils. The solutions of the compounds according to the invention at these various concentrations an prepared by diluting la a test buffer (50 mM Tris, pH 7.5, K) M MgC!> 2mM DIT and I mM EOTA) a stock solution in DMSQ at a concentration of ÎOmM. Next, 5 pL of dephosphoryiated casein are added to a final concentration of 0.2 p.g/pL, 70 pi of CK i epsilon to a final concentration of 3 ng/μΐ, and 20 ui of ATP-P'T to a final concentration of 0.02 pCi/ut mixed with cold ATP (10 μΜ final - approximately 2 X 10* CPM per wed). The final total test volume per well is equal to 50 μ!.

The "11"-bottomed Falcon* test plate mentioned above is vortexed, and then incubated at ,m tom umpc'^are tin λ ho, n \>vr ' v s, 'he vnetmt ^ Mopped h\ andtng an me cold soumon of 65 μΐ of Λ IT mM) prepared m test buffer. 100 μΐ <ύ the reaction mixture are then tratisihryed^ trónt the 'dyxhottomed bale«· piste i\ \> XHhpi K X! \Γ'* ű ο» phsov piointpreqnated with in μ! ot icc-coid iOOVs k,A,

The MilHpore MAPH filter plates are agitated gently and m kft to «d at ambieft tempetatee ferst^ tega|30 plhdteato precipitate the proteins.

After 30 nhtmtes, the filter pintes are sequentially washed and filtered with 2 * let) pi ot 20% TCA, 2 X 150 μ! of 10% TCA and 2 \ 150 pt of 5% TCA (0 washed ait total per plate 900 μ I per well).

The plates are left to dry overnight at ambient tehtpcratare, McXh 40 μ.| of Mieroscint--20 Packard* scintillation liquid are added per well and the plate are closed in a leaktight manner. The radiation emitted by each well is then measured tor 2 annules in a Packard " Xopcount NXT scintillation counter, in which the values of CPM/svell are measured, fhe percentage inhibition of the capacity of the enzyme to phosphoryiaie the substrate ouvert! is detvi aired to ^.,¾. i io\c itiaao o"' eompv tn d teted Ί1 ^ v. n 1 i i on ou ta expresscdaspercentages are used to calculate the IQ.) value Ibréach coînpound ecanparetf path the controls,

Fhe kinetic studies determined the K,\,; value for ATP as being 2! μ.Μ in this test system.

Table 2 below gives the IQ§ values Ihr die IhblbhlPn : hi phosphorylaiidn if edselh kinape !

Table 2

Under 11¾ conditions, the most active compounds of the invention show 1¾ values: (concentration which inhibits 50'0> of the enzymatic activity of casein kinase 1 epsilon) of between 1 nM and 2 μΜ,

The capacity of the compounds of the invention to inhibit the phosphorylation of casein by casein kinase 1 epsilon and delta: may he evaluated using a FRET <MFluorescence losonaneo Energy Transfert fluorescence test with the aid of the "ZMyte5M kinase assay Mid5 Creforenee PM3h® fnvitropn ismpsrationTM) accdiiag: to the nianufcmrer# instructions.

The casein kinases t used ^«ÍÉhimÉfern%Ämgsb Curpelon (human (MS epsilon FV35O0 and human CEi delta FV366S), A peptide substrate, ktMlied at both ends with a ifuorophor donor group (coumarm) and a ifuorophor acceptor group (fluoresce;in) constituting &amp; FRET system is pirosphorykted in the presence of ATP by casein kinase 1 epsilon or delta in the presence of Inereaslng Concentrations of compounds of the Invention.

The mixture Is treated with a sitewpecihc protease that specifically cleaves the peptide substrate to form two fluorescent fragments having a large fluorescence emission ratio.

The fluorescence observed is thus related to the capacity of the products of the iméntiért to inhibit the ptm\rsher>lation of foe peptide substrate by casein kinase t epsilon or casein kinase 1 delta.

The compounds of the invention are: dissolved at. different concentrations starting with a 10 rnM stock solution in DMSÖ diluted in a buffer containing SO mM HEPS. pH 7.5, 1 m MEGTM, 1.0!% Báj-35, lOntM Mg€% for casein imase 1 epsilon and sn|^>l<anented with Triarna. Base (50 mM), pH 8,0. and NaN ? (0.0184 final) for casein kinase i delta.

The phssphorylatfona of the: peptide substrate SIRÄIR 13 obtained lkán fnvltrogen Corporation™ is performed at a fiba! concentration of 2 uM. the ATP concentration is 4 times the Kst. this value being 2 μΜ for casein kinase 1 epsilon and 4 μΜ for casein kinase 1 delta.

Idte emitted: is measured si wavelengths of 441> and tGOnm {eseitaiina M 40C hi§.

