HUE024988T2 - Új (heterociklusos/kondenzált piperidin)-(piperazinil)-1-alkanon vagy (heterociklusos/kondenzált pirrolidin)-(piperazinil)-1-alkanon-származékok és alkalmazásuk P75 inhibitoraként - Google Patents

Új (heterociklusos/kondenzált piperidin)-(piperazinil)-1-alkanon vagy (heterociklusos/kondenzált pirrolidin)-(piperazinil)-1-alkanon-származékok és alkalmazásuk P75 inhibitoraként Download PDF

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HUE024988T2
HUE024988T2 HUE10801662A HUE10801662A HUE024988T2 HU E024988 T2 HUE024988 T2 HU E024988T2 HU E10801662 A HUE10801662 A HU E10801662A HU E10801662 A HUE10801662 A HU E10801662A HU E024988 T2 HUE024988 T2 HU E024988T2
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compound
acid
rti
ethyl
oxo
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Marco Baroni
Françoise Bono
Sandrine Delbary-Gossart
Valentina Vercesi
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Sanofi Sa
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Description

ILI («ETEROCIKLUSOS/KONPENZALT PIF£RIS>IN}HPEFERAZrNIL)-l-ALKA?ION VAGY tHETKRCO^U&ÖSa«M«HE^^
SZÁRMAZÉKOM ÉS ALKALMAZÁSUK FIS INMiBFKMAKEKT
The sabjeci »f the present inventmn is (hetsroeycie-fUsed derivatives ftml (Iwterocycle-fused f ymôlMmeHpiperaæinyl)- Í -aikaaose derivatives, the preparation thereof and the therapeutic Use thereof.
Thecompotmds according to the present Invention have an affinity for the p?5N :i* neurotropbin receptor.
Neurotrophins belong to a ismlly of proteins^ of which the biological effect is in particular ce ll survival and diifci-ejdistiort.
The p7Sra i; receptor, which is :ffie receptor for ail neurotrophins, is a transmembrane glycoprotein of til«: tumoral necrosis factor (TNF) reeépíor fitmily (WJ. Ptiedinah: and 1...A. Greene* Exp. CelL tes., 1990,253, 13!-142). The $75Ni)l receptor is expressed in several cell types, and several biological imetions: have been, attributed to said receptor: firstly.; modulation of tire affinity of neurotrophms for reeepof lyrosioe kinases (Irk); secondly, ip the absence of trk, induction of a signal for cell death by apoptosis. Moreover, the rteuroifophiU precursors, pfoneurotrophins, are capable of binding to p?5N,'R with a hip affinity, and are considered to be powerful inducers of ρ75χ:’ “-dependentapoptosis in neurons and certain cell Hoes.
At the level of the central nervotts system, pany studies show that apoptosis Is hrvoived Ummfot psShobgical conditions, such m amyotrophic lateral sclerosis, mulopls sclerosis, Alzheimer's disease, FaÄson’s disease, Hnmmgtop’s disease and prient diseases. p7f*m is also known to be: overexpressed in various types: of henrodegetterarive disuses, sup as Alpenper's disease and amyotrophic lierai sclerosis (ALS) (Longo F.M, et ah, Curr. Alzheimer Res. 2007; 4: S93-606; Lowry K.S. et ah, ArnyotrG#, GateaOl Scier. Other, Motor. Neuron. Disord. 200:1; 2:127-34),
Resuhs suggest fep75mR mayglay a predommast role in the mechanisms resulting in posHSchamme apöpíöíic neuron death (P.P. Roux et ai,J. hfenrosci., 1999,19,6887- 689«),
Results (V. Ddia-Bhmca et al, J. Biol Chem., 2Ö01, 276: 38929-33), (S, Rabfeadeh et at. Froc. Ä. Acad; Sel. USA, 1994,91, 10703-19706) support the hypothesis Ihat pf#^ ptays m important rote m neuron death induced by íhe inlectíous prion protein (transmissible spongiform encephalopathy) or by beta-amyloid proteia (Ateheimer’s disease),
The p75N,K receptor is also: associated with the Nogo receptor attd iswoived Ip the SlgnaMmg of the inhibitory effects of these myelin proteins with respect to axon growth. As a result, Ésc p?SN® rocepUerplays » major role in the regulation of neuronal plasfieity and is ncuron-glia interoetsorss and thus ;ropt«hfs a therapeutic large? of choice .for-promoisgAefyOii^Miife
Beyond the nervous system und scurodegenerative diseases, R has beep suggested that p35m could play a role in cardiovascular diseases, such as mherosclerosis and myocardial ischaemia (M,L. BochatomPialaf et sl>, Am. J. Pathol, 1995,146, 1-6; H, Pethnan, Circulation, 1997, 95, 981-987). Recent studies show an increase in the expression of p7S*rR and of neuröírophins; and massive apoptosis io dthetöscierosis lesions.
Several studies also suggest that $7$*®*· is m mfiammatioo mediator (RMI M. et al.. Atm. Rheum. Dis, 2005; 64(11):1542¾¾ Rayehaudhuti S.F, et al, Prog. Brain. Res. 2004; 146: 433-7, Tokuoka S. et al, Brd. Pharmacol 2001, 134: 1580 -1586). p7$m& Is also described as playing ad importait role 'm mfiaimsatory pia. Specifically, nerve damage appears to selectively increase the expression and she axonal transport of implicated: in the induction of neuropathic pain. Furihsrmbre, the use of a p75N!R-speeific antibody dr of ollgodeoxynueleotide antisense capable of block ing tbe aeilvity of Ősé; receptor m vivo appears to be capable of reversing neuropathic pain (beat and cold hyperalgesia and mechanical dllodynia) induced in rats alter lesion of the LS spinal nerve (Obata K, et al., I. Neuroses. 2096: 26: 11974-11986). An äöt|*p?SNi® neutralizing antibody considerably reduces ihiammatory pain induced by the injection, of an adjuvant into the plantar arch in sniee, and also in a model of sciatic nerve crush m mice (Watanabe T. et áll, A Mentősei. Res, WM; §6: 3566-357; fakor Y. et ai. 3 Orthop, tes. 2010:.28(3): 279-83),
The expression of p75NTR is also described In chronic pancreatitis, with implication In the apoptoiic process of the exocrine and endocrine pancreas (Zhu Z. et ah. Dig, :D|$, :Se|, 2093) 41 (4); ? 17,21),
Ofcf reports have also described the importance of p75^äR In tire development: of hepatic fibrosis (Kendall TJ. et al., Hepatology. 2999; 49 (3): 901-10). p7fm also plays an essential role in tumour biology.
Many compounds are known to internet $yst«tpio bave tm MöF-fype fiterve grbwth factor) activity. Thus, patent application M> 00/59893 describes substituted pyrimidine derivatives which have an NGF-type activity and/or which increase the activity of KKlh on PG12 cells.
Dpcumeni WO 0&amp;/51984 describes 2-aryliaduíe derivatives which have tachykinin antagonist activity, in particular neurokinin-1 receptor antagonist activity. The compounds 3-ehioH>i-(5,6;7,8-tetrahydro-i;6-iaphlhyridin-6-yl spropan-l-ohe and 3-ehierö-145Ä7^rietrahydro- t .6-n<^hthyrklin-6-y!)ethan-l-one are also ia«W;.
The subject of the present invention is the compounds corresponding to formula (I):
m in which:
- A represents a group: ~ n represents 1 or 2; -m represents0or I; - Y represents a carbon, nitrogen, sulphur or oxygen atom or a single or double bond; - X, Xj and X2 represent a carbon, nitrogen, sulphur or oxygen atom, It being understood that at least one of X, X; and X2 is other than a carbon atom; - % and El, located on any one of the available positions, independently represent a: hydisgen aföph á halogen atom, a (CS-C4)aiky! group, a {Ci-C4}alkoxy group, a pertlnoroalkyi: radical, a triftuoramelhpxy radical, a cyan©, or a GÖOfl, DÖÖalkyl, 0DMK5R6 or MHCÖR5 group; erűi represents a group choseu from:
the definition of R remaining unchanged; - R3 and: R4, located oa any one of the available: posioons>::h3d«peíidetóy représenta hydrogenfoom, a halogen atom, a |€l-C4)aliíyi group, a (CÎ~C4)s}kmy group, a: psyfotoreaîiiyl radical, φ -radfoal, a cyano, er a GÖÖH, COOalkyl. CONR5R6 or NHCOR5 group; - -W- iis a nitrogenous heterocycie chosen from:
- i -2 represents I er 2; - i-3 represents 3, 2 or 3; - R2 represents a group of formula:
· &amp;? and 3¾¾ located on any one of the available pos itions, independently represent a hydrogen atom, a halogen atom, a (Gi~C4)alkyl group, a iCl~€4)alkoxy group, a trifiuoromethyl radical,: a triRueromsfodxy radical, a cpno, or a CÖÖií. COOa&amp;yL COOcyctealkyl, SOa&amp;yl, SOgtlkyl, GONHj, CONR5R6 or NHCOR5 group; or one of R? and R8 represents a heterocycie chosen from;
Z represents an oxygen or sulphur atom; R5 and M represent a Imdfopa or a C i -Ç6 alky I group.
The compounds of formula f|) may comprise one or more asymmetrical carbon atoms. They may therefore exist in the form of etmuifomers or diasfofoolsomem, These ehamfomfos and diasforeoisomecs, and also mixtures thereof including meem&amp; pmltsfos, torn? part of the invention.
The compounds of formula (I) may exist in the form of bases or of addition suits with adds. Such addition salts form part of the myenfiop.
These sails may be prepaid with pharmaceutically acceptable acids, fent the salts of other acids that are userid, for example, for purifylhg or Isolating foe compounds of formula (I) also form part of the invent Ion,
In the context of the |jrescm invention: * lise term '“a halogen atom” k 'Menésé termem a fluorine, a ehiorme, a hmàiim or a» iodtos; - the term *φ: Äyl group” k intended itj mean: a linear, kanchpd. or cyclic, saturated aliphatic jpoup, By wayof examples, mention tpay be madepfá Ci*C4 j$rptp 'which 0$%· .represent;':» mc&amp;yl* «%1, propyl, isopropyl, Ipfÿl, isöhoíyh terbhatyí, eyelopropyl or eyelohutyl; =« the term “a Buufoalkyj group” is intended to .mem: m alkyl group: of which' ose or more hydrogen atoms have bees substituted with a fluorine atom, · the term ”a peril uoroalky! group” is intended to mean: as alkyl group of which all the hydrogett atoms lave bees sahsiftuted with a fluorine atom, lor example a blBuoroaikyl group snob as triSuoromethyk - És term rtan alkoxy group” is intended to mean: an -O-ulkyi radical «tee the -alkyl poup is as defined above: the term “a periluoroaikoxy group” is intended to mean: an alkoxy group of which si the hydrogen atoms have bees substituted with a fluorine atom, for example a hinutealkoxy poup such as irifiaoromethoxy; the term % eyeiealkyl group” is intended to mean: a cyelie alkyl group. By way of examples, ntentkm may fee made of cyeiopropyl, methyleycidptopyi cyeiobutyi, eyefepentyl, cyelohexyl, etc., group.