We 3 below gives the wipes for the inhibition of phosphorylation # 3M&amp; kmm t delta for a number of compounds according to the invention. liilii

Under these conditions. Éæ eoarpoah# ©f the mveniion. that are the most active have 1(¾¾ values {concentrait®!* that inhibits 50% of the enzymatic activity of casein kinase 1 delta) of between 1 n.M and 2 μ'Μ

It ts thas jeett lhal ihe utmpottnílá according to the invention have ^ thé: casein. kinase ! epsilon or casein Mnase I delta ehnpne.

feaigoMiis.feáíksM

Mperl-Iac Rat-1 (P2C 4) fibroblast otdiures were prepared by dividing the cultures every 3-4 days (approximately 10-20% of confluence) on "tSdfnf degassed polystyrene tissue ^uHu.e xhwhs ilaLorv et5 n maned n syowto medium lEMfcM tt».ebgw # I0-0I0-CV); 10% foetal bovine seram (PBS; Gibco # IÍÍI§dN4|r and S0;Ä/ml of pcnicillhî-streptomycia Klelkro # 30-001 -(.1)] at 37*0 and. under 5% (2(¼.

Cells obtained from Rat-1 fibroblast cultures at 30-50'% of confluence as described above were cotransfected with vectors containing the selection nprker for resistance to ?eocm lor «Äs âàusltake rsprier %mm OdnitbJisd by the ifiPdr»! pmmoter,

Aller 24 to 48 hours, the cultures xtere divided oh OőmMlplates hhd MafhiMried in growth; medium supplemented with 50-100 pg/ixd of zenein t'htviiTogen* # 45-0430) tor 10-14 days. The rc**cm-resista»t stähle imnsfcctaots were evaluated for the expression of the reporter by adding 100 μ.Μ luclferm (Promega* # El-603 to the growth, medium and by assaying the ludferase activity m a TopCount* scintillation counter (Packard Model # C384V0Û), The Rat-1 cell elopes expressing both zenein resistance aud iigcerilase activity controlled by mPerl were serum-shock synchronized with 50% horse serum [I IS iGibco'' # 16050-iiE!)} and the .tclivhs of the cîro.tdian reporter was evaluated. The P2CM clone of Mperl-iue RaM fibroblasts was selected to test the compound,

Mperl-iuc Rat-| (P2Ü4) flhrehlasts at 40-50% of eonilbenee, obtained according to me protocol described above- were plated out onto 96-well opagae tissue culture plates (Perkin Elmer* # 6005680), 'I'ho nultdres are maitstameâ m with 100 ug/ml of zeocin Onvltrogon # 45 0430) until they reach 100% of confluence (48-72 b). The cultures were then synchronized with 100 pi of synehimixaiioR. ntidiutn (EMEM tCeligro 4 iÔ-010-CVg 1001.0. /m! of peufciliin-streptornycin iOeiigro # 30¾ 001-Cl); 50% H$ (Gibco # 16050-122)] lor 2 hours at 37*C and under 5% 0¾. Afler synchronization, the cultures were rinsed with 100 pi of EMEM (Cellgro # IÛ-01CMP2) for 10 minutes at ambient iempemtir|, After rinsing, the riepum was replaced with 300 μ.Ι of CO.î-htdcpendenl medium [COT (Gibco #18045-088); 2 rnM L-glutamiue (Cellgro # 25--Ö03-C1 ); 100 U-L/mf of penlciflin-slreptompm (tellgio 30-001-Cib 100 μΜ luet féri n (Promega #E 1603)}.. The compounds of the invention tested for the eircudian effects were added to CC)j-independent medium in DMSO at 0,3% t final concentration). Ehe e tut arcs were immediately ekwed in a lea Might manner wtîh lopSeal-dim (Packard # 6005185) and transferred for the hsciteraxe activity measurement After aynohmmz^lonMhelesi plates wem maintained at 37°C in a tissue otdluré Ihdihatof (Eonna Scieniiic Model # 3Í14), The M vivo luceritase; activity wi estimated by measuring the relative light emission on a TopCount scintillation counter (Packard Model #C1|4¥00):,

The period analysis was performed either by determining iight emission minima over several days or by fmurier irmtafemrv The two methods* produced a virtually identical period estimation oa a Äp oh ehtiadian periods. The1 power E reprated hi CE Delta ft-Hhh which is preseated as the effective micromolar concentration that induced a i -hour prolongation oi the period. The data were analysedBy adjusting a hyperbolic curve to the -data :expie»d"as Aa$ge of period (y~axis> as a Mictnm:M'%§-:$mmníratím of the test compound (x-axis) in the ΧΙ,Πΐ'{Μ software and the CE Delta (C- ih) was interpolated from this curve.

Table 4 below gives the CE Delta (H-ib) for a. number of compounds according to the invention, litfeki

linder these conditions, the compounds* of üiuduvehridhitÄ Ute flianaM actiVCdtsve ίΟΙί Delta (f'i'lh) values (effective rderoinolm concentration Put induced Ui Chour prolongation of the period) of between i nM and 2 μΜ.

By inhibiting the dnuwnes C’KI epsilon and/or CK, i delta, the compounds ÉM are the stipeets of the invubflon modulate the circadian periodicity, and m§y$e useful for tfeatlpg nipadtan Btytäro itsoidep.

Tlie compounds according to the invention may in particular be used for the preparation of i medkament for preventing or treating sleep disorders: circadian rhythm disorders, such aäyp padién I ar, those caused by jet lag or shift work. \ .none . ο ï Cv ' disona \ s h à, .«o eyvs ml ' J 'Once vted ae f γ-ji \ rieep c ve dem such as dyssontmu fiäf example primary insomnia).. pan^frirtia, hypbiSomiria (te example excessive somnolence), narcolepsy, sleep disorders related to steep apnoea, sleep disorders related to ihe circadian rhythm and otherwise unspecified dyssormuas, sleep disorders associated with medical -'psychiatrie disorders.

Ik co I o>mads t uk ... sioa^s o* die s \ union also cause a circadian phase shift and such a property may be useful in the context of a potential monotherapy or combined therapy that is clinically effective in the case of mood disorders.

Amena the meed disorders that are especially Oeampmsoed are depress % e ^orders (unipolar depression), bipolar disorders, mood disorders caused by a general medical complaint and also mood disorders induced by pharmacological substances.

Among ihe bipolar disorders that are especially distinguished are bipolar I disorders and bipolar 11 disorders, including in particular seasonal affective disorders.

The compounds tiaf are the subfeets of the invmtiôri, which rmxifdate the circadian periodicity, may be useful in the treatment of anxiety and depressive disorders caused in particular by an impairment in the secretion of CRE

Among the depressive disorders that are especially distinguished are major depressive disomeri dysthymic disorders and other* he unspecified depressive disorders.

The compounds that are the subjects of the invention, which modulate the circadian periodicity, may be useful for preparing a medicament for treat ing diseases related to dependency on abuse substances such as cocaine, morphine, nicotine, ethanol or cannabis.

By mhthitiog casein kimw I epsilon apfef 1 delta, the compounds according to the invention may be usedJbir prepÄ|| lÉgdteaments, in particular for preparing a medicament for preventing or treating diseases related to hypesphosphorylation of the tau protein, in particular Alzheimer's disease.

These: medicaments alá#· fed their m. ib^r^fk M pafecbiar :ίο life tw&amp;tmmt fe prevention of disÄSf caused: et exaoeimted 'fey the pmfeîefatîôit of cells, isi particular tumour cells.

As tumour cell proliferation inhibitors, these compounds am useful in the prevention and treatment of liquid tumours such as leukaemias, solid tumours ithat are both primary and metastatic, carcinoma'-. arid cancers, in particular. breast cancer, lune, cancer, email intestine: cancer, colorectal cancer; cancer of the respiratory pathways, pf tfe oropharynn and of the hypopharynx; «esophageal cancer; liver cancer, stomach cancer, cancer of ife hie ducts, cancer of the pll Madder, pauerealie cineer; cancer of the urinary tracts, including kidney, urotlteltum and bladder; caneem of the icntale gipifai dpict, mcludfng: cancer of the uterus, cervical canecr, ovarian cancer, chloriocarcmoma and ttxiÉoblastoma; eMpers^teíPÉfejpisl fest, ineludlng prostate; mmm* $mxr of the seminal vesicles, testicular cancer and germinal cell tumours; cancers of the endocrine glands. Including thyroid cancer, pituitary cancer and cancer of the adrenal glands; skin cancers, including haemangiomas, melanomas and sarcomas, including Kaposi’s sarcoma; brain, nerve, eye or meninges tumours, including astrocytomas, gliomas, glioblastomas, retinoblastomas, neurinomas, neuroblastomas, schwannomas and meningiomas; malignant, haematopoietic tumours; leukaemias (Acute Lymphocytic Leukaemia (ALL), Acute Myeloid Leukaemia (A.ML), Chronic Myeloid Leukaemia (CMD, Chronic Lymphocytic Leukaemia (CLL», chlommas, piasmocytomas, T or B cell leukaemias, Hodgkin or non-Hodgkin lymphomas, myelomas and: various malignahtlitiemdpathies;

The compounds according to the invention may also he used for the preparation of medicaments, especially tor the preparation of a medicament intended for preventing or treeing inflammatory diseases, such as, in particular, inflammatory diseases of the central nervous sptem, for instance multiple sclerosis, :eubepha!itis, myelitis and encephalomyelitis and other infiamr'.uon encases or irs ,,, ox n^cul w pasvdogW'· atherosclerosis, joint irdlanonanuus .vlbro'V- and rheumatoid arthritis

The compoonds: according to the iaiôft may ihus he used lor the preparation of medicaments, mpadlchlar of medicaments for inhibiting' casein kinase I epsilon and/or casein kinase I delta.