Among the cotnpotmds of formula (1} whip te subjects of the invephom anoÉer group of eotnpounds consist» of iheemnpouads of formula in which:: - r: represents 1 ; and/or * m «presents 0 or 1 : and/Or Y represents a nitrogen atom, or a single or double bond; and/or - X, Xi and X? represent a carbon, nitrogen or sulphur atom, it being understood that at: least one of X, X, and Xj is other titan a carbon atom; and/or * 1. and I I, Ideated on any one of the available positions, independently represent a hydrogen atom, a halogen atom or a (CI--C4) alkyl group; or else
Rl represents a group:
and R is a hydrogen atom; and/or * R3 and R/f, lusted on any one of the available ρο#ϋ﫧,: represent a hydrogen atom, a halogen atom, a (Ci-<34} alkoxy group or a perflaoroaikyl radical; and/or - -W- represents:
or else
; and/or R2 represents:
; and/or - R7 ásd RS, located on any one of the available positions, independently represent a hydrogen, atom, a halogen atom, a(Cl<14)alkyl group, a trillppfojp^hyi radical, or a COOîï, CCfQ&amp;ikyi SO&amp;ikyl or SC^afkyl group; or else ope of R7 and R8 represents a heteroeycie Äsen from:
and/or; r RS and R6 represent a hydrogen atom or a rnofriyi group; in the form of a base or of an addition salt with«: acid. âfoottg die compounds of fonónk (I) whidh: are subjects of the invemiott, mendon may in pafricnlar be made of Èe following compounds : * Compound No. 1: !~{6jmibydri>-41l-thieno[3 >2~Cjpyridm~S-yi}-2dd-{5-fliuiropyrimidin-2-yri-3J- disgafcieyeio|3.2.1 ]oet-3-yll«iteoxie; - Compound No. 2: 248K5-inoroppitnidind2-yl)-2s8foia;5#ieyeipp,2Jfoefr3^^ dil-foiaî!oio|S?4-c3pyridinrS-yi)etbano;ne:; - Compound No. 3: l -(2-elîîoro-7s8~dibydm-5H'|{ÿ6]napbthyridinm-yi^-p-{5-0uôropyrinndin^ylHJ>> dia/aN«yelo[3.2,l joet-3~yijethanone;
Compound.......No... 4: t«trahsdropyr;iaolo[4>3^c;}pyriidin-5-yl}eifranone; - Compound...........No,..5: 6- i3-p-oxo^-p-jmeayi-6.7-dihyilro4K4hiazoloi5i4-clpyiidm-S-y<l)efr1yi]-3 Jv d:iazabicydo[3.2.1 ]oct-8~y!} nicotinic acid methyl ester;
Compound Mo. 6: 6-{{3|,SR)-3,5foime%b4"f2-oxo-2-C2rpfemyim,7-difrydro^H-thia5»io|;5,4--e|^iridm-S^ yljethyi|pipera?in~ 1 -yl| Sfieotinie acid; - ^4342~05io4>rp.pfrenyi4,7-dütydio4a4foaxo!qiS4-p]pyridin-5-yl)eiiyfi-3:,t·. diaanhicyclop.2.1 Joct-S-yl:|nieotinie acid; - SlEBEÉiiaUS: Hfo8>M>C,SfoimefoyM^2-oxm2423phehyffo,7^fo^^ ^1)«ίΙϊν3]|ϊίίρ^Γ^|ί3~ 1 -ÿii};}aie<ïtiiirc acid: - . .No.·.9: 2-[{2S/>R}-2J6-<Íií):Hitfíyl--4.{54riíluoron>ethy]p¥ridin-2'yI)pipc-ra?in-l -ylj-1 -{2-p';K:nyl-^7nlihydro~4H~M^le^5,4-c]pyridb^5^^#iaMne; £gi8gM]4JS&amp;lA: 2"[{2S.6R)-2,6”dinsetl:iyl-4-(54rií1:«ortímet}5y!pfnAÍ0-2“yl)píi)e5‘a2Síí"l-ylj4-’:C3''P^Sflíít 24,6J--teirahydropyra;io!o[4>3<]pyridin~5-yl}ethanone, - 4-[2-oxö-242-pteyl'6,7~dihydro-4|l4bÍ&amp;KolofS,4~cÍpyddiP~5-yl}ethy£]-MS-
SiÄSggä____________ No. 12: I -C2-|^ssyl'-A7'idiiíyAm*4ííitlíiaxo1ö[5i4-c]pyridiö^5-y^-2-P45'“
Cornpotmd No, 13: 142iAieny!-2/ls65l4eteahyd^ymgo3o|:4,3-c}pyxídíö^$-yl5“2'p45* - Compound No. 14: 4-^-0^0-2-(2-^0^1-2,4,6,7deîE-ahydropyraiæfep J~cjpyrîdm-5-yîMhy l|- 1 -(S- pifil®fÂethy]pyndm-2^1^ïpe:faxia-2-ooe; * Compound 24e. 15: 2rf(2S,éRH-(S~iu(m>pyrimídi«-2-yl)-2,ő-dÍírie{;hylplpeímli5-l -y(]~l -(2-phepy3->6,:7-dlfeydÿo-4Î4^1Î3^olo[5,4»d|pyfMîn-5-yl}efeaa0Re;
Compound ,,,,,,,:¾ ,16; 2~((2S<éR)-3,^-dimetiîyl-4~|3-y 1 -jyinsérai?:ieî~íí1 -^2-•piMSïïÿi'-S tetraiîydropyra^obî^jA-cjpyndiîi-S-yllethaeo««;
Confound No, 17: 2-((2S,pRHAS-lIlfôri^îynmîdin-S-ÿO-S^-'Éidedîylpipeîdzinrl-yl^-1 -(2*ppspy 1-2.4.6,1« telTahydroppa2ol»[4,3-p3pyrídín-S-yí;)eíhaítone;
Contpormd No. 18: 2*^2S,^R}~2?6-d;î;metliyl-4Hl6^îi^oro^Îe4^Îy!p^M:ÙÎ:-3^*ÿI^i|pér^m--ï^|ji-i3 C\?-dil5ydro-4H-thiazo!o[5,4-cjpyridín-5-yl}ethanon<;;
CeiïiîoupA No. 19; ô-IS-P-ô^-ïï-iî-pïïa^j^^.P^^^ydpdppsafeÎlJ^^riÂ-S-ylisdiyll-S.S- dk^isyclïsp.2. ïjoct-8-yl3ftleôilôlc «ad methyl ester;
Compound No. 20: 2-[{2S,6IC)-2,6*dirnethyl-4-(6-trîl]uoroinetfiylpyF]dîR-3-yl)pip<;;rar:!i)- l -vj]- 1 -{2-phenyI- 2,4,6,T-íelrfíydfopyra^íopj-c^pyrsdln^Syy^^aööite; - Cotsmound No. 21: 6-{(3S,5I4}-3,5-d!nK4hy!-4-[2-ox<t-2-(2-pheí)yí-2,45f>j4etníhydropyTazoJo[4,3~ y3pyridäß-5-y!)etbyi|p?peraxiiV 1 -2?§:sfcotl»fe'«^É· - Compound No. 22: 2-fpS,61pl,6»dt3n#wl-4^p®p5tdm“5^yi-plpraziprlxy1|-l-(2-phenyj-d,7-dü?ydK)-4i{-thíamlo|5,4-cjpyr«íio-S-yÍ)c;i:haHO;se; - Ccrotpound No. 23: 6-p'3S,5:R)-3,3-dimet6yl-4-(2-<)xo-2-(2-phestyl-2,4,6}7-;etrahy(in>pyrago!o!4,3- d|pyridiií-5-yl)etlty!]pt|)eraaÍ8- l-yi|j5(o<4:mie acid isediyl ester; - Compound No. 24: 6-|34243xo-2-(2-piienyl^,4,6,7-tetraPydtdpyrazöidp,34:]pyridö5-5-y!}«liy||4i;J- ëiaaaPî^cbp.2d jt^í-S-ylfaíCödöte acid;
Compound _ No. 2$: ÿl>y^î^plôÂ?ï“yy-»iCOt}iRl6 add methyl ester;
Compound No. 26: 2-P-(5-&amp;oropyrteidsn-2-yi|-3,S~dk^&amp;kplopJiI|ocC3-yl]-i-(:j[-phepy^l:,4,6,7-tetPïbydropyr<ÎZ<slo[4,3-e3pyrtdïn-3-yl}eîhanoae;
Compound No. 27: !-{2-pl:teHyi-234,6,7-teöÄbydtopyra2öfepJ-e]pyridip-6-yi)«2-l4-pyridärb'3- y!|l ,4 jdtazepap-1 ^l)«bandpe;
Compound No.23: 1 <2^pbenyl~2,4,6i7-í^áliydr6pyt»zolof4,3-c3|^írídm-5-y])-3-(^pyrídin“3 -ÿl-3,8- diatiabicyeio|3.2. rjoet-3-yi}ethanaoe;
Compound No. 29: trÄ0fome^|^idm~2-y ί:)··3 «8-disÄieyeiöp.2.1 |oet-3-yi]ethanone; - Compound No. 30: C(2-phefiyi'6P-dihyd«)-4F!4hjazo!o[5/!-c]pyTid:to~5'>i}~2“(4-pyridin -3-yi- I { ,4|diazepan-1 -y!}eihanoise;
Compound No. 3 i : l-P~phi^ï-2,4>6^24sPrahy#opyinaoki:|4p^|pyridûi-5-yi;)42-p^yr«nid5Tî^5^yi-3s;8-dia2abicycio(3.2.1 |oci~3ryi)ethanone; - Compound No. 32: 2~[8-{5^flnöPöppíí«idín^-yÍ)-3>S-díazafekyoÍopj2Jjöcí-3-yí|-l-p'inethy5-2i4^2“ íeírakydK^p^2ol:öf43 -c^pyridM-yi)ÄiHöS£;
Compound..... No. 33: 6-|3-[2-oxeC2-{2-phenyi-4di-dihydropyfro3o[3,4-d]tkiazoh5~yi)ethyi]|-3,8~ É82ai)íCplöÍ3.2.1 Jmc8-v1} nicotinic add methyi ester; - Compound No. 34: 4-|2-P44-mdtoxypbeny 1)-2^,6,74ötradydrspyra^o[4,3-e|pyridín--5-y]J>-2- oxostbyi|-t^5"dtSoöron)eibyipyriämwyl^3itpensdn--2-one; · Compound No. 35: d-P^Hd-Söín^pbepy^^S^tetrahydropymsíelop J-cIpyrídín-S^yÍ j-C^oxoofiyO - ! -P“triflooroînetbyï|^din-2^y%speînzfe2-«ns;:
Compound No. 36: 2-f^5-Snorp^0xiMio«2-y{)“3 J'diazábíeyelofS^JJocCl^yj^-í^dnethyl'd»?* dibydro-4H-thiazoio[5ehe}pyridin~5-yi}dh8none:;
Compound No. 37: ô"p-p^P4p-rnedîôxy|4ienyÎ)-ôP^dnîÿdro~4Bdhîazo?o|5.4'c]j^«dïP~S-yil-2^ oxoethy í} -3,8-dteabieycíö[3.2. ilôdP-ÿ^nïeotïruc apid methyl, ester;
Compound 'Mb. 38: 643-í2-[2-;(4^íÍuerophenyi}-6,?~dihydrö-4íÍ-thia£oIö[5,4-elpyridin~5-yÍ]-2-oxoethyi}-3v8-diatusbíeyslop.2.1 joct-S-yF)nicötinic acid methyi ester; - Compound No. 39: ß^’P^osp-S'IS^SdriifeoröÄhylpyridteS^l^S^^P^etrabydf^rarfippr e:lpyríd!n'S~yl]eíhy](-3J-dntóabicyc]o{324loot-S^yí)nkotmie acid metbyi ester: - Compound..........No..|Q;: 2‘[S<5-iluorapyT3mtdim2-yl)«3J-d!a2aMoyoíoÍ3.2.í|m't-3-yí]-l-P-^- lriBuprdmeÉyipyridin-2^ÿi)^2d,6J-idrahydmpyraadkifH)3"ô50ridiîî-3-yî|edîmï0Pe;;
Compound lb. À It 4-f2-oxo-2H2-phcaiyl-7JrdibydrO“Sl!i?yrido|4?3*d|pyrîmïdn-6-yi}etby1j-l-(5- trifkoro:methy!pyridía--2--yí)píper;uin-2--or!e;
Compound No. 42: d-^-oxo^-Clkyt^beu-S-yl-d.í-díÉydro^Miazofep^-el^ddm-S-yijetteí'll-l-CS-trifluororaethyIpyridin-2-yi)piperazin-2~one';
Compound_No. 43: 2-fS^5-iuoropp!midd-C-yJ}-3?S"dtas:abicycto[3.2. I jpet-S-yikj-fS-id- metixw.yphenyi^AdJ-tetrahydropYta^olold.S-cjpjTidin-S-yileihanone;
Compound No. 44: 6-r3-[2mxoC424hiophep-3^y!rß;74ibydrc^4If4hiazoioi3>4“e3pyrid;m-'5-y!)etbyl:j-3,d-dlazabief aldfl >2, t Joct-8-yi} nicoi in ic acid;
Compound__No. 45: 2-18-íS-nuoropyrimidin^yO-Sj8-dfezableye:fep.2. l|oci-3-yiJ-]-|}-{2,2,2- tti8as®o«%i^5 ïï-tndazoi-5-yt jethæôôKèi
Compound No. 46: 2~|8'(5-iluoropyripridm-2-ÿ^4>MjaÂiey(;!o|3,2,13od~3-yt|-î-[l-(4- inetboxypbenyl)-·! .4,6,7-tetrabydropyra^oio[4.3-c]p>'ridi{J'5-yi|eibasöne;
Compound_No. 47: ^-[S-iS-fluoropyrimtdb^-yij^J^iaxabtcyciolS.S.lJoct-S-yll-I-p^ib,?- tetrahydropvrazo k>j4,3-cjpyndm-S -yi)et hanone ; * Compound No. 4&amp;: b-pi-|2-oxo-2-(l-phenyi-l,4,dy7-t^3^bytepyraxolO;Pi3-e^ynÄ-5ry|)ethy||-3,8^ dsazabieyclo[32.IJoct-S-yl} nicotinic acid methyi ester; * Compound No. 49: 6-|3"P~Oxa-2-(l-pfe(S^I-1,4s6i7^tral5ydrepyTazôtô|4s3"Î;3î>ÿridla“5“yl)ë&amp;ÿli--3j8^ diazabicyclo[3.2J joci-8~yl}mcoiinic acid:
Compound No. 50: í -(í-tert-butyl* 1,4,6J-ieirahyteppase1<){4J<|pyr|d:M^5-y^“2-|S-{;5”ftooxopyfi:HiJdin^ 2-yi)-3,8-diazabicyck>j 3.2,1 joct-3-y] jethanone; - Compound______No. 5 i : i -[ ! -(4-nuorophenyÍ34,4,6 Jdetxahydropyrazolop^clppMnCNyy-S-P-IS- fluoropyrimidm-i-y I )-3.S-diastabícyclef3 2 ? joci-l-yíld&amp;anone;, - Compound No. 52: 6-{(.2R,5S)-2,ji-ííimeÍiyÍ-4-i2-öxi)-2-(2-pbeoyl-2,4,6,?-tetrabydfopy5:aí:ólo[4!3‘ c]pyrkiiïi-5“yî)etityl]pip<îrazif!~! -yljnleotinomírile;
Compound...........No. 53:- 6-ípR,5SN2?5-db^eíJiyÍÍ-í-[:2-oxo-2-(2“pbeoyÍk2,4,őj4eiTaby#opyfazolof4,3- cjpyridm-5-yi)e£hyl|piperazm>;l"y!|iiicoíinic aesd;
CompaÉhá..,,,,,,No. 54: 2r|8^(5-Sooropyri:nïtilla»2-yl)-3,S“dîazabieye1op.2.1jotá-d-yij-l-(2-phenylMt,% dibydroPH>S«0:roÍ2^3<.3p><ri;dlB^6‘y])eíbasose;
Compound No. 55:: 2- [8-(5-fiiioropyrimi dirs-2-y i)-3 J~dia;^bicycio[3:2J]oei:-3-yij-l42“phenyl~i ,4,5,7-tett^iydropyîToloPp-cjpyTîêm^ê-yQethanôse;
Compound No, 56: 6-{S^P-oxö-S^S-pheáyldgp-dibydró^H-thíazoiop^el^yídsiP^S-yOetbylM,^ dia?a!>icyc]öP.2J|oei:-3-yl}afeö£ffiie acMBfôiftylosîsfi - Compoand No. 57: 6-{8;-P-öxO'2:-(2-ptoiyíi-2,4Jp-}eírahydfopyT33:f)!í>|4,3-cJpyridín-5"y}}etlíyl3“3,8-diazabieyelo £3 .2,1 |ock3~yl:}®icotinie aeid me$Qd esípi";
Compound No. 58: 2“[S~(5-4í«o:ropyríKridia-2-yi)-3 J-diazabicyclo|'3.2.] |oci-3-y!]:-l~(2-phenyi-6,7- díhydre~4H-oxa20ÍoPf5--e]pyirklHfc>3^W)a8ípe:; - Compound No. 59: ^-{(2R,5S>-2t5-dinÄy{“4“[2-oxov2^phsnyi*ö,7-dihydm4M4b53«o!o[Ss4^||)ytMin>> S-yÇedîyîJpipers^ia-i-yiJnkoiinofutrîle;
Compound No. 60: 2-f34545-metivvd-iL2.41oxadsa2oi-3-vnpvi-klin-2-vi]-3.8-ii;ay.abicvck'>i3.2. i|det-3-yl|-i-(2-pher1yl-6,7-dihydrö-4H-thia2olo[5,4-c]pyrid!n-5'y!}e{ha!'(One; ~ Compound No. 61: 6-(842-oxo~2-(2-phenyi“2,4,d,?-ieîrahydropyTazoîo[4,3-p| pyridln-S-y!)ethyil-3,8-díaKabscyfií0Í3,2,:Í:]öcfe3-y3} nicotinic acid.