Thus» according to another of its aspects, a subject of the invention, is medicaments which comprise a compound of formula (I), or an addition salt thereof with a phamtacedicaily acceptable aeni. or ulternam elv a hydrate or a sok ate of the compound of formula fl).

According to another of its aspects, the present invention relates to phamiaceulieii compositions comprising, as active principle, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention or a pharmaceutically acceptable salt, a hydrate or a solvate of said compound, and also at least one pharmaceutically acceptable excipient.

Said excipients are chosen, according to the pharmaceutical lorm and the desireddndie of administration, from the usual excipients known to those skilled In the art, in the pharmaceutical compositions of the present, invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, tnmsdermal or rectal, administration, the active principle of formula (1) above, or the possible salt, solvate, or hydrate thereof, may be administered in tmit adminisitdtfonldrm. as a nnxfore with standard pharmaceutical excipients, to humans and animals for the prophylaxis or treatment of the above disorders dr diseases.

The appropriate unit administration forms include oral-mute- forms such as tablets, soil or hard gei capsules, powders, papules and oral solutions or suspensions, sublingual, buccal, intrairadldni, Inhalation forms, topical, tmnsdermai subcufaneous,mt»dseuiar or Ifofavcffousadtmnlstration forms, rectal administration forms and implants. For topical application, the compounds according to the invention may be used in creams, gels, ointments or lotions.

By way of example. a unit administration form of a compound aeeordihf to the invention so tablet form ^oyoMpáso fe following components;

Cbmpound according to the invention 50,0 tag

Mannitol 223.75 mg

Sod lam crosearameiiose 6,0 mg

Com starch 15.0 mg liydroxypropyitrJcthylcdkilose 2,25 mg

Magnesium stearate 3.0 mg

Via the oral route, the dose of active principle administered per day may reach from 0.1 to 20 mg/kg, in one or more dosage intakes.

Iberrmay fee parieuiar eases in which high«r^'fc»'l«fges» appropriate; srt dosages do not depart from the context of the invention. the dosage ffest ts:äppnopriÄ^Ä&amp;:;ptieayf'ÄiinMed by the practitioner according to the mode of administration and tire weight and response of stid patient âecordiog: to another of its aspects, the present; invention •ate-Äi^töxaimetted-för treating ;the pathologies indicated above, which comprises the admihistraiion to a patient of an effective dose of a compound according acceptable salt or hydrate or solvate thereof.

Claims (9)

1. IMBÁBÁLMI IGÉNYPONTOK 1. (!) gj»kim>s képiem vegyülct:

   ahol a képiéiben - 1¾ jeleniéá; ári lesöpört udou ecetben szuhs/utoálva a kővetkező közül sitezfeB vágy lifcb sznhsztitusnssei: halogéuatomok ék I-6 szfeàîômosülkil-, 1*6 szénatomos alRilmxiv 1-6 szénatomba alkihtio-, I -6 szénatomos fluorÄlK I -6 szÉtatosnös ííáor-alkihoxb és «€Μ·#φίι| vágy |i2jül^iü·· se l~t> azénatosnos alklk 1-6 szénatomos tkor-atkil, 3-'? szénatomos eíMo&amp;lkík ^ágyJ-íszéüáíöíyos cikloa3kií-(J*6 szénatomos alki?)-csoprt; - Λ jelentése I -7 szénát»«?«» alkifénosoportsíjotí: esetben sztjbszíimálva egy vagy l#!% és#ötRal|;; 8 jelentése 1-7 szénatomos alkikkncsopert,iáértesgt&amp;en szubsztityálviR* csoportiák - !.. jelentése vagy mtrogénauan adott esetben sznhszíltuálva R* vagy F..< csopoÄlgvägY szénatom varo/ütnuba l\5 csoporttal és R,. c^y orsód vagy kot ív; csoporttal, az A és 8 szénatomja? adott esetben s/imsztltuáltak egy vagy több .¾ esoporhalpruaelyél lelteinek azonosak vagy egymástól különbözőek; - Rs, H; es R Jelentése olyan, hogy; két R,·. csoport együtt 1-6 szénatomot; alkiléncsoportot alkothat; ÍJ és Rh együtt kötést vagy I -t> széoatomos aiküéncsoportot alkothat; ív és R egye ; kötést s y\ 1-6 számuom-v alkiiéocsoportot alkothat; Rs és R. eg x int kötést X ag> I -6 szénatomos alkiléncsoportot alkothat; - R,í jelentése a következők körül választott csoport; hidrogénatom és 1-6 széna minős alkib, 3-7 szén-atomosdkloalkik 3-7 szémüomes eiklealki1-{)-ő szénatomos siklik hkiroxi-(í*6 szénsípipos alkil}-, 1-6 szénatomot* aiUl-oxi-t,1-6 .véntüomos alkil)-, 1-6 szénatomos alkll-im-C 1-6 szénatomc-s alkil}-, 1-6 szénatomos Huor-aUdl- vagybeuzUcsoport: * l^i jelentése -NR4R5 csoport vagy cikhsos m»noan?in, amely adott, esetben tartalmaz oxigénatomét, a ciklusos monoamin adott esetben szubsztmtálí a kővetkezők közül választott agy vagy több szubsztiixísnssel: tluoratom és 1 -6 szénatomos alkik 1-6 széoatomos alkiboxi és hklroxilcsoporü két Rí.-, csoport a szénatommal, amelyhez kapcsolódnak, ciklusos monoammt képest, amely adott eset-ben tartalmaz oxigénatomot a ciklusos monoamin adott esetben simbsztituáit egy vagv több Rr cso-> amelyek lehetnek atomosak vagy egymástól külônhOæôek; * R? jelentése 1-6 sctónatómos aikik 3*7 szénatomo* cikloalkii*, 3»? szénatomos ctkloalktl-l I *δ ηζΜ* atomos alki!)-.: 1*6 mâmwmm aikil-oxi-(l-6 szénatomom alkilK hktroxKl*Ó szénatom«» alksl}-, 1-6 szénatomé jiiür^Öíi*, festi- vagy benztlcsopoitp - R.j és- R< jelentése egymástól függetlenül hkteogéaatom vagy 1-6 szénatomos tök 11-, 3-7 vzénatomns. cikbatkli- v&amp;gy 3-7 széttatoBtosdkloalkü-Cl-fí szénatom«» aíkíiKsopon: és - R? és 1¾ jelentése egptvástól íiggatlanúlliídrogáti^om vagy 1-6 scéöatomos allliesopori; bázis vagy savval képzett: addldós só formájában,