Compound· No. 62: ó^lS^P-oxo^^p-phepyRd^káibydro-dH-ífeiazolofS.d^lpyridm-S-yíJethyij-SjS- diazabîcyclof3.2.1 joci-3-yljnicotímc add;
Compound No. 63: 6-{(2R,5S>|<^ÂSyi'i4Pp^ft-2-(2“ph®aÿlH^,7^ydro-4BÂia?soMtSs4-c|pjdàia-5-y Oeihy i]pipsr»zki-1 -yijpjcotittie add;
Compound: No. 64: :248-(5-l1adropyrímídin-2-y33-3,8~díazab|eyp!ö|3.2J:|ecN3-:yíl-NC2-pyridkí-4-y3~6,7-díhydro-4kNtl£ÍaXöfci5,4-c]pyTÍd|a^f-y1Jetban0nö;
Compound Ne.-651; 4-p*0xp*2-[2-(5-tr!tluoramethy1pyridin-2-y 0-2,4,6,3-iopahydropyrazoio|4,3- c]pyridM^5-y1!^hy!3-i-p'irif]iioross3%ipyTidin-2~yi)piperaz.i!i-2-one,
Compound No. 66; 4rP-®x<H24p^2t2^-Mtusa5iÿç|^ïfl)* ! ,4,6,74e^bydK^p?®ölO'· i422^e]pyndin-5~ yijethyl) -1 -{S-tid ûuo{®m:eâbyipyrf:dmr2"yS}pipefàân4*onsi ” Compound____No. 6?: 2-p-(S*ü uoropyT3mjd|p2^yi3^3;!:8-diaKâbîëyPîop,2. Ϊ3οο63^Ι|-Ι·42-ρποηνΝ7,8- d ihydr 0-5H -pyrido [4.3 -d'jpyrim idín-ö-y] jethanon«:; - Compound No. 68: 3-(6-{3»[2-ö^24[2-phe«yfc|»4#^íefehyőrie|!p®s»Io[4:,3-<«5| pyrid!n-5-yl)sííiyljj-3,S-diazabicycfoí 3.2.1 ]ock8-yj|pyridiP-3-y1)"4íi-[ l,2s43öxadíazoN5-öse;
Compound No, 69: 2*{8Hf5-eí^r<^^mid>o-*2.-yÍ>i3:<^éö0iÉ%eloP<2ví3ocí-3-yÍJ|;iÍ:^2-}jhesj^«SA^?:· fetâ^l^drotfitidâzo^jS-elpyfym-S-yheîbanone;
Compound No. 70: 3^{3-p-roxo>2^2^heHyi^r7iÂ^#4H^to»îô[3<4-cj^|iiô«5^y})ôÉÿi|^3:i8~ dta;mbleyde|3,2J Joet-Sryí}pyFklm-3*yy-4íír|l ,2,4}0xtóstó4?-one; - Compound No. 71: 24B<5-tfei^^ddmi(imr2-y1^3J-dwahkyeioPC.1 |oct-3-y]i-3 -(2-pteiyM%?- díhydro~4H-thiazoío[/i55'C]pyíidln-5*yS)eíhanone;
Compound No. 72: 2'f(3S!SR)^3.5-dHnfidiyN-[2~oso42^{2^phepy!'6>2“dfbydi'o-4H"ddazeia|5,4*!4pyri^te' 5^i)«%l]p}piâ2in' s 'yl}pyf{midme*5<Mkjxyííc add;
Compound Ko. 73: 2'(8~C5-fi«ompynmídm'2-y!)'3^^diazaibÍpyefep.2J]ocí-3-yii-i42-pyrídm-3-yi-i>2“ dihydro^Hd:híazolöp,4--cjpy3'ídm'5-yl3etí!aoone; - Compound No, 74: î 42-phepyí-6Ptóhydro~4í4-thtatóöfS.4-cj3>yddin»5-yl)-24S-p:4iÖ-feiFä2öi"5* yî)pyddfn-2-yi|~3 .B-díaxafcícyeloiPJ. î: jocí-3-yJ ) ethanene; « Compound No. 73: 2- £{3S,5 R)-3,S-dimethy|:-4-P-oxo-242-phenyl-2 AbP^etf^ydropyrasmlePjd- clpyf idm-5-yl)eihyi)pipera2m- 1 -yí) pyrinddme-S-esthoxylie tód; * CompomsdJNo, ?6: ö43't2“Í2-(4-í1«ompheoy])-6,7-dsby,dí»-4íí-thkzoío|5d*c]p5a'^*ö"S-y5|-2-oxöetbyí}“ 3,8-d!azab5cyek>[3.2. 3 joet-8-y3)nkotmomtrde; - Compound No. 77: ë- {342^xo-242-pbonyîP4#î^!eô^ÿ^0PÿraœM^3^]pP:ÂP-yl)eibyl|P>S·' dtóafefcycfep .2 J |oct-S‘-yi} HÎomiïtmdtrile; - ilmgmiá______No. 7H: 4-i2*ox04242-pb«nylP,456pdsb#^rôimidazp(4i5-(|pyrîdldr5*ÿl}êîhyl|rl yduommethylpyddin-2>-yl}pípe:ra?j«-2-'í>ne;
Compound No. 79: 6~|pStS^|'3iS*dttóíbyi-4-P-<)XoP42-phenyl»2,4^7*teírahydrppyraziökí|4s3^ clpyFidin-5^^ihy!3piptó2d“Cy?|o^dÍpie acid; ethyl ester;
CpmpopM.......... M&amp;Mi Cp^|4-Ídpí«í^enyí3-bp^dtliydtx>-4M-tbta^ío[54-olpyndd5-5-yll'2-p”CS- nuoroi^rvrínddinC-yOC^-díazabieycIopC.íloct-S-yljethanone;
Compound......._ Μο,Μ: 2^p43*ötó'opyt'imidin-2-yi)-3 J-díaKabícyelo[3.2.1 jOet-S-yl^í-P'Cd- methoxyTíhenylH'jJ-dlhydrotól-thiatóolB^-cIpyTidtn-S-yílethanorie;
Compound No. 82; 4'p-6Xo4242i^«yUd>2-dihydí«i-4M'4hiaxo3o[4,S-c]pyHdm'S-yl3etby!]“l*!(a'· ΐΓίίΙίΚίΓοηίΰΐηνΙργΕΜίΐηίΐ-^νΟρίρβίίίΖϊη-Χ-οηβ;
CompoundNo, S3: 442^ötó2424Ée53yMP^5hydro^H-oxa2’olo(4p<]pyndló'S-'yl)ej}Íy|'-14S- írid8oroKíetby^ytidm-2”yl)pípeítóp^-oSíe;
Compound No. 84: 4-[2-ôxô424^-pÿrïdIn-3-yl-ô>7"diliydîO>4H-thîa20ïof5J4'C]pyndm-5--yî)edtÿl|-'Î-(3-trífiüororí3ethyipyridin-2-yl}pi;>era>;Í!j--2-one;
Compound: No. 83; 2-fB-f:5-C2-meihyJ-2M4eínt2ol-5*yl)p5T3dí:a-2->4|-3,B~díazabícycío [3.2.ljtó*3->4|r|-· (2i>«henyl-24d|2tórahydropyra:o>lo|4p^jpyrk1m-S-yí}ethaTtone;
Compound No, 8$: 2- {(2S>dR)42,b-dtmethy!-4-|;5-( í-mtóyC IM-MrazoCS-yi)pyridi«-2 -yljpiperazimí rylj-3-{2-pbenyl-254!6,2ded'ahydropy^olö[44H:|pynöÍm5~yi)eítóióne;
Compotmd No. 87; 2-1^8,61)-2^0^^0^1^-1342-^0^1-214^(^203-5^^)^4:(0-2^1133^0^1^1^1:1-142-fhónyl-2>4>d,2detitóydropyratóö[4,3-e|pyríd(n-5-Y3)edíafione; - Comixonnd .. ; ; No, 88; 34S^5‘;luompyri£nÎdin-2-yl)-3>8-dîa2abkycio[3.2.1]oeP3-yl]-4-[l 44-tdddötótóhyljdtóy 1)-14?hsí4óí!dhydTopyn52olof4,3-c|^rld3n-5-yl|ethanone;
Compound N>>. 89: 2-f(S$^6lt^-âÿ6^iitR©iîiy!"4--|S45~ïneïhyi|'l,2,4]oxad^æ3l:-3-y3}-pyïîdiîî-2-y]]]ïtpeâ'a2în-i-v3Í^t^^-Í^:é^Í^2i4^ói?^í^al!íy<1rixpymK0Í'0[4í:3--c3|?^r3d}xí--5--yí)ethancírie; * Con:iï>ouiKj No. 90: 2-f(2S,6R)"2.ó-dhsKahy 1-4-( 5-f i ,3,4joxö<Í^^N2~>í4pyridííi“2-yl>píperúa;£íí-· I-yi1-^2-p:h«tiyl-2,4,6,7“ieh-ahydi'()p)-ni?.i'>!o|4,3-cjpy:,idiriö--yi)eÜtör:0{w; * Compound No. 91: 2“{(2S.6R)'2>6-d?tnethyi-4i'5d3~mclhyl-||J2i4|oxadiazol-5-yi)i5yr|d:h-2'y4]pi|)8i^Kr!·· Í^y|}-]d2-phenyI“2,4;6J-te{nihydropyra2ol(^3-c]pynd{s-5-yl)eíhane®e;; * Cegpgnd No.. 92: 6-(<.>5,5Η)-4~[2-{1-ίεΛ-»υΐνΙ-1 ^d^-tetrat^dropyr&amp;KoioHjO-oJpyridin-S-yiy^- osoothyi]-3,5-dlRK4hyipipera2in-ί-y Í}nicotinic acid methyl ester; * C’mapePad ·,..·..&amp;ί3: 6-{(3SJ&amp;4-|2-(í-teíí-P«iy!-i,4.6,7-tetra^dfO(maxetö(4í3-c]pyridi8-5-yt)-2-cKWíCíhy ll“3 »5-di8i€ÉsyÍp(perax3R-i-yí} n icotia ic adkl; ” SÂgSSSâ....HiteMl d^{3^(24îd®^’hî%W,4>6,7-tehrahydn>pyt'axote|4J3-c^3yï'idS}-5-yl)-2-<sxoedïyl|-3(8- dis^McyekíÍ3;2J|oct~S-yí}aíemmte add; - Compound No, 95: d-IS-CS-RöömpyrimidiH-i^R-S^-dÍaxabícyeiepj-IÍed-B-yi^l^-phcajd-d^ d(hydm-4H-oxazol0Í5i4-e|pyddi«-3”yl)eihanone;
Compound...........Hil-JMí 4-p-oxo-2-C2-pheî3y!-6>7-dlhydro-4H-0xa2efep;4^e3pyddl»-5-yi)eihÿI|«l'-(5- triílo0romethylpyTÍdín-2-yl)p;perazio-2-o«e;
Coropoand No. 97: 2-{PS,6S)-2,6-dsB5dl^Í^45-ir5nöor0Bidhy!pyrídÍBp-yl^síperazm-1 -ylj-1 ~(2-|>3séSí5-'í-4,7tei:hydrö-5H-iIiioro[2!3-e]pyddin-6-yl}e4hanone;
Compound No. 98: 6-((3S,5í^-3,5'dimeíhyí-4-p-®ö-2-(2-phe8yi-2.4.6v7-tetrahydropyrazolof4>3- clpyrídiB-S-y Oethy ljpiperazIn-l-yllBiediHíie: add isopropyl ester; ‘ Compound .........11¾.¾¾ tril7uoro:methylpyridis-2-yl)-3s§-dia:zahieyeloP.2. t ]oct~3-y Ijetbanonc;
Compound No. 100: 2«[(2S,PR)-2i6-dimeitsyl"4-(?-trifidön»oethyipy7idlB-2--yl}piperazm-1 -ytp 142- aieihyl~2,4,6s7-oi:trcteydropyrazoio(4.3-c]pyrsdin~5-yi}otl:;ar;oae' :SplÍPfitteá.ÉPv.MI;J-(2-pheívyl-4,7-d?hydto-5H-lluöro[23te|pyrsdm-6-yS:)-24S-(5-mflooi'omdhy|pyridte» 1 ’joct-3-yl jeîhanone;
Compound No, 102; 6434'2-[2-(44loorophenyl}“6/^dihydro-4H~th:laz.ok>;(5s4~e} pyridm-5-y1jH2~ oxoethy?} -3,d--diazabicyolo[3.2,l ]oot-S-y)teicotinic acid;
Compound______Mo. 103: 2-[(2S,6R)“2!6"diínethyl-4-(5-tdfluoromethylpyrjdio-2-yí}p5psrazsn-l-yt|-!-|2~p~ td5o<!ron5ethylpyridlB-2-yl)'-2>4;,6>7-teirahydrop>s'azok)(4t3"C]pyddio-5-yj:|ethaBOBö;
Compound No. 104: 2“[8"(5-tríduoro{ne;hyipyridifi-2-yl>3.8-diazal3Íoyeio[3.2.1'joct-d-yil-t-P-p- tdiixa’öíoeteyipyridiK-S-yíl-S^jőJ-tetrcíhydropyrazolold.S-cjpyTÍdio-S-yildhaBOBe;
Compound Nia. 105: d-((3S,SR)-4-[24á-tert“hdtyi444,6,7-toíT8fcydropytezolo[453-c]pyT';ídte-5-yÍ-2- os:oeteyl5-3,5-difHethy1piperaziB-l -yij ifcótmk add;
CoiBpoüod No. 106; 24;S-pyrk(m*3”yR3s;8“diaZííbÍeyp|öí3>2dJoCí~3-yi3~i-[245-teíÓüOíx>medty(pyti:dm*2-yi|-2s4j6,7-tetrahydröpyräZö(ö(:453-eJpyrsd:ip-S-yl|eih3iiooe;
Compound No, 107: 2-[5-(6*udf!u(j^tadi^yndazm»3^i>!^J*d^b3cyete[2;.2..1| Srept-2*yi-4-|2-(5· ίπβροΓρϊρ»%'^πάΐΒ-2->1}“2,4,6,?-ΐδΙ^ί^ΐθρρ·8ζοΙο[4,3-?] pyridm-S-yljethanone;
Compound No. 108; 2 - (61- oh toro-2,3,5,8dôtrahydto[ L2^hipyrazmy) -4-yl}~1 -(2-(5-tei5«orímteíhyfe«dÍ8-d-yil-S.d.o.T-îetrahydropyrazoiol^hS-ejpyridiri-S-yljetlïanorie;.
Compound Mg. 109: CÍ2-phenyl-3/t?ö.;7-K4r3hydí\oimída?^)[4,5-e5pyr;din-S-yS}-2-[8-(5·· trlflyôrômeÉÿ^ .B-diazabicyelolï .2;. í|o<d-3-yl|óíÍ3aoone;
Compound No. i i0; 24P^<^-2,6~dlî8edîyM-p4Hf5îKæMî^ÿl|3yndîô'2^1^)p«ra2Îïi'l"ylj-l“(2-î5heîiÿi- 3,4,6 J4eíralíydmíHÚdax0p,5-eJpyríd:iarS-y|)eíhaíösne;
Compound No. ill: 2-j|2:S,5R|-3,5^|modîy^3,5,ë-tëteahyîfeJ'l,2,]fe5pyraxmy!-4'-jd|-1-(2-(5- twtoomníOihyípyridiíS^-yl^d^y^eíFahydr^ymxololdJ^ilsypidíö^-ylIedsaooos;
Compound______ No, Ü2: 2-í(2S,éE|-4-'p-chÍoropyridín-2-y^2^-dtae#ó4pípefas38~i-y1j'-NP'(5“ triiaorG^ot!yy!|^dtn-2^yi>2,4,6,?4eim?iiyikopvraxoäo|4.3-e]pydd!K^-yi|eötauone;
Compound____No. 1 i.3: 2-[4^?<h:iofx^oà30lïO“4^%ïp^ïm"l-yî|-l-(2-p3's«oyi*2,4,6,,7-- fetral^dropyf3Ä)3ep.I-c3pyridin-5-y3)elhanoKe;
Compound___________No, 114: 2”[44S“ehiorop^dm--2~y3|piperazin'l-y:ij:-3-(2-^euyN2,4:j6,2-· {etfahydmpwm2o3o(4,3-c3pyï:3dÛ5-5'y3)etfeaH03îe; - Compound..................No, 135: l-(2-pyrid;n^4-y 1-6,7'-ddiydro~43Cthia2o3o[5;4-<:|pyt-idm-5-yl)-2-f 8-(5- tnflüoí^methylpyridltó-yl^^-diazabicydop^, 1 ]oct-3-yi]oth£mooe;
Compound: No. ! 16: 6-|(3S,5S)-3,S--dÎm^l}ÿ!-4-p“Oso^(2^heîiy3-;3JiJÿ2^iyhydroÏ3îdda2oi4.5' clpyrädän-S-yllothyllpipOmzm-1 -yUmcotinic acid;
Compound No. 117: 1 -(2“pyndin-2-yí'2,4Á24£|r^yd^^3^íp|4,3-ój^f idis-6yyl}v2-[8-(5^ ^«<»oimethy]pyTÍdm-2^i|^3^ía^bkydop;?J'jjiocí-3--y3^Í^Pj|!éj· * Compound.........No. i 18: 2'[(2S,6R)-2i)'ds3n«ihyi~4-(5-£rifíuoromeíhylpyT3öiu-2~yi}piper8ZÍ!í-l -yij-1 .{2- pypdt&amp;í2-yl-2,4,6p4eímhyÉ^pyrazo3opJ-e|pyridfe'Síy!|cttecme;; « Compound No. 11$: 4“^oxO"2^(2-pyr3dätt>-2'f|*3,4;6JdőímhydropyrazoíoHJ-c| pyrfdmCCyi)Ayi]-·1-.(5-. tFifmo3XHneíhylpyddmP*^ * Compound No, 120; 4-|2^|2-(4-duoroiSisnyÍ|-3j44y?~fe®a33ydrom>sdaZ0(4>5“C]|íyHdm-d-ylJ'2--oxooí:hyl|·-l-{5-tritluorí>niÍdhy!pyridín-2-yl)pípe:ra7jrí'2-o:ne;
Compound_____No. 12 i: 248-pyridirn3"yi"3,8-diazabicyclo(3,2,l|ocí-3-yl5--N(2-pyFídm-2-yl72!4,6,7-' íe-ö^^Í^yra2olo{4,3-c'jpyridin-S-yl>elhanof3e; C.Q.mpoaód.......No. 122: l-r2-(2,2,2~trsfluoroothyíV2,-C6,?'íetrahydropp8zofoi4)3-c|pyridin~5-y{3-2:-P-(5- lFídporoníethylpyTÍdin-2-yi)-3,B-díazabícyc!ol 3.2,1 ]oct-3~yl jethanone; - Compound No. 123: Í-P-Cd-íluooíphenyO-S^.ö.^^K'irahydroímidaKofd.S-cIpyTsdín-S-yí^rP-ÍS-· 4idifl:u0íométhyípyrídín-2-yí}-3,8-díazabic>elop.2. !]oet-3-yI jetii anime;
Camjponftd......No. 124: 2-í(2S,6R)-2,6~dÍ3neiS3y!-4-(5-;Tíno<sr03nsthylpyrklm-2-yÍ;}piperaz;Ín~i-yí]-l-[2-(4-· 3íuoFOpl3onyl}“3.4,6,7-íeirahydíOÍmída2:o[4,5-cjpy'ndio~.5-yi]eíhsno«e;
Compound......No. 125: 4-{2-oxo-2-[2-(2.2,2-triJluoroeJhv!)· 2,4,6,7-teiFähydropyyiizolo |4>3-'C|pyfidin-5- y!|ethyj| -I ^S-tóíísomm^^yridio^r-yffllisraz^^aej - Compound No. 126: 2-f{ 2S,6R )--3,6"dím*dbyM-i5-trí nuyromeihylpyFídm4-yl5pÍpotóní 1^:]^ί-ρ^ρ^2^2·- tnduon>at:hyl:)-2J4,6,'7-íctrahydrop>nizolp|4jR:lp^'ridin-5-yl|eíha33ö;nd; “ Compound _____ No. 127: 342^liesíyl-2í4}65^N1ra%dPöpymzoiö^,3-e|pyridÍ3í-5-y3)-2--p-(3- l37lRa^FOíríed3yÍpyridin-2->yi)'2,5"diazabicyclo[2.2,llhcpt~2-yí!etha3íóne;
Compound No, 328: 6~{3'[2~oxo-2-(2-phenyb2.4.6:?-tePahYdropyrazo!o[4,3-c]pyridi:n-5--y3)ethyl|-3,8~ á|ö^lcydi43^.|l!®^^Í«íeotWc acid cyclobidyl ostor;
Compound No. 129: 2-(C2S,6S|^6-dfee^wl^-qoínolm-2-^^)ipe{aíín--Í-y{yl·- í -{S-phenyi-S.d,^,?· teíTakydropyfazokfdC'-i'lpyridm'S-yOöthaííöne;
Compound.........MoJJR 6-{(3S<5R)23,5K}3mothyM^[2Haxo4^2q333snyK2!4,Rj4ctnîbydr0pyïaz0.lo[4,3- c]pyridin-5-yl)ethyl jpiperam- ! -yí}nícotmíc acid etted ester;
Compound_____Na. Bi: 2-4:0^,dR>4-(5-0Kdhunes«lphonylpyTÍdm“2-yÍ)"2/^dimethjdpip&amp;raz!u-í-yi]-l-@- p,henyi-2,4,6;7-ietrahydropyTamfoI4>3<jpyjMsn»5-y^ediaHOHe;
Compound.............No, 02: 2-{'f2S,6R:H-(5-íluörop>anmídin-2>yi)~2,6KÍimetbylp:ipöí3^:m-Ny1j'!“í3“(4·- me{höxypk^yí)~6.7<iíhydro^li-thíazote[5;4<|pyridm-3-yí}et^afione;
Compound Na. 133:: i"p-(4-meíÍKsyphfiny1)~6,?“éíhydro«-4K4hki2o3o[5í4~c1pyí'ídin^5-yl]-2-|5-(5- SFÍlls5rom8Í!yipyrídÍK-2-y1}-2,5-díá2al3ícyciö[2.2Jibept-2:-y3Jed}snóBe;
Compound......No. 134: I-(2-phenyi-dJ-ddíydro-4H-d:s:iaxöfe|S,d-cjpyridm-5-y|^2^p-'|5-<í2H--py!'azol~3- yî|pyridm"2-y^pipsFâ2m4-yi}ethauone;
Compound No. i 35: 2-[(2S,6R)-23>-d^ediyi445:"ídíaao3~2:'y|)yí3din'2--:y|píp«Fa:ain'-í-yl]yl-{2-pÍí«syi-2pi/),7-ietTahydropyr^aio[4,;Ccj|yyridiri''5-Ad)eT.hanone;
Compound No. 136: 1 -(2-pheïsyi-6J-dibydFO"4íí-dnuzofo|5i4^ei|pyrsáin-5^y|^2^p^S^i;azajr2-y]pyr!dm-2 - y i)~3,8 ~d i azab i c> cio {3,2.3 jocí-3-yljethanone;
Compound Mo. 07; 2-[8-{5~! 12,d]oxad3aaoi-3~ylpyr|d|n#'yij~3 J-diazateCyelé: [3.2. t|0>#3-yí}« 142-phonsd~2,42>J~fetrahydropyra:?olo[4,.Vc]pyrídín'-5-yi)stbanons;
Compound______Nt?. 133: 14>e^1r2s4,4;%|^!ÉV#<^yr^Íp|^^|pydÉfe~54j?l>*lfP^ tnf1«.orot««d5yipyrídíxn2»yiy3.8"diai<abicyck!Í3.2.1 locNd-yijeihimono; - Compound No. 139: phonyJ^d.dj^^ctmdydmpyiazolold^-clpyrtdimS-y^^ilsnooe;
Compound No. 140: 6~ {(3S,5R)-3,5~dimet35yl-4-j:2mxo«2>-(2*pyrîdm"2-yî»2idj.dt7*tetmhydrop3uuzoio[4,3* cjpyridin-S-yi)ediyi]pjp«raxt«--l*yl] nicotinic acid;
Compound.......No. 14.1: 2d;(2S>6R}2^d:imei:hy3-4-pyíiáÍm3-yÍpÍ|xma>sn~:i>p)-14;2^yridm-4-y1-;2>4>6>7" tetf^yÄ^ymaoio^S-'Cjpjn'idm-S-yOethaoono; « Compound No. 142: 2-({2S,6R3-2,6~d5med)yi:-4-pyFysn-3~yipipera2;m-3 -yi|· Í -P-(S-i«ompyridin-2-yl}-· 2.4,4,7d®dÂ^ôpyf'a2olo[4s3“C|pyridnn-5-y3jeîhs{Jon«; r Comjmand No. i4>; 24(2S,6R}Píd"dlmeÍ5yÍ^pyridío-3-ylpípefaz3n-i-yi}-!-|2-(5-tFÍífeoromeíby3pyddín·-2^y3^2,4,ő,7-mu'ahyd:mpyoaKOiö|4,3-0|pyrídin>>S^yÍodiioíooe; - Compound No. 144: ö-3i(3S,:5R)-3>:5-d3o50ÉyN-p-öxo:C3-{2~pyí3dm^2-y!-2>4,d,74oRa;bydropyFá2;oÍo[4J-c)pyrídia-5-y]}edsy]|pipen3z:in-i--yi}nícoíinÍc acid methyl ester;
CptppodM............No. 343: 2^·¾2S>dRp2,4^d:t3ïeä|iyM·-pyrídïό·*3yyipîpem¾m"î-y:i|il·^Ç2-pbεuyii3:;4,4,7- îôiraiîyd3O3mîd;3X0Îds5re!pyTidin~5-yl}edïaîxone;
Command No. 344; 2-[{2S,4R)2,6-din3ethy34454r[t]uoîôméÉylpyî'lÉBÆ-ÿipïparazm-Nyi^i'(2- pyrÎdazinCi-y5-2,4,6,74éRahydropyFazoiof'i,3-c]p>Tidiîî-5~yr)ethanonê;:
Compound No. 147: 2^f,(2S,6R)-2,6~dimethyl4-(Sdrí0iu'.noníet3iylpyrídíío2ryÍÍpiperazm--l-y3:)-l~f2"e%^· J^jd.T^eíraiíydropyrazololdyd-cIpjn-idm-S-yileíhanone;
Compound No. 348: 4-j;2^2^dîyi^,4sd,74eR^dF0pyr^otof4,34:i|5yridm4-yi)^2-oxoethyî]-l-{S- ííiRooFom^y^yodin2*y%ípefa2m-2^öus;
Compound No. 149: s^fQ?rídiní-S-yí}etfejí%spera2Í«- î ~y?ï nicotinic acid; ~ Compound No. 150; d-^pS.Sl^S-djmpthvM'pKÄOP^ä^henyiP^J^iÄy&amp;o^s^löPiS·' e|^rid:in'5-yí)eth^Jp^om2Ín-Í-yl|öíCótmi:C acid; is die form of a base or of 38¾ addition sab «1 ao acid. is the sabseepent text, the term ‘^roieciive group Pg" is intended to mean a group- which stakes it possible, firstly, to protect a reactive fonction such as a hydroxyl or as amise during a synthesis god, secondly, to regenerate the intact reactive fonction at the end: of synthesis, Examples; of protective groups arid also methods of protection apd of deproted ion are given is Prôtmwe Groups in Qrgwfe àt,,. 2nd Edition (John Wiley Si Sops, lue.. New York}:, ip afecordatree with the invention, the compounds of general formula (!) are prepared tteeordtng to the process which Mows.
Scheme I:
More specifically, the process for preparing foe compounds of general foffoEla \l) in winch R, ÜI, X, Xi, X2, % W, R2, m and n me as defined above: comprises the reaction of a Ei formula fii).
(ií> in. which: 1,. Rí!, X, Xî, X2* Y, ta and n are -deßned as in genera! formula (I) and Haï represents a haipgefi afonb ß>r example chlorine; and of a compound of genera! formula (111.!: H-W-R2 ΠΠ) in which W and S2 are defiised as In general formula (i), according to inethods Known to Ötöse skilled in fee ail, for exafopi® In fee presence Of a base, in a solvent as described, fe WO 03/104225. Thus, by way of base, mention, may be made oforgsole bases sods as irieihylannoe, M.Hfoiisopropylamine, diifopxgtylsihylamme :|DPEA| Of K-nïieÉÿlïOoiobOïiïis or alkali metal carbonates or bicarbonates such as ^tassíam Caibifoafo, sodium carbonate or sodium bicarbonate and in fee absence Or in the presence of an alkali metal iodide such as potassium iodide or sofeutn iodide, The reaction is carried ont in a solvent such as aeetonttrde, M,fei-dimethylfocmamíd® (I3MF), M-foeti)ylpytro!idlt30ne, toluene or propua-2-ol, and at a temperature between aothicot teosperatare artd fee reflux temperature of fee solvent. The ‘’ambient temperature” is intended to mean a temperature between: 5 and 25a€„ By way of example, the reaction can be carried out in the presence of sodium, bicarbonate and of sodium iodide In a solvent such as DMF. These reactions can also be carried out in a microwave reactor. in the compounds of genera! formula (!) fens obtained, R, Rl, R3, R4. R5, R6, R7 and :RS can be modified by treatments commonly used fey those skilled In the art, for Instance by hydrolysis of ait ester gtenp so as to give a earboxyiie poop or of a eyado m as fo obtain a tetraaoi® group,
Generally* the add addition salts of the compounds of general formula ft) can be obtained by addition of tbe%prt^laie abid, such as hydrochloric add. hydrobromic acid or oxalic acid.
The compounds of formula (fíFg cpfonalíy In fee form of salts, can be prepared from the corresponding compounds of the formula {VIII):
Pg-W-R2 (VHÍ) in which W and R2 are as detlued in formula ft) ami Rg represófíts a protective group for à nifoígén foorn of W, Rrefeahly, Rg Is a benzyl group and the deprstsetion is carried out according to conventional methods well known to those skilled in the art. for example by catalytic hydrogenation 0« Rd/C or by peatment with chloroformâtes followed fey hydrolysis in an acid medium.
The compounds of formula (VIII) can be prepared from feecompounds of formula (Vfk
Pg-W-H (VI) and (VO):
Hal-R2 (VII) in which Pg, W and R2 are detlued as above and Ha! represents a halogen atom, preferably chlorine. This reaction is generally carded out under fee same conditions: as the reaction for preparing the compounds of formula 0) from the compounds of formulae (II) and (III). Àfsentativdy, the compounds of formula (Vitt) can M prepared by the BuchWätd coupling method in the presence of a palladium catalyst and of an opportunely chosen phosphine, using,: as solvent, inert solvents: such as toluene or xylene. si a temperature between ambient temperature and í iö'C. la the compounds pi general formula (Vtll) thus ohtamsdj; RY and Rh can h« ntodlfied by treannepts commonly used by those skilled in the art,, for instance the synthesis: of ah oxadiaaels group fern a cyano group, or else by Suauki couplings: as described: in the scheme below.
Scheme 2
In Scheme 2 above, L represents a leaving group such as iodo, bromo or R7 represents a ireterocycle as described in genera! fomtoia (ï), ES is as defined in píréra! luk (I) and B represents a boron atom.
Examples of such reactions ate described^ in the experimental section:,
Tlte Couipoonds of iírtnula fill), optionally in the form of salts, when W represents an oxopiperaaine, ate cotntnercia'Iy available or described in the literature, or else can lx; prepared, from the corresponding edtUpoonds ofteiola (¥:llb according to methods which are described or known to those skilled in the art. Examples of speh preparations are described in the experimental section.
The compounds of fbrunda (if) can be obtained by reaction of a corresponding compound of tbrnmla (IV î:
in which % Rl,. R, Ef, X2, Y and tp are defined as ih general formula (1|, optionally in,: the: form of an acid addition salt, and of a compound of formula (V):
(V) in which Hal and; n: at® as defined in formula. (It) and Hal' represents a halogen: atom, which mgy be identical I# or difeest from Hal, Preferably, Hal’ represents a chlorine atom.