2. 2. Az I, igénypont ezeriníá (0 általános képlete vegyölet, azzal jdtenmzve, hogy: - R> Mentése femíesopon. ad«ft esetben szabsztimaiva egy vagy tófeh halogénatommal vagy 3-6 s®én~ atomos alkil- vagy !-<$ szénatomos OuorMkil-csoporttak 3;, Az 1,5g#typtnt ;periau (!) általános képleté veg>1iktv^^î füiyi -yRs közöl választott csoport: 1-6 s^«atómot-iaÍk% !«6 u&amp;wá&amp;mM rippr- alkik 3-7 szénatomom cikitmlksi- vagy 3-7 mmatonx® olRloalklbf l~6 szénatomra a ikil)-csoport<
3. 4, Az i-3 Igénypontok bármelyike szerinti (!} álíaMöéi képlétó verdict. a«zsii|eitei»cz^e, Hogy; - R? és kktegénatóm yfgy metilesopottv
4. 5. Az 1-4 igénypontok bármelyike szerinti(1) általános képleté vegytilet, Itógy: - Λ jelentése 1-7 szénatómos alkiiénesopon adott esetben sznhszt imáivá egy vagy két Rs csoportit!; - F> η e *'\o 1 ' v uralom o-> aluLncvs v t uo r esetben szubsztítuálva Re csoporttal; -1. jelentése nitrogénatom adott esetben szobsztimálva R< vagy R.ä csoporttal;; az Λ és B szénatomjai adott esetben szuhsztUuáltak egy vagy több Rs· caopotítsk anMyek ílebetnék azonosak vagy egymástól különbözőek; • két Ra csoport együtt 1-6 szénatomos alkiléocsoporíot a!kotbát| Rs és i\ eg> (itt kötést vagy bő szénatomos alkrténesonortM alkothat; Rs és Rj együtt kötést vagy 1-6 szénatomos alklléncsoportöt alkothat; - Rí. és Rs egy Un kötést vagy 1-6 szénatomos alkiléncsopmlm alkothat; - Ra jelentése a következők közül választott s söpört' hidtogcuatom es í~ö szemtom»^ alksk 3-7 atomos cíkioalkik 3venatenvuetkkniu' (' r vuut"mosoikrtk hsJtco,s·;'-ö - ’'eoaknnosa.Aslk léi szénatomos afkibox 1-(1-6 szenatomos alkük 1-6 szénatomos alkd-öo-fl-ó szénatom«.» alkti)-, kö széttatömos ünor-alkii- vagy benzücsoport; és - 1% jelentése 1-6 szénatomos alkik 3-7 szénatomos eikloaiklk 3-7 szénatomosclVioalkil-U-ö spin atomos alkiIK 1-6 szénatomos alkS%xl-<|;As^énM0mris&amp;áÍkiÍK hídroxHiRí szénatomos alkílH t*6 szénatontoa Ésor-alkik vagy fernlcsöpcst.
5. 6. Az M igénypontok bármcly&amp;e sKrinti (1) álttOáttos képiem vegyület, a***l jelkmezve, hogy: ~ A jelentése l~7 szénatom©* alkiíénesopart adötí eselhen sznbsztltoálva egy vagy két R, csoportisi; - 0 jekntc.se I -7 szcnttiomos alkiléoesöpofí adott esetben szebsztituálva R* csoporttal; · !.. jelentése szénaiom adón esetben szobszi Imáivá két R,·.? csoporttal; íiz A és B szénatomjai adott esetben szubsztituáttak egy vagy több R* csoporttal, amelyek lehetnek azonosak vagy egymástól különbözőek; - két R,·: csoport a szénatommal, amelyhez kapcsolódnak, cikhisott:tbdiifiiihli%:. képpas, amely adott esetben tartalmaz oxigénatomot, ezvn ^ iktam moooatnm adott esetben szobszíipíi egy vagy több Rf csoporttal, amelyek lehetnek azonosak vagy egymástól különbözőek ; ék · Rf jelentése 1-6 szénatomom alkUcsoport.