This reads«» is generally carried «ut its the presence of a base, Such as tdethyiamme, (1 i Isopropy lethylamine or N-nrethylmorfteoline, iss a solvent such sis dichioromethane, chloroform, tetrahydrofuran, dioyabe or a mixture of these sbiyenis, and at a temperature between i>*€ and ambient temperature. The compounds of formula ^ commercially avaltable. öptipnslly, the pôçess according: to the mvendon comprises the subsepaetft step coosmmg iss isoWssg the desired product obtained.
The products of font-usae 0% (¥% and fVli), and dse reactants, when their nteihod of preparation is not deserilxsd, are commereisdy available or described in the literature, or else can fee prepared according to methods which are described or known to those shitted in the art. Àhernatwely,; the compounds of formula p| can be prepared according to Sehssne 3 which fol lows: Schonte 3
Móré specifically, the process ter preparing tee compounds of general formula (S) in which R, RI, X, Kl, X2, Y, W, R2, m and n are as: defined above and Q represents a residae capable of forming m ester, such as methyl, ethyl or benayl, comprises the reaction ofa compound of terntuia p£IV)r
in which R2 ( W < nd n are defined as in general formula (I) and of a compound of general formula (I.V)
is which R, R I, $, %I, %2, Y ond m arg defined as is general formula (I), according to methods known to those skilled in foe afofor example,. hi, a solvent such asfofofefofomsthaae, DMR or THIy hr the presence of a Mse sneh as pyridine*: tó8:í%laíaioái Mdilfobsppropyiamine or diisopmpylefojdamíné' (OPEÄ) and of a condensation agent such as BOR, 11BÖ or DC’S. The reaction Is earned outrât:« temperature between ambient iemperfoure and the reflux temperature of the solvent, The term “amfeieat temperature” is tended to mean a terepeFatere between 5 and 25°D. Mf way of example, the reaetiott eaa be earned ©ot in foe presence of sodium bicarbonate, of sodium iodide, ht a solvent such: as BRIT. These reac tions can also be oaprijfe# put in a aôerewave reactor, in the compounds of general formula {!.} thus obtained, R, Rf, R3, ltd, R5, Rő, R7 and R8 esn be modified by treatments commonly used by those akiied iß the ad, for oxempfe by hydrolysis of an esfor group so as to give a earbosylic gronp or of a eyaao so as to give -a tetrasole group.
Generally * foe seid addition salts of the compounds of general formula (1.} can he obtained by addition of the appropriate aeidi, such as hydrochloric add. hydrohromie acid Or oxalic acid.
The eonfooonds of formula (.XIV) can he Obtained from compounds of fonnuia (XIII}
In which RZ: W and h arc debited as in general formula (5) a«d.#;Pepspftts a residue capable of forming: m ester, such as incityl, ethyl or bensői, by hydrolysis of the ester bond according to methods Mown to those skilled fo foe art, for example by a treatment in an acidie or basic aqueous medium, or else fey redtwtioh Is polar Solvent such as ah alcohol or THF, under a hydrogssr stream.
The compounds ,df formula (XII) can fee dfetainedfiom compounds of fomnla (111) H-W-R2 Oil) lb: Which M and W ate defined as in general formula (I); optionally in the form: of an acid addition salt, and from a eompomfo of formula (XII):
(Xll) ίο which Q represents a residue capable of forming an: ester such as methyl, ethyl or benzyl Hal represents a halogen atom, preferably a chlorine atom, n is as defined , in general formula (I).
This reaction is generally carried out: in foe: presence of a base, such: as trlefoylatmiM fofofe diisopropyiethylamine or X-ntethylmoraholtne, in a solvent such as dielttofOmcthane, chloroforms: ístrshydreíman, dioxanc or a mixture of these solvents, and at a température between 0¾ snd: ambient temperature. Ute: compounds of formula (XÏ1) are generally commercially available.
The compounds *f formula (1U). optionally in the fenn of salts, can be prepared ltom the corresponding composants of fonnuia (Vlll):
Pg--W»R2 (Vili) tut' which W and X2 are ss defined io formula (1) and Pg represents a protefoive group for a nitrogen atom of W. iXeferahly, Pg is a benzyl group and the deprofociiou is carried out according: to convernlönul methods known to those skilled in foe art, for example by catalytic hydrogenation on Pd/C or by treatment with chloroformâtes followed by hydrolysis in as acid medicia.
The compounds of formula (Vlll) can be prepared; from the compennds of formula (¥1}:
Pg-W-H (VI) arid (VII):
Hal-R2 (VII) in which Pg, W and S2 are defined as above and Hal reposent» a fiafogén atom, preforabîy chlorine. This reaction is generally carried out under foe same conditions as in foe reaction for preparing foe compounds of formula (0 Írom foe compounds of formulae (IV) and (XIV),
Aiternatiyely, foe compounds of formula: (Vlil) can be prepared by tiurBucfewald coupling mefood in foe presence of a palladium catalyst and of m opportunely chosen phosphine, using, as solvent, lsed isoivefos such; as toluene of xylene, at a temperature between ambient temperature and 110°C, in the compounds of general formula (V1I0 thus obtained, R7 and M can be modified, by treatments· commonly used by those skilled 1rs foe art, for instance the synthesis of an oxadlaxole group fi-ofo a eysno group, or else by Suzuki couplings as already described in Scheme 2 already set out above.
The compounds of fotanula (111), optionally in the form of salts, where W fepesenls an oxopiperafone, are commercially available or described in the literature, or else can be prepared, foam the corresponding compounds of formula (¥11), according to methods which are ;áesciifoed.or;|^ilt'fo|boseskMWfo the art, of such preparations are described in the e^entnental; section,
Optionally, foe process according fo foe invention, comprises foe subseptient step consisting in isolatfog; foe desired: product obtained.
The products of formulae (IV), (VI) and (VII). and the reactants, when their method of preparation is not described, are contfoerctally available or described in the literature, or else can be prepared according to tnefoods wbich are described or known to those skilled In the art,
Examples of such preparations are described rathe experimental section.
According: to another of its aspects, a subject of foe invention is also compounds of formula (II)
(II) in which Ri, R, X, X1, X2, ¥, m, n and Hal are defined as above; In lire form of a base or of an addition salt with an acid. These compounds are of use as synthesis intermed iates for die ceptpounds of formula (1),,
The following examples difibe foe prepmatipn of certain compounds in accordance whh the invention. These examples are not limMng and merely ilifofoate foe present invention. The numbers of foe compounds exemplified refer back to those as were given in foe table hereinafter, which illustrates the chemical structures and foe physical properties of some compounds according to foe invention.
Thé physicochemical measurements were carried om in the following way:
The Inciting points w«K! we«aitd wish a Bnchi S548 instrsmeni
The pratsm .aaciesr magnetic resonance ÍIHNHíR) spectra were recorded »«der the: iollowmg CdodiiiostS; &amp;). at 50(1 MRz on a Brisker instrument equipped with an Av ance ÍH console;: b) at 400 Mife on aBroker instrurnetît equipped wish an Avance I console.
The chemical sblfis are reported si ppm relative to theTMS frequency.
The spectra were recorded under the following temperature conditions:
Temp. A: 48°C Temp. 8: 38°C T he abbreviations used io characterize (he signais are the following: »“ singlet, bs- broad singlet, m * multiplet, hm ~ broad mulsiplet, d ^ dbuhlet, M ^ broad doublet, t ~ triplet, tf - ftoadciqdeh * - not integratabie because of interforeuee with « fero&amp;d peak date to water. *·*:;ϊ tidi mtepfttabie because of interference with a peak, dsse to the HIMJR: sol vent. ΙΕδ * Mo partially snperimposesl singlets. 2Xbs - two partially superimposed broad siftglets, 2XsnÄ two partially superinposesi ftmltlpleis, fhe HPLC was carried opt by means of a ThermoEîseiron I. GQ 8eca XP Max system equipped with aft ism Mp mass specbxftftetry detector and a diode array detector, "The conditions for analysis by liquid: cteinaiogmphy coupled so mass spectrometry (LCA>b;MS} am (he Mowing;
· chromatographic system A
* Einem A - ITO ; 0.01% TEA
- Eluent B - CHjCN - Gradient of 98% of A to 95% of 8 in T9 mintám, «te» e»#» W® ^ **** 5 mmtA&amp;s,
Flow rate 8.S mFmmais; temperature 40°€ injection of 2 μ.Ι of solution at 0.1 mg/ml in a mixture of CHjCN :HsO ” *
~ chromatographic system S
* Eluent A -- H20 - 0.05% TFA
- Eluent 8 - CHAIN 4 0.035% TEA - Gradient of 98% of Ä to 95% of B in 12 minutes, then eluikm tv# oi ® *** §
Flow rate 0.T mfomnate; temperature 4SPÇ
hqeetion of 2 p t of solution at foi mg/snl in a mixture of CMaCNriisG -· ckamatagrapMcspítemyG
* -Eluent A ^ 5 rnM ammonium acetate buffer, pM -8:.5 ~ Eluent B - CM3GH - Gradient of9$%pfA to#S%of 8 in it)minutes, then elution fttÄ8 fo* 5 minutes.
Flow rate 8.5 mlMiadet temperatss-e 48-43 * injection of 2 pi of sblatlou at 8,1 mgftní ín a snixsure of GfíjGH:HaÖ9:L The products are detected by UV at 228 nm.
Theeolmnns used are: CIS- Columns with: a prtielesize between 2 andS pm, preíerabiy 3.5 pit.
For the: mass spectrometry part; tarage® maete: positive electrospray (ESfo)
Scanning from 100 to 1200 uma. 'Has thihdayer chromatography was carried out on Merck Sil|ea gel SO TL€ ptes.: Tfifc silica pi for flash column chromatography is sold by Biotage or Supeleo,
Ail fite sol vents used are of “reagent grade“ or “HPLC pádé" purity.
Preparation i 13R,58)^3,5^lîisset&amp;ÿlri-(5'tHlî8«iomefîiyipyr5di®-âpi)pîpi-szj«é 0.8 g of 2<hloro-5-itrinuoromethyi)pyridine (compound of formula (Vili), 0.5 g of cis-2,6-dimeihylamiuöpiperatüne (compound of formula (VI)), 0.67 g: of ppiptum earbouate and 0.3 g of Mat are charged to 8 mi of DMP. The reaction is carried out in a GEM discover microwave initiator for 30 min at IdCEC. The resulting product is then poured into a saturated aqueous solution of sodium chloride and the resulting ouxture is extracted with ethyl acetate. The organic phase is dried over NavSCfo filtered and evaporated under vacuum. 1,1 g of an oi ly material eorresptemg to foe EEs product are obtained.
Preparation 2 2'|8^MöoropyfÍmídÍ8-2^S)^3jS~di8asafoleyeioPi2vl|óetaae hydrochloride 1.44 g of 2-<lïloro-S»=É«iÈ^1»tîdl»e (compound of formula (VI 1)), 2.2 g: of l'henKyl-3,8·· diagafeieycloP,24]Eclahe (compound of formula (VI)), 1.2 g of potassium carbonate and 0,23: g of Mal are charged to 27 ml of M-methylpyrrolldone. The mixture is heated at O0°G for 5 hours. "fho restdEng product is then poured into a saturated aqueous solution of sodium chloride and the resulting mixture is cMmefod with ethyl acetate, The Organic phase is dried over h}%S€fo filtered and: evaporated 'under vacuum. 3 .2 g: of an oily mateiM me isoted:, and purified by flash chromatography m &amp; Biotage® column, elution befog carried out with M cyelohexane/S ethyl acetate:. 1.4¾. of white solid are: isolated, and dissolved in 35 in! of 1,2* dichloroeihane. 0,72 ml of l-chloroethyl ehktroformafo is added at 0¾ and Em mixture: Is: let to; stir under a nltrOgeu stream for 1(1 minutes at 6fC. and then. 3 hottrs at :8S°C. The solvent is evaporated off and $3 ml of methanol are added,. Mealing Is carried out for 30 minutes at the reflux temperature. Tim: sol vent is evaporated off and foe residue is treated witii Isopropanol:. A white solid is obtained, which fo impede aaá ^ÖÖ:;ie|;-ff'|ide product are «feted. Mp 236-239,:C.
Preparation 3 (3^3SH,5-fiïm*iÎ8yi-î:-(E-trîîîuoromeihyipyridiu-2-yl)piperaaine 2.2g. of Sdrifiuoromeihyl-S-bretnopyriEine (compound of fonnula (VII)),; LI g of οΙδΈ,Ε·· dimethyipiperarine (compound of formula (Vi i), 0.22 g of palladium acetate, 0.28 g of sodium t-featojdde and 1,3 g offiid^butyl phosphine: are charged to 16 ml of PAyfetiS; Heating is carried out at 12(fC;: for 6 hours. The: resulting product is filtered through eeliie and foe solvent is evaporated off; .1.8 g of an oily material corresponding to foe EEe product are isolated. 3$Änafii«ye!ö|M, S joeS^Wfoif^fok arid methyl ester hydroebiorlde 0.42 g of methyl 6-ehloremcoEnate (compound of formula (VU)). 0.5 g of 1-benay 1-3,8" dia4ahkycle|3,2:J]dctane (compound of formula (Vil), 0,4 g: of potassium carbonate and ÖLI 7 g of Naî are charged to ? of Moneihylpyrrolidone. Heating is carried 0¾ fer 7 bows át l iÖ%2 The resulting product: is dien poured into a saturated aqueous solution of sodium chloride and the resub ing mixture is extracted with ethyl acetate. rise organic phase is dried over Na;SÜ4, {litered and evaporated under yhcunm. LI g of an oily material are obtained, and purified by Hasis chromatography on a Blptageith column, eintion being carried opt: Wish § cyclohcxanerii ethyl acetate. 520 mg of a light oil are isolated, ||se product obtained: id the preceding step is: hydrogenated at: 49nC under atmospheric pressure for 2 hours: i&amp; 20 ml of ethanol and 2 m! of lsopropahol,MOs in the presence of 0,22 g of fd/C si 1(1%. Fixation is perforined, evaporation is carried out under vaetmtm and 440rug Of She title product are isolated In the form of a white solid.
EllMBÍlBíá 6-(2-Oxop iperazm-T~y1 )nkof ink add methyl ester hydrochloride
Step a) 6d:2rBen^1ami«oethySapÄ»)Ä acid; methyl ester: 4.6 g of methyl 6-chSoronicotmate and 40.5 ml of N-benzylethylenediamine. are heated at BS:>C for 6 hours in a«tun<Bbe4Äted flask. The resulting product is poured into water and exiraciod is carried out with elhyi acetate. The resulting product is dried and eXaporamd adder vacuum; the crude product thus obtained is purified by flash chromatography.
Step bTb-(4-Seoayl-2'OXoplpëraain-i^ylptemi acid methyl ester:
The product of step a), 2.2 g, is solubilized its M ml of a 2N solution of HQ. S g of trbneric glyoxal dlhydrate ígé added and the mixture is left to slir at ambient tentperattife for 12Ö hours. Extraction is carried out with ethyl acetate, The resulting product is dried and cvaperiítedI under yactrumt the crude product thus obtained is purified by flash chromatography.
Step c) (6-f 2-Öxopipcrazin-1 -·> !}mcoti«k: add methyl ester hydrocMoride)::
The isolated product of 1.4 g is solubilized in iSirtil of ethsmof and then 4nri ofa solution of isopropanol saturated with MO and 0.6 g of .Pd/C at 10% Ore added! The mixture is isit to: react under a hydrogen stream for 4|tours at a temperature of 4ü*ü. Fibration is performed. arsd evaporation under vacuum is carried out. and Ö.52 g of the title compound is obtained.
Pr.v.p3faiion.6 2-€hloro-ri-42-phefiyl-6,7mshydro-4iI-thiazolo{4,S~c|pyridm-5-yl)eth8iKine
Step a) ( 2. -B rom o-4-p i pe r I do ne ) : 10 g of 1 -Boc^piperidone trie dissolved m 2M ml of dichloromsthane. &amp; g of bromine are slowly hided and the mixture is left to stir at ambient temperature for 2 hours. Evaporation is carried out mules vacuum and a solid :1s obtained, ! Is treated With isopropyl: other so as: to obiam a white solid which is filtered.
Step h) p^PhenyMJi^^rietmhydndhiaaoiofS^d^elpyridine):: 4,5 g of the product of step a) am charged to a rOUnd^bottomed iask with 34 ml of DMf and 2.6 g: of Ihiobenzsottde. Metghtg is carried $ Ι1*ϋ»6 of 60®C lor 6 hours, rio aqueoas ammonia solution is added until a baste pH is obtained aridev^otmlcri is carried out under vacuum,
Purification is carried out on a eoluntn by flash chromatography by means of a Biotage<8 cohmrn which is eluted with ethyl acetate and then with methanol. 4 g of a brown solid are isolated, and crystallized with Isopropanol. Filtration is carried out and 2.8 g; of a beige solid are obtained.
Step p| p-Chloro- f ^2-pheayi*-6v2^Íbymxí^ri-lhiazöÍ6p J^lpyridmrs-yflstbanone): :1.6- « roond-hotomed flask with a magnetic stirrer, 2J g of this product arc suspended In M nd of diehioromethane. 2.S ml of trlethylatnine are added and die mixture is brought so Ö’5C:. At 8C€, I -5 mi of chloroaeetyl chloride, Le. the compound of general formula (¥1 in which BnMlal-O 'and tr«l,. are ron In dh^ririáb, The- mixture Is left to reset for 1 and a half hours and poured info water. Extraction is earned oat with, diebloromeihanfc The organic phase is dried over NajSO«, filtered and iexapdratedi under vacuum. 4.1 g of a dark 0% are isolated, triturated, and then let So stand in the cold. The resulting product is separated by settling otd and the supernatant is evaporated off under vacuum. 1.1 mg of the title product are. isolated in the form of a light oii.
Preparation 7^1 and 7-11 2-€lhlpro^:fff2^phenyi^,4,é,7''ietrphydr»pyrax(í|ö|4!3^cipyr5din^S“yl)eíha8dne :(741) and 2^ehiôro^îrS;l'-phenybl,4,6J"tetrâbydmpÿrasKïIo|4,3'-eipyfi^â5î-S-fÎ5eihar5oae{?"1Ilf Step a) (34i~Píaelby5arntnometh'|Z)^iidene]r4^oJtopÍpertdÍ!íe'l-carboxy'Íie) ;âeid íeff-htttyl ester: H) g of l-Bdc-4-píperidöoe and 7,2 g of bii^diinethyiiarniaunde dinwihylapstäte are tbEuxed in a round-bottomed flask. The crude product thus obtained Is coitnen-puri bed by flesh chromatography, and 2.4 g of an oil V mmetlal are isolated.
Step h) 24díenyí4.\4,6.?-íeírahydfpp>mzoÍ0|4,3^é3pyridine-5<atbóX5'Íeneid ÍM-hutylester (M) and .1-phenÿl- i .4.6.?-teirahydropyra2olo|4,3-eipyridine-5-earboxylic acid terffbutyl Met (b-i)):
The product of step a) ¢2.4 g| is dissolved in 27 mi of methanol. 4.J4 g of phenylhydrazln«: aroadüed and the medpre is refluxed tor 3 hours, Evaporation is can ted oat under vacuum and column-purification is carried put by fiash ehminategraphy using a BiotagesE) column, elution hsing carried out with a mixture of ethyl acetate and cyclohexane, I ,® g of an otiy material are isolated,
Stepc) {2-Fltenyl4í>4,Ö)7de!ríd5ydtopyraasÍe|4,3<|pyridi:ne'' hydaoehlerlde (c-i) and l-phenv 1-4,4,4,7^ letrahydj¥pyraxolo[4,3-clpyridine~5- hydrochloride fe-ll))
The nrixture of the products of step l>) fb-f and b-ll, 2.4 g) is slowly dissolved in §0 ml ofiffifiuotoaeetie acid at Ψϋ.. The mixture is then left to stir for 2 hours at ambient tempemiute, The MfiudroaMic apid is evaporated off, 3734 hydrochloric acid is added and the resulting mixture is evaporated to drypess under vacuum, Crysialhnation is carried out with Isopropanol. I g of beige solid l$ #t8in#.
Step d) 2^Chioro-ld2-pbenyh2^d,7-tetrahydropyraxolo[4,3-cipyrldin'-S-yt)ethsoohe: (fd) and 2-clbpriw 1 (7-11)
The mixfitre of the products of step c) (c-l and c-il, ! g) is suspended in 26 ml of diehioromethane. in a round-bottomed flask with a magnetic; stirrer. 1,23 ml of Methylamine are added ai!^ the mixture is hrottght to fi°<2 At ÖÖC, 0,5 nil of chloroaeetyl chloride, he, the compound Of general formula (V) in which ffal^Haï'^Ël «4η·~ί? is run in dropwise. Tire mixture is led to react fist 1 and a half boors and is poured imo water. Extraction is carried out with diebiorotaelhane, The organic phase is dried over Ma-Sffi, filtered and evaporated under vacuum. The residue is purified, by Hash eluomategssphy on a Biotagedh column, elution being earned out with $ cyelohexanefi mby i acetate . 8,15 g of the title product 7-1 (more polar product) is isolated in the form of a light oil and Θ. I S g of the title product 7-¾ 0ess poiar product) is isolated in the term of a light; oi l. Preparation 5 2-Ch h)rt>-l~|l-(2,2,2~trifluoroethyl)-f ,4,6,7-tetralvydropyra:roh)|4,3-c|pyridin-5-yllethanone By carrying out the procedure as described in preparation 7, but using (2,2,2ytriflooroeihyi)hydraxine instead; of phenythydraxine, the tide compound is obtained in the form of a light oil
Preparation 9
Step a|#ÍPyridm~2-ylhydrazono)píperÍdí^^^ acid ?ert-bu;>i ester:
The following are charged to a: round-bottomed Park with a magnetic stirrer:: 5 g of N-Boc-piperidone, 2.45 g of pÿridia:-3~>'ihydi-a2|8o, 180 ml: of methanol and; 95 ml of a .solution ofutethsub! saturated whh Ϊ1ΕΤ The mixture is left to react under a nitrogen stream for 2 It at reflux temperature, the soi vers? is evaporated off púder vaptiutn, the resuiting product is dissolved with díehlnromclháne and washing is carried o«t with a saturated apsoas solution of NaHCO?. 1¾¾ organic phase is dried -©^ÄstO«. and die solvent is evaporated off, and 4.0 g of the tide product are isolated in the form of a red oil .
Step l>) 2-PyridiB..2.-yl-2:,4,b(2-iehahydropyrazo3o|4,3~c)pyridine-5~carhoxyiic: aeid teri-mSyl ester: 33 nil of DME are charged to a romid-boitumed flask and 3.7 mi of PQC1S are added slowly at 8*C. The mixture is kit to stir at 8°€ for 38 min and then 3 3 mi of pyridine, 4.Ö g of the: product of step a) and 5 mi of 13MF are added. The mixture is then left to stir for 4 hosos at a temperature of 228 ini of water are added and extraction is carried out with ethyl acetate. The organic phase is dried over Na2SO* and the sedvent is evaporated off 4,8 g of fe title product are isolated in the form of a black, oil, which is purified by iasp ehomtatography on s Siotage# column, elution being carried out with § ftexane/2 ethyl acetate. 8.78 g of the product Is isolated in the form of a yellow solid.
Step cj ä^yrtdm-S-yN^S^Tnetr^ydro-dH'pyrazoioiid Jtelpyridte hydrochloride: 8:38 g of the product of step 8¾ is dissolved at ψ&amp;χ in a roohd-hottemted flask, with 21 hi of triiluorcacetic acid. The solution is then ich tO:^|r#r2.h0)IES.il;^rtÄ;l^terah»ey
The Iritluoroacctic acid is evaporated off under v&amp;cputn, 33¾¾ hydrochloric acid is added: and the resulting product is evaporated to dryness under vacuum. Crystallization is carried out with Isopropanol, (MTg of a beige solid is obtained.
Step d) 2“C}iloro-ff[1-f2,2,2--te):8tiOf®etl^l:)-|,4!di7":fetraltydropyrazoio|4,3-c3pyridm-5yyi:|ethanone 8.3 g of the product of step c) is suspended: in 4 tnl of dichloromethane, m a round-bottomed flask equipped with a magnetic stirrer. 8.36 ml oftriethyiamine is added and the mixture is brought to ftri":. At 8*92, 8.12 ml of chlsroacetyl chloride, he. the compound of general Toramte (V) In which TlaMM~€i and n~f, is run in dropwise. The: mixture is left to react for % and a half hoars and poured into water. Extraction is carried out with dichloromethnne. The organic phase Is dried over 11¾¾.. filtered and evaporated under vacuum. The residue is purified by hash chromatography m a Biotagol! column, elution being carried but with 9 cyclohexane·· i ethyl acetate. 8.19 g of the title product is isolated in the fort·', of a light oil. iheparation.10 242,2,2~Trinuoroethyl)“4,^{h7-tetrahydro>2if"pyra20iol4Jtelpyridl»ehydPöehlöride:
By eartymg. out the procedure as described^ in Example 9 up to step of btït using (2,2,2-triOuoroeihyi)hydrazme instead of py rid-2-yihydrazine, the tide compound is obtaiued in the form of a pale yellow solid.
Preparation 11 8-((3E,^)-4~€a#0xymethyl»3,5-dl8teil^ ethyl ester
Step a) acid ethyl Mer:;
By carrying out the procedure as described in prepafarion: 3, but using nicotinic acid ethyl ester instead of 2MíBöGfömethyK5-bremöpyrídins, the tide compound is obtained: ht She ferm of a lígfoesl.
Step b) 6-({3R,5S)4-B8ït^ioxycsiî:bo«ÿi:mOibyi”3sS“diisei^lpipeman~i-yi)ftioei«ïîe acid ethyl ester The following are charged tö a roaisd-feotidmed flask equipped with a mapeie serrer:; $à g of the product of the -preceding step. 132 mi of TI4F, 2 A « si of heßayihromoacetäte and 4.4 ni of tristhylamme, 4M mixture Is left to react under a nitrogen strewn overnight at"ambient; temperature, Ik solvent is; evaporated off and purification Is earned out by Hash chromatography on a Biotage# Opium«. elution being carried out with ? hexane; 3 ethyl acetate. 2,9 g of the title product are isolated ,:iW the form of a clear p|.
Step e) 6“í(3R,5S)4^ÍMteyffiedtyl'í3:#-dtpie%lpperaM^^ 23 g of the product of she preceding step are spWlked 50 290 ip| if ethanol, and É® 1,S | of Fd/€ at 18% are added. The mixture is left to react under a hydrogen Meat« for 4 hours at a tsaspdpture ©FdlHC. The resulting product is filtered and evaporation is carried out USder yaeutsm, and 2.2 g of the title compo^ 4{T obtained in the form of a white solid,
Préparai ion id {{2R.i»SV2,6-I.Hmethyl'4~(5-trii1uoromethy!pyrid!n~2-yl)piipcraKin-i-ytiacetic acid Step a i [{2 R ,$S)>-2,d^f?inu?thy t-445^riiiuoroihethy ipyridin^2 -yl)pip®ra3sn-l-yf aeetic acid ethyl ester By capping out the procedure as described in step M of preparation fi, but using The compound of preparation 3 instead of the compound of step af ofipreparafioo 11 an# hromoacetie sóid ethyl ester instead of hronmaeetic acid henryf ester, the title compound is ohiainetUn die; form of solid.
Step ÍPf^6S^2,643imethyl4-^5-feÍflnoronu;thylpyridin-2^1)piperaxíml-yl|aeeric acid: 2.5 ;g of live preduct of the preceding step are solubilized in 22 ml of ethanol, and then 5 ml of a 48¾¾ aqueous MaöM Sektion are added. The mixture is left to react for 3 hours at a temperature of PTC. lie pH is regulated at 6 using &amp; IN solution of flCi Eslraudon Is camted ont with mhyfacetate. Me Oi^pie pliase la dried over Na>SO,s, filtered and evaporated under vacuum. 1: J g efthe title product are IsotWed to the form ©fa white solid.
Preparation 13 pB,5Í)43^4te S -y!}nkotsuic add methyl ester
By carrying out the pMcdure as described in preparation 1, bat using 6-chioronicotinic acid methyl ester Instead of i^pdme, the title compound is obtained in the form of an olt.
Freoaration 14 2-OsIoro-142-t5-trifiluomnK-tbyipyrtdm-2-yi)-2,4,t?,7"tetrabydropyrnzoi(>[4,3"Clpyridi«“5- yljelhanone I g of 2^o4riBnotxmtethyipyndsnv2-y:l>4,5,6>"-tetrabyd.ro~21f”pymaofo|45;3^ejpyT5dins hydrochloride is suspended in 12 tni of dichioromethane, in a round-bottomed flask equipped with a magnetie stirrer. 0.95 ml of trlethylamine is added and the mixture is brought to 8<;C. At 0ο€, 0,33 ml of chloroacetyl chloride, he. the compound of general formula (V) in Which HaH4al~Cl and n~ 1, is run in dropwise. The mixture Is left to react for 1 and a half hoars and is poured into water. Extraction Is carried out with dichloromethane, The organic phase is dried over Na;.S04> filtered and evaporated under vacuum. The residue is purified by flash chromatography on a Bsotage® column, elution being carried out with 9 cyclohexane/1 ethyl acetate, ί M g of the tide compound are alhafoed in tMferm of a yellow solid. S-^ríd8«~3-yi-3iMlaxabíeycl»|3.2^f}«dÉS!ae feyároeMerMe ;§íep a) 3-Benay!~8*uyridin-3-yl-3.S~dia28bsvyclol3.2J:]©ctane;
By carrying out she procedure as described in preparation 3, bur using a-bfomopyrMfoe Instead :.of 2-:j$$aomatp^yi-5-fceomopyridine. and !-benzYS~3JKÍÍaíabicye]ep,2.Í|octane Instead of ds~2,ö-dimcfoylpiperarine, the title compound Í* obtained in she form of an oil.
Step b) S-PyridinB-Yl-.kS'diarabicyeloES.Î.l jodane
The Isolated product of 1,1 g is soluhiixsd In Tö mi of ethanol, and then 4 ml of a sofottoa of IsppwpÄi stprated with ÜCi and 8.bg of PÉC m 1Ö% sre s&amp;d The mixture is Ml to reset under a hydrogen stream tor 4 hoars at a temperature of 48¾. The resulthrg product Is filtered and evaporation is eanied e® enpr vacuum, and 0.84 g of the title compound is obtained.