   1. Az 1-4 igénypontok bármelyike szerinti (1} áltálánős kepietuvegvülei, azzaljéllemezve, hogy: * A jelentése s-7 szénatomos alküénesoport; -•B jelentése 1«? szénatomos alktlèncsoport; jelentés« szénatom szabsz* ituáh a Rsí csoporttal és R* csoportul; - -R« jelentése hidrogénatom:; - R*; jelentése -NR^Rj csoport vagy ciklusos monoamm. amely adott esetben tartalmaz oxigénatomot a ciklusos monoamm adott esetben szubszutoált egy vag> több R, csoporttal, amelyek lehetnek azonosak vagy egymástól különbözőek; es - R,· jelentése 14 szénahihis álkil-, 3-7 szénatomba elkloaiitl- vagy 3-7 szémnom.os eüdoalkii-(.i-6 szénatontos alkll besöpört,
6. 8. Az I., X, 4: és 5, igénypontok bármelyike szerinti Ü) általános képíetü vegtyöletvazzfl |elleBtezve> ítogy; vE? jelentése tnsíiiesoport; - g' ö t Ί1- áltól ke;ο,νό -nkhmos .mm aientexe \R"l· i-metd-pjpeiazui- lob, 3,3-din-etil'· piperazin-l-H-. \citsy?,é -dhoetd -piperaÄ?l?ll-, 4-tzdfttopil-piperazin· J -ti- vagy (ctszM-metÉ· hexaiádropnro!of3,4-e'jpuro!-3( i/fi-íl-csoporti és - R7 és Rs jelentése hidrogénatom, íi k%. % 2-, 4 és 5. igénypontok bármelyike szerinti (!) általános képletét vegyület, azzal jellemezve, htlgy; - R2 jelentése 3-öuoí-feml- vagy·· 4-tluortfeötihesopert; - az -N-A-l-R- által képezett ciklusos mfä- jéllnt#®·; :p)4-mefe#pepzW4k> 3,3-dlthetih pipetazín-i-il-,, Certz>3,54ímetil-píperazÍh-!-lRs drtzopropIRpiperazjn'-llfi'·, d^-diazaspiroid.Sjiee-tMló 3'fenl4ptperazin~l-Í!', d4enzil-píperazm-Í--íb, 3-hldroxi-íne:t!l-plperazin--!4tN d-P-hidsSxh ctli ípiperaztn-1 · U-, (i?}-4 -(3 -hiriroxi-propiíjpiperazhí-1 -11-, (ő'V4-(2-hidrox opmpdjpiperazm-1 -11-, -I ·( t -h utroxi -3 -otetÜ-ptopan- 3- d)pip«razm-1 -d -, <1 ~(2 -his:hmï-2-mehi -propüjpipcrazm-1 dk 4~(3*h«droxk3"me«l-butil)pipem.2»n- 1 -il, < R}«3 -fend 'piperamn - 1 -iK (;b"3”féthí#peía*m4dk 4-fee8zil-piper&amp;2in*)«ü> .(^M^S-m^i^a^hidropInroloCB^-cjpimsl^C'I/0-0-. <c^)~>(2”hi<!m&amp;l* «t0^exahidtopirroîo[3.4-c]p)troi-2<' Î /0*0«. (^/^./o^^l-metíl-oktah^Ch^'pimílo^S^-felpMdíB'· $âlk>„ (4aS,?aSb i •'m«rU-<)kuh{drO'6//-p>m>loP,4-bJpjr5<IÎR-ihU-« vagy .{ däambkäk!o[2.2 J }h«pt-2-i1-< sopmt; és - RT és 8* jeteniés« egymástól tbggetbnîd Èndrogênaiom y agy mtnifckPpÂ
7. 10. Λz ?.. 2., 4, és 0, igény pontok bánmdy ike sxetmt? (?) általános képiéi» vsg>«lei, &amp;e*»l jelleme*-ve, hogy. R;; j elöntése 4 - fíuoi-f on ti-csoporí; #:¾¾ -N-A-L-lh áltál képei# cílslusp áptlsjeleétásé 2jO»dla2a:sp|ro[$.S|tmdee-P-il~esopoR;# -1¾ és Rs jelenté# hidrogénatom. íl. Az L, 2,4 es ?, igen> pont A barm« Isike szerinti (!) alud&amp;UviS kepletu xegsídeu aar/ai jelleme*- ve, hogy: - Rj jelentése 4->f1uor-4énil«csoport; - &amp;?. -N-A-L-8- által képedet? ciklusos asniijokÄse4^pim>11diífc 1.4Ι>;ρ1^«4«?Φ$Ι“8.§^?τΐ| - R-; és Kijelentése hidrogénatom. î%êz I. igénypont szsrmti vegyüiet a kd#tkezőkköze? válakAva: 1.2- meti 1 -6 - [(A >-3-snet il-plperazin-1 - ti]" 34 ? //-jpteb|2^-lilfÂt^kllpmid^||ÿl2-iiplrÿa^r» 2,04'3,3 -D?metil"pipertiKln»!41)-:2-tnenl 3 11H pimde|2.> biptndm- ?-ii}iniklazoj?,2'b]p!rkiszin és trdndrokfondja; J> J#lPietJI~piperazii>~ ; -il]*2-meiil-3~( IA?-f>iritilo|23~b]ptridk"4" il)imidazoj ? ,2-b]pírid<mn és ifilódrokbndja: 4, #^4«i*o^||l-pipera2io-HI>2>'rn«tU-3-(l//-pinolo|2,3-b)pi«dm-4-.tl)imiô^K3i||,2.||ÿ;y<i«:ii,és MhldsÁlorldja; 5.2- m#íb~|(eM*}'$'-méiii-hmmhjdÍöpl^ .ií)irmd&amp;*o( i.,2-bjpsrtda*in és trihidrokbndja; é. 2K4-Soo^feHÍ?