Preparation 16 pE,SS^d,S'i>lmetbyt-!-(5-{l>2,4|oxsdis^>f-3--flpyri(!ia->2-yl)piperaxine
Stop &amp;) 6-0R,3 S|-3,Si-Dimethyipipemain-1 -yipficotinonitrile
By carrying out the procedure as described in preparation 1,. but using 2-clh«ío-5‘-cymiopyridíná instead of i-eblororS^trlfiuorometby ^pyridine, the title compound is: obtained in the form of an oil.
Step b) (3 R, S S}“3,5:-Oitnsthyi-1 -p-p y2,4]oxadia;sol-3 -ylpyridnr-2 -ylipiporazins·
The following are ebarged to a round-bottomed flask equipped with a magnetic stirrer: l g of the product of the preceding step, !5 ml of ethanol, an aqueous solation of hydroxylantine hydrochloride (2 equivalents), and a solution &amp;f®.M g ofblaiSO* in 7,2: ml: of·water. lire mixture is lei: to react under a nitrogen stream for 4 h at a temperature of 90¾.. The précipitât« which forms is filtered offend 8,5 g of the resulting crude product 0.7 g) Is evaporated under vacuum. It: is einnged to a rotmd-Pîîomed Sa&amp;fe, to vririeh M ml ofacetic anhydride are added at 0CC.
The mixture is let to react under a nitrogen stream for 2,5 bouts at the pfiax temperature. The resulting product Is evaporated under vacuum aud the residue is taken up with ethyl acetate and a saturated aqueous solution ofEyCOj, The organic phase is dried over INa^SO*, filtered attd evaporated under vapnrn. 0.27 g of the resulting crude produet is dissolved in 8 ml of 6M IdGI. The solution Is led: fo react under a nitrogen stream for 2 h at foe reflux: temperature, The pH is replated at 9 with sodium hydroxide and extraction is carried out with ethyl acetate. The organm pase is dried! over Ma^SO*, filtered and evaporated under vacuum. The residue is purified by Hash chrotnafogtaphy on a Biotage® column, elution being carried out with 8 ethyl aeetate/2 methanol. 8.1 g of foe title product is Olnmned in the form of an oil which has a tendenp to solidly.
Preparation 17 I d5~{2TI-Py raxoikhyfipy rid m-2~y1fpiperari ne
Step a) 4-p-löáo^íridio~2^yf)piperarine“GcarhoxyÍtc acid tert-bntyl ester
By carrying ont foe procedure as described in preparation L but using i-forofo-S-lodopyridine Instead of 2~ehloro-5~Brlfimuometh0^yridine aud IH-Boeygiperarioe instead of eiS'2,d-dimefi^ipiperazmei the title compound is obtained in the form of an oil.
Stepb) 4-|5^2I.^i^^o!*3«yÍ)p^d^2»yl}pípet®É^1rea^X3t|!feMldfE^fe!a^Í:§s^ 8.¾ g: of compound of step a), 9.069 g of IHrpyTazole-Sfooronle add. Ö.83 g of palladium tetrakis(tripheoyiphosphme}. 0.08? g of sodium bicarbonate, 15 ml ofDME and 2 ml of water are ebarged. The modoré is refluxed lor 7 .bows.. The resulting product is filtered through csille and dm solvent is evaporated off 0.23 g of Sê product is isolated, The residue is purified by flash clwomaíography on a Bioisgeéb column, elution being carried out with ? hexane# ethyl acetate. 0.11 g of the title compound is isolated in the form of a pate yellow solid.
Step c) H5^|$í#>T^oi-3-yl)pyrtdfe"2tf|p^tüjÉ^M0ö«rö®éíd^!é·
The compound of step b) (0.,11 g) is dissolved slowly in 3.5 ml of trifluoroaeetic acid at OX. The respiting product ts thcpjeíl to stir for 2 hours at ambient. temperature. The trifluoroaestfc add is e vaporated of? under vacuum and ®,M$ g of the title compound Is ob tained In the fórra of a white solid.
PifiÄiohil (3S^Syh3ÿS-03metbÿl-î“(54Mâzoï«2-ÿipyriàÎa-2^fiilpi|ieraïîùe
Step a) pS,3id-3,5~Dlîootbyi-1 r(5riödo~2-ylpyrÄ
By carrying out the procedure as described in preparation 1, but: using 2-flucro-3-iodopvridine instead of 2^éloro*5'*C^î8a«®Â^yi|ipyridme, the bile compound is obtained in the form of au oik
Step blpSjdS^Sjb^imethyi^^S^odOrS-yi^îàdimS-yi^ïiperapioe-i-carbôxyiio acid tart-butyl ester Täte following are charged coder a nitrogen stream at OX: OJ5 g of compound of stup a), ft.26 g of fBoe)yO, 0.46 ml of triethylaroiae and 5 mi of DMF. The mixture is heated at 140X: ford hours. The solvent Is evaporated ©E 0.49 g of crude product is isolated. He residue is purified by fiait chromatography on a Biotage® eoiumu, elution being carried out with ethyl acetate. 0,43 g of the tide compound is isolated in the form of a pale yellow oil.
Step e) 1(28^1^2,.6-0^ 53,2]diosain>tolah-2^flpyridim2“yl]pipemgme- 1 -carboxylic acid tert-butyl ester 0.43 g of eompouud of step b), 0.29 g of his(pknmoi}dibomn, 1)3)36 g of palladium G_> (dppDXEjCT, 0.31 g o f potassium acetate and I D ml of DMSO are charged to a rotmd^feettomed flask undor a nitrogen stream. The mixture is heated at 85X for 2 hours. It is poured into a saturated aqueous solution ofNaCl and the mixture is extracted with ethyl acetate. The organic phase Is dried over blapOn Altered and evaporated under vacuum. Θ.32 g of an oily material is isolated, and is purified by dash chromatography on a Biokqp® eofonnu elution being carried out with 9 cyclohexane/Í ethyl acetate. 0.28 g of a yellowish solid is isolated.
Step d) CSS^R^hiDmtefhyi-4-tS-thiaxoi-2“ylpyri<im-2-y l)piperaxioe-1 -carboxylic acid tert-huiyi ester 0.28 g of compound of step c), 0.092 g of 2-bromotb:iaxola, 0.032 g of palladium tetmkitO-iplreuylpbosphihe: (ΡΟΗΚΙηΐ!), 0,094 g of sodium bicarbonate, 20 -ml of DME túrd: 3 ml of water are charged to a round-bottomed flask under a nitrogen stream. The mixture is refluxed for? hours, it is poured into a saturated aqueous solution of KaCI and extmef ion is earried ©ot with ethyl acetate. The organio phase is dried over MasSfT,, Altered and evaporated under vacuum. 0.3d g of an Oily material is Isolated^; and is puriiled by flash chromatography on a Biotage® column, efetipn being carried: out with 9 cyclohexane 9/S ethyl aeeSgte, 0.2 g of a yellowish: oil iS: isolated.
Step e)(3S,5S.)-3:t5-Dimethyi~3:-(5-thiaíiol-2~yippidin-3ryl)pípéraxínc tníluorosceiaíc
The compound: of step d) (0.2 φ is slowly dissplyed in S ml: Of trifluoroaeetic acid at 0X. The resulting proditet is then left to: stir for 2 hours at ambient temperatare, The trifluoroaecrie acid is evaporated: off under vacuum and AÏS g of the title compound is obtained m the form of a beige solid. EXAMM1 2“j{2S,6R}-2,6-D{meihyl-4~(S~írjf1«óromethyIpyridsB-2-yl)pípcraxií!~í-y8]~8-{2-plveayS-Í5,7"d8hydn>· 4H~tlfoixolo|5,4-€jpyndin~S-yt}€ihanoee 0.2? g of the compound obtained in preparation 6 (compound of formula (11)) 0,22 g of the compotmd obismed. in. preparation Í (compound of formula (iff)}, 0.13 g of potassium carbonate and 0.06 g of Nal arc reacted In 4 ml of ÖME. Thereaction is egried ont hy means of a GEM diseoysfmicrowave in itiator fur 30 mm at 160'€. The resulting product igpopped lid water and extraction is carried out with ethyl acetate, ffee organic phase is dried over Na2S04, filtered and evaporated under vacuum. 500 mg of an oily materia! are isolated. Golomu-ptuiöcatitm is carried out by ilashchrornatography using a B klaget® column, elation being carried out ^ cyclohexase/2 ethyl acetate mixture. 4Ö0 mg of a pals yellow solid are Isolated,: astl crystallized with ethyl ether. Filtration is carried oat and 025 g of the trite product is obtained in the form of a wade solid.
Mp; (IbfollffC NMR (apparatus b): δ (ppm, dmso-dd): 1.04 (rn, 611); 2.65 - 2.76 (m, 2H); 2.82 ·( 2.94 (2 x m, 211); 3.15 (m, 2H), 3.64 - 3M (tn, 413) 4M. - 4M ffo, 2H); 4M t 4M (2 x % 2«>; 6.94 (d, 1H, 3- 9 7.44 - 7.54 (m, 314); 7.76(dd, 111, J= 9 and 2 Hz); 7J9 p«2H); 8.38 (bs, IH). EXAMPLE!
Compound No. IS: 2-((28,615)-2,6-0iMtethyl^-ptriSsOF0mefby3pyridia42^piperaz5«-lp}-f^2-pbenyl-6i7^di!8y'dro-4tLih!»zoiofS,4~eff>yridm“5-yi)eihamme
By carrying out the procedure as described in Example Í, but using the compound of preparation 3 instead of the compound of peparapn i, the title compound is obtained in the form of a white solid.
Mp: (168-169)'*: MM®>; (apparatus e)- δ (ppm, droso-db): ! .66 (m, 61¾ 2.57 - 2,65 (m,: 20). 2.76 — 3.Ö6 (m, 2M) 3.25 fm, *): 3.65 - 3.92 (m, 6H): 4.75 + 4.90 (2 x bs, 2H); 7.40 (dd. Jfo 8.9 and 2.4 1¾ í H); 7.45 ~ 7.53 (m, 3H); 7.60 (d, fo 8.8 Hz, !H); 7.86-7.92 (m, 2H); 8.39(d, 1-2.7 Hz, ill). EXAMPLE 3
Compound No. 19: 6-|3^í2-Oxo~2-(2-pbesyl-2,4,6,7-tetrabyáröpyra«6laj:425-c|pyrtdin-5-'yi)eíhyl|“3,§-diazahteyelo[3.2.1 foct-S-ylfo lentink add methyl ester 0,46 g of the compound obtained in preparation 7T (compound of formula (11)), &amp;45 g of the compound obtained in preparation 4 (compound of formula (ill)), 0.6 ml of duseprOpyfefoylsmlne and 44 nd of DMF are reacted together, The mixture is heated at lillFC for 2 hours. The fesuiting product is poured info water and extraction Is carried out with ethyl acetate, The organic phase is dried over MaySCfo Altered and evaporated under vacuum. 700 g of a solid material are isolated, tfolomnfooribcatfon is carried: out bv dash chromatography using a eofomn which is eluted with a 7 hexaperS ethyl acetate mixture, 0,5 g of foe title product is isolated. It is treated with dtethyl ether, bfeatioo Is carded out, and; 9,45 g of a white solid is ofeíáitred,
Mp; (2G4-205)eC MMR: (apparatus b) δ (ppp dmso-d6): 1.73; (m, 2H); 1,81 - 2J3 (m, 2H);: 2.29 - 2.43 (m, 2H) 2.58 ~ 2,65 (in, ill); 2.66 - 2.76 (m, 2H); 2.89 (m, IH); 3.1? (s, !H) 3.22 (s, *); 3.94 (m, 4H) 3.86 (m, 1H); 4J3 -4.70 (m, M); 4.7? (bs, ÍH); 6.77 (m, iH); 7.27 (m, ill); 7,44 - 7.52 (m, 213); 7.73 - 7.79 (m, 213) 7.92 (m, IH); 8.28 + 8.33 (2 x s, IB};. 8.63 <m. IH). 1XAMPEE4
Cfompound No- 26; 2-ffo(foFi«oropyrtmidM5-2~ylE3,fodiazabkycloj3,2<1fo€b3~ylH~{ l-phenyl-1,4,6,7-teirahydropyra2o1oj43-e!pyrjd!0~S-Yi}eth«none
By carrying oui the procedure as described in Example 3, but using the compound of preparation 7-IÍ instead of the compound of preparation 7-1 and the compound of préparation 2 instead of die compound of preparation 4* foo title compcnmd is «drained in die forth of a white solid.
Mp: (148-158)^ NMR: (apparatus fe), .&amp; (ppm. dtnso-dd): I .74 fm, 214¾ L79 -1.99 pi. 2¾ 2.3! — 2.43 pt,: 2B>; 2.61 -2.75 (m, 2H); 2.84 (m, IH); 2.98 (m, !H| 3.18 t 3.22 (2 x s. 2H); 3.74 + 3.83 (2 x m, 2H); 4.4? - 4.63 (m, 3H); 4.71 (s. Ill); 7.33 - 7.42 (m. Hi). 7.45 ·· 7.66 (m, 5H); 8.44 <m, HI).
KAMELES diazabícyckd.i2,!|od-8-y1|nseoiitííe acid 0.4 g of the compound of Exatupfo 3 is dts§o|v# ip 8 mi of 20% aqueous NaOM solution and IM 9f methanol. The mixture is tefluxed for 3 hours. The methanol is evaporated off and the resulting priRibci is washed with ethyl ethers The pH is adjusted fo 4 with a IN HCI solution and extraction is carried out with ethyl acetate. Drying Is eaiTied out and the organic phase is evaporated, and 280 mg of an oily material are obtained. The latter is treated wild diethyl ether. nitration is carded out, and 9.45 g of a white soM corresponding fo the title product is obtained.
Mp: (2112-286)73 NMR: (apparatus a). § (ppm, átnSo-dő}: 1,73 <m, 211 j: 1.83-2.91 (¾¾ 2H): 2.28 2.44 (m, :¾ 2,57 -2.64 (m, IH);: 2.66-2:77 (m, 2H): 2.89 (m, IH);3. id(s, *}; 3.79 4 3J7 (2», 2H); 4.33 - 4.69 (m,:3||);: 4.77 (s, IH); 6:74 (m,; IH); 7,2? (in, IH); 7,:44: - 7,51 (nt,: 2H); 7,73 - 7.79 (pl, 211); 7.99 (m. i H); 8.28 4 8,22: (2 x s* IH); 8.62 (m, 1H); ! 1,:92 - 12.54 (bs, IH). EXAMPLE 6
Compound No. II: 4-[2-Oxo^2-(2-phenyl-657-dslsydro^4if'thlaxol«jS,4i'C|pyridii3H5”yl>cthy,ll-l”(S“ tri8ueromethyipyndin~2-yf}piper»zin~2-otse
By carrying our the procedure as described in Example 3, but using the compound of preparation: 6 instead of the cotnpound of preparation 7-1 and the cotspoohd of preparation S instead &amp;f :0diig$Bid of preparation 4, die title compound is obtained hi the form Of à white solid.