>-é~[(3/0"3-metikpÍpemzíti'l"il]"3"(?/Ap?rít>?o{2.3"b]piridin44l}jpÍdíiiö]1J~ bjpirldabn; 7>:|4-P"(4~f]uobf||ij}-;3"CÁ/Apirmfof2#b}# 11} metanol.; bjpindazin; 4. b"C3,3-diiriettl"píperaziin?-tf]-2"?J3-Ébee~fbP5l)-S"Ptetib3R|lAp5m>lo[2,3-b}ptridiH 'd-> tî)tmMa2O[ 1,2-b jpír idazín; ?0.6-(3,3*dm)etil-pipe«K:m“t“il)>2-<^-nMoed«njl>S-metíl”34 ii4i>lmdo[2.3"b)pirb|v4" sílsmid&amp;íoí! ,2-b jpd idaz.m; 11..,. #4(£·«£}··3,3~di®oiili«p4^4hM -i? j^-^bíöfr-fenü )-3-( l /^pirrofo[2,3-%||)kyiü»):-d )í m ( d;«c{ 1 ,2- b)p s rkl warn: O'jpípemsin-1 -i^etímo!; 13.2'|4-[2-<4«0uor-fcnü)*8~meíilv.1-.(í/í«plttobC2>3-h]pír<dm-4->il)smídíUK)n<2‘b}p}r}daa:!n«6·· iljpipefsixm- Ml) mrsöíi 14, 2-( 1H-p&amp;sÄ|2p*li|py bjplndszin:; 15.2 -(d-fluor. í-i!>>B-metü-3 41 if*pírro!o[23-b]piridíe~4~ dbmida^oj 1,2-b]píridfí*íí>.; ! 6. (#V1 - í4-i £4JpHdÄ«4* Ujpíp^razisv I-d îpropars-2'θΐ: 17. (Ä>!»f4 !,2H4-?]«or-readVK-mebkk(|//.pin'o{op2kb]pdädln-4-dHnndaxo[U2-blpin\iäÄi!t.d-iljpiperaxin* ! -íl}prop»a-2*ol; 18. fe-46!9-d}a^spúx>C4.5jdec-9j>2-(4-fle«É»Ílp-petík3-(l//ipim>ío|2í3«|JppÍIM?4*' d)mïk1;ï?o( i 72-b'jpínda?bv. W 2-{4-p.(4«nuor-fetMÍ)-3'<1i/-pítmlo|2„'*h}p{rid«\4-}rm«id8/o|K2.b}p»nda/iR-<>-ií}p||efai»l- 0} ~2-m(:iii-propm-1 -ol; 20. J. IΛ-f^-C^-fluor-fcítíO-^-í· 1 iH-2-sÎÎeît i-pröp3{} 2~ol; 21. 1 « (4 -Γ2 · fiuor-fe«H)-S*mcd 1*3«( \ 7/.pbyo!op.3-Hp\ndtM -il pm idayoPÄ^rkfÄ^ U'jpiperazi » · 1 - Il | -2 -tnsHI ~propaa-2~oi; 22. M4-{2 -«d-íloot-kmlí~8-motib3~{;/ï pbTolo|:2.3-blpirb:b'B-4-i!}ifnkls:mri.2-'b]piridaids5-d·· iljjpiperaam-1 -4i}-2-mcpi·-propim-2-ob 23. 4-{4 [2-(4,il5.sor-fea d KM 1 /kpin-ote|2,3-b]pmdíft-44U^idaxóp.>2^%Mtei«-^il]pjp^^|4 il) -2«metil-buíaR-2*o!; 24. (/()--2-(4-Buor'-feH!)'-6-i3-feoíbplpacagin-kíl]-3-(l/fpl)Tdi|)(2)|-bjpiíldíP~4~iil|-ímida^oí. 1,2-h}psrld&amp;£sn és tribldrr>kíoHdja; 2'' (^5-2-(1 flüo^lends.b^3-feo.d.p{pmKbvi~ilj-3.(lÄi'pjfrok>[2J'bjp{ridSn-4-ii>4Hnd&amp;f?o|k2·' ^bjpiridazm es mbklroklöridja; 24, 24 4 - ftuwfeni! hB-ö&amp;4ti-M3 bjpind&amp;srm;;. 2 7 : :6-(4»beR2ïkpîp®raz}«-> KdK2-í 4->fluoH2íí»ÍK>H 1 /^piiroiolSivkblpMdin^ll^bJldaKof 1,2-bjpMdazfd; 2d X .csík'-Md ïod *x>v4mlu\\o do ' - <- «tsoî 'VW'Ht'»' (17*' p»«olo 2,i bjpÍTÍdi:o-4-d)bnsda;?.o(122'b)pb5daxkv; 3.9. (cík I fiyii^M iMf. pííTok'l24 4lptndln4oi )nn.ida?.oi i .24]pírí<fait|«;' 30. {44)-2- { 5-(2-(4 - Onor-oené í-3--( i//'pim>íö[2J4)pin<!in^”Si)itnid<^í?£ l.î-bjptnd&amp;irin-h'' 0jhexshi<!ropirrok>p,4<]p«‘n>k2(r/0'kí|§íSíKíií 31. {ctó-2~|5-|2<4-f1«OT;-fok0”8>íne0k3-(i//-.|5TOlÍP,34?Jpksdm^0í}s®5<fe^Pí2--bjpn<lss?í«-^ líjixs\ahklroplm>lok3..4-e|pnK4-2( 124)-11 }et.3noi; 32.2 >(4~fJ«or· feni1)»S»meU!*6<{ 4&amp;8> 7úR'rí 'ia«ü)~^i^ites^^^froM3»4“b‘Jp}rid«j<4-U>-3-< IH-pjíTolof2,3“feJpíndííí-4-SÍ)iííítdá?fs(l,2-b]piridaxín; Ä]pÄsäf: 34. 2^4-fiu»r»fimii>4K( 1 ÄT46>5*»ii~2^teMÄIt>R2. 4 -i 1 mnkhitoj 1. Ihbjptnüszin; 35. 9'p'(4-n«om4©«ii)4>41/·4ptfΓok'{234jpí«din4'il)ímída^öLl,24]ptrîdS2in*6"i11-2,9" dw.&amp;spíî'oi$ 5'juftdekáu; 36. ! *í l^peridsö~Mi> 3-{ 1 //'pjrmîol^^-bjpiyidm^-ibiii? ida*o{ 1,2« b'jpískiaz.io.
8. 13. Eljárás as 1. Igénypont szerinti Cl) általános képietü t egyület előállítására. axæsf jd&amp;emexve, hogy (.U } általános képlet-5 vegy «teteit

   ahol R;.. R? és 11$ jelentése as 1. igénypont szer«« meghatározott és Xs. jelentése íávosócsöport, rés-gáUalonk (l.U> általános képlett) amjennlt

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