Mp: f 165- i 66)°C NMR: (apparatus a), δ (ppm, dntso-d6): 2.80 - 3.93 (m, 4B); 3.40 ~ 3.59 (m, 4H t; 3.72 - 4.05 (m, 7H); 4.79 4 4.88 (2 x s, 211); 7.39 :- 7.55 (m, 3H); 7.74 - 7.94 im, 2H); 8.05 - 835 On, 2H); 8.82 (ä, 0.4H); 8.95 (s, 0,6H). EXXMPEI7
CoBtpóWSd Nfo 23; ^pS^^3,S~fâïtaeth>fM-|i-8xi^2^-phen¥î^2^Â7-ieirshÿàrôpyFaz<)!ôf4i,3»e||>yrfdla*S' acid methyl ester hydrochloride %f eartfmg out És imseèdure SS described k Example 1, but using És compound of prepádon 7~1 instesHöf site compound of preparation S and Ée compound Of preparation 13 instead of Pie eompoond of preparation 1, the title compound (free base) is obtained. It is dissolved in isoprppspol and éco a solution of hydrochloric acid in Isopropanol is added, fhe title product is obtained in tbs form of a while solid.
Mp: 210-212 ÿl&amp;ïftfi^amas a, temp. A), δ (ppm, dmso-dd): 1.25 -t L32 í2X.m, 6H), 2.75 ··· 3.00 (ox, 211), 3.id -3.63 (m, % 3.66 - 4.01 (to, 6H), 4.32 -4.81 (xsx, 6H), 7.0? i/m, ill), 7.29 (m, Hi), 7.49 (m, 2H), 7.78 (on 2H), 8.06 (m, 144}, 8.27 - *,48 \m>. IM% 8.71 Cm, ÎH), 9.19 És, Ö.5H), 944 (hs, 0.54¾ EXAMPLE 8
Compound No. 21: 6^|C3SC5E)-3,6-Pi»ietfefIr44[2^xo-2“C2^phenyí-24<Aí7Éeírafeydí-opyra20É14J"'C)pyrídm>'6* yS)cOsyl}pipfe^z«K>-l-yS|«leoíipÉ seid: hydrochloride
By carrying out the procedure m described in Example 5¾ but using the ecsapund of Example 7 instead of the compound of Example 3, dm title eompotmd (free base) :1s obtained; it is dissolved ín isopropaool and Éeh a solution of hydrochloric acid io Isopropanol is added, the title product is obtained in the form of a white solid;
Mp: 209-211 HMR: (temp. B). δ (ppm, dmso-db): 1.24 (d.. j -- 6.5 Hz, 2,7H}: ] .32 (d. J == 6.5 Hz. 3.311}, 2.80 (ox, C5.8H), 2.94 (m, 1.21-1), 3.14 - 3.36f&amp;. Hi), %M(m, 1H), 3.49 -- 4.26 (m, *), 4.35 - 4-.80 (m, 6Hp 7.0i. - 7.fi Cm, 14¾ 7.29 (m, 1H), 7.49 (m, 2B>, 7.73 -- 7.84 (m, 211). 8.05 0«, 111), 8.33 (m, 0.811). 8.39 (m, 0.2H), 8.66 - 8.72 (tn, 111),9.28 - 9.44( 2Xbx, IH), 12.1 13.4 (bs, 111). EXAMPLE 9
Compound No, 1.06: 2-(8-Pyridin--3-yl-A,j8^diaaabieyel6p.2.1}oct-3~yi)'-l-i2“CS“iriOsioronxethylpyr!din"2~yl)424f6<'7-tet ra by dropy ra2oio|4,3~ci py ridsn-S-yl jeth anoire
By carrying out the procedure as described is Example 3, but using the compound of preparation 14 instead of the eeinposord of preparation 7-1 and the compound of prepm-atlon 43 instead of Ée compound of preparation 4. the tide compound is obtained in the toon of a white solid.
Mp: (150-151)-0 NMC: (temp:. B). I (ppm, dt»so-d6): 4.69 (m, 214), 1.83 - 1.97 (m, 2H), 2.34 - 2.66 (nr, **>, 2.75 (tn, 111), 2;93 fm, lil), 3J1#>: 414), 3.47 Cs, 1¾ 3.89 (m, IH), 3.88 (ra, 111), 4.26 (m, IB), 4.33 (m, IH), 4.59 (s, 41¾ 4.81 (s, 141), 3..11 - 7.23 (ox, 21=¾ 7,86(m, 4B), 8J4(m, IH), 8.iS(m, 114),8.34 (nr. 111), 8.53 fs, Û.SH), 8.57 (s, 0.511), 8.86 (m, IB). EXAMPLE m
Compound No. 89: 2'|i2$,68)-2É'Binretiâyi-4-|5-CS-rnHhyl-j:lHH|»xadiaæôlr3^5d)pyryîn~2-yl|pipera2;în-|ryi|-I-4;3r phenyi-2,4,6f7-t«îrahydropyrazolo(4j3^e!pyrldl»-5-yl)«tbaHOp*
By· carrying out the procedure as deseHhed Io Exantpb 3, Isst using, the compound: of preparation 18 instead of the compound of preparation i ami the compound of preparation 7-3. instead of the compound of pnfrtaraiioh 6, She title compound Is obtained Is the todp of s White solid.
flip:: (I(«-164Y:C NMIfr (temp, B), 6 (ppm, dmso-dd): 3,05 (ms ôîîf 2.63 (s, 3H), 2,63- 2,75 fro, 2.738. 2.84 (m, 3.31(). .3,3:7 (m, 2M% 3.67 - 3.84 frn, 4¾ 4.20 (or, 23¾ 4.56 + 4.68 (2X5, 231), 6.96 fri, J- <>.0 Hz, iE), 7.2? (m, 3 H>. 7.47 (to, 233), 7,76 (m, 2H), 7.99 (dd, J» 9,0 and 2.3 Hz, ÍH), 8.29 (s,W), 8.67 (d, 2.3 Hz, 3 33), EXAMPLE I t
Compound No. 45: 2»|8*(5-FlsoFepyriisidm-2-yl)-3i^d3azsbicye8o(3JJ|e£td3^yS|-l-[3-(2^,24Hf3oö«>«thy^^4,S,6,7-tetmhydro-1 B-œdtixoî-S-yl^ethaaone uxsdsfe
By carrying out the procedure as described in Example 3, but using the compound of preparation 8 Instead of the compound of preparation 7-f and the compound of preparation 2 instead of the compound of preparation 4, the: title compound (free base) is obtained, ft is dissolved in acetone and then a solution of oxalic acid in acetone is added. The title product is damned in the forts of a white solid,
Mp: (160-162)¾ NMR: (iernp, A). S (ppm, dmso-d6): 1.61 - 1.78 (m, 2.H), 1J1 - 1.98 frn, 233), 2.34 · 2.49 (ut, 211), 2.59 -r 199 frn, 4H). 3.23 + 3.32 <2Xs, 2H), 3,78 fro, 233), 4.40 - 4.67 (m, 4Ü), 5..02 (m, 2H), 7.44 3· 7,46 (2Xs, IH). 8.44 (m. 211). wummmi
Compound No. Hit 6-{(35,5a)-3,S-l>iínet3iy!.4”|2“Oxo~2-(2-phenyS~2,4,6,?-íetrahydrepyraKo3o|4,3~c|pyridin-5-yfrethyl jpiperazin-l-'ylloieotinsc add ethyl ester 1.88 g df 2^80)(1-4,5,6Jfrefrahydrp#:l-ppgzpipp,2'Pi^ are suspended in 123 mi of diclilofdmethahe, in a round-bottomed flask equipped with a magnetic «Irrer. 2.5 g of the compound of preparation 13, 44 ml of Methylamine and 3.5 g of 803' are added. The modoré is reacted for i hour at a tempefrdeis of 29-25¾. 11« resulting product is then ppsred into water and extraction ;is carried out wiife diehloipmtdhane. Tire organic phase is dried over NafSCh, filtered and evaporated: under vacuum. 6:07 g of as otiy material are isolated. Said material is epîumn-pmifted by flash chromatography using a» automatic Bioiage® cotumm ehdios being carried out with ethyl acetate. 1.8 g of a white solid are isolated. NMR: (apparatus l>, temp. B). § (ppm, dmso-dő}: i.CH (m, 6H), 1,29 (m, 3H ), 2.7() (m, 233), 2.83 + 2.94: (2Xm, 2%3Π6: (nt, 2H), 3.63 - 3.85 (m, 411), 4.13 --4.33(¾ 413), 4.48 - 4.77 frn, 233), 6.87 (m, IH.3,7.27 (m, 111), 7.47 (m, 21-1), 7.76 (m, 233), 7.92 (si, ill), 8.29 (bs, ÍH), 8.63 (bs, 1H).
Mil
Cons pound No. 126: 2-f(2Ss6K)-2,6-Bimeffeyfr4-*(5-trlBooros«e(hy3pyr3din>'2-yf)pitperaxin-i-yl|--i-|2-(2,2j2- îriBnôroetfeyl^î^^r-fetrdhydiimpyraïuJô^dfrrlpyrym-^ylIethaneaenxâiai«
By carrying out the procedure as described in Example 12, bot using the compound of preparation 12 Instead ofthe compound of preparation 11 .»ná: &amp;e #jipospd -Of preparation 39 idstesdS of 2-rphetRyí«4,S,ő,7>· hydröchtoríde, the title compound (free base) is obtained. It is dissolved ír acetone and then a solution of oxalic acid in acetone is added. The title product is obtained so lise fans of a while sol id. I4MR: (spptatm b. temp* 1¾ 3(pppy dmso-dd): 1,1 í (m* ód), 231 - 3,P 41-¾ 3, 10 ·-; 4.73 (os. '*χ 5.04 (ni, 2(¾ 7.02 (οι, i H). 7.65 (ίο* 1 H), 7.82 (os. i i l). 8.42 (ro, IH). EXAMPLE 14
GompoosKl No. 134 }-42“Pfeessyl^^dshyéFO-4lí-íhiaxoío|Sí4-e|pyrMÍR-5~f!)42-{4~}5^-píí-|>yí'**o^3^fl)pyrid:hs~2·-vl||>ipr^a-l •'ylléisRáo««
By carrying out the procedure as described in Examples, b«l usirtg fc cörßpooad of preparation 17 instead of ide compound of preparation 4 and the compound, of preparation 6 instead of (be compouhd of preparation ?-!, lîfâ title compound is obtained in the form of a white solid.
Mp: (23i-233p2 NMR: (apparatus a, temp. B). ö (ppro, d?nso-d6): 2.34 - 2.69 (ro. *), 2.85 -t- 3Jö (2xro, 2H), 3.16 - 3.68 (ro. **), 3.89(tn. 21¾ 4.67 ··· 5.05 (m, 21%6.62 (ro, 111),6.86 (ro. 1H), 7.49 (ro, 3(¾ 7.74 (m, ill). 7.83 ···8.01 fro, 30), 8.56 (ro. 10), 12.68—43.26 (ro, IH). EXAMPLE IS:
Goto pound No. OS 2-lf2Sÿ68)~2>6-I)koothyi-4r(5-l:ldsa:ol4îrylpyrîdio^2fi'|)pÎpenaxro^3~yli-I~(2-phenyI~2,4?6j7»
By carrying, oui the procedure as described in Example I, but using the eoropoand of prepaiidseö 7-1 instead of (he compound of preparation 6 and the coropousd of préparation 18 instead of the compound of preparation i, the title compound is obtained in the form of a free Base,
Mp (173-174)37 34MR;: (s^pæ-altfê a, temp; B), δ (ppm, droso-d6): 1.05 (m, 6(¾ 2.67 (ro, 3H). 2.84 (or. ί H), 3.17 (or, 211), 3.63 - 3.8? (ra, 4(f), 4.18 (ro, 2H), 4.56 - 4.74 (ro, 2B), 6.93 (d, Ϊ- 9.01¾ IH), 727 (m, Hi). 7,47 (ro, 214), 7.64(d,3--= 3.3 Hz, Hi), 7.76 (m. 2H), 7.83 (d, .1-3.3 Hz, iIf), 8,00 (dd,3-- 9.0et 2.4 Hz, 1(¾ 8.29(s, Hi), 8.66(d, 3--=2.4(¾ HI). fire following table depeehesthe examples obtained by application and-or adaptatim of the methods described, by means of die apppspnste reactants and starting products:
The compounds aecordingto the invention were the subject ofbiocbemieai studies.
Cel! culture:
The BH-SY-5Y mm. item aMrtkstoma) U:ôâMeà eteysætkmalîy m a DMBM culture medium (ôoibeceo's Modified Eagle'8 Médium) (Glbeo BEL, Emnee) eontaining PCS (5%) ffeetal calf serum) pofdîrfsger iüMp, GertnasyE sodium pyruvate (t mM) mâ glutamine (4 j»M|i in culte flasks coated: with colingen (Beeson Dickinson, Erasme).
The SK-N-BE parent strain (bums® ïÂSÉIaSteâ) and the Bep: 75 cloue, stably expressing the whole foi;® of ÉS human p?SNTR receptor (SK-N-BE^ Bep 75) are cultured1 conventionally in: an SEMI entere medium containing ECS (55¾). sodium pyruvate: (1 mM) and glutamine: (4 mM)., For tte SK-N-BE Bep 75 cells, hygromycin (200 μΙ/20 ml. of medium) is added as selection agent.
Study of tse dimérisation of tbs :;p3SS f 8 receptor independently of Its ligand.
The p75Nm receptor dimerization study is carried opt; op a cell suspension Of the SK-N-BE Bep 75 stela. The cells (2.5 χ W· eeilsiwell) are placed: in wdis (9i5-well plate) iof 24; % and then pre incubated fef 1 &amp;, at 37Cl© in the presence or absence of the Compounds according; to the invention,: Supernatant is then added,, this supernatant feeing derived from the culture of HFK293 humait cells of renal origin expressing, alter 48 h of transfection, and secreting a soluble fen® Of the p75N1R receptor (extraceikdar ;part of the receptor) coupled to an alkaline phosphatase, at the Inai concentration of 10 nM,The quaferBenfiOO: of the specific binding of the soluble p75:v; !' receptor to the receptor present m SK-N-BE Bep 75 cells is determined by measuring fee alkaline phosphate enzyme activity alter incubation of the cells for 1 boor at 37'5€ In the presence of the supernatant. After filtratl«® and transfer of the filters into 24-well plaies, the alkaline phosphatase activity is determined by adding CDF-Star chemiluminescent substrate (ready-to-use, Eschs). The coneeterations inhibiting SteÇGfe.) of the dimerization of fee :p?5^8 receptor, of the compounds according to fee mventios, are tow and range from 18'6 to lCTiäM.
For example, compound No, 9, i 1, 19 and 24 showed an 1C« of 0.73 nM, 1.9 nM, 14 nM and 1.55 nM, respectively.
Measurement of apoptosis
The celts (human neuroblastoma strains SB-SY-5Y and SK-N-BE Bep 75) ate placed itt 35 mm diameter Petri dishes (Biocoat collagen I, (!0:> ceiisAveli)) in an appropriate cultttre medium containing 5% of PCS, for 24 h. The culture medium is then removed, the cells are rinsed with PBS (Dulbecco's Phosphate buffered saline), and then either fresh medium containing 5% of FCS or medium eotening NÖF fat the concentmtiou of 10 ng/ml), or Mtp-amylold peptide (Af|i;-4d) (at the concemratiou of 10 p.M) Is added, this being in tbs presence or absence of tbe compounds; aceording to the Inyehtion. the degrees: of apoptosis are measured 48 be-ms utter the treatments in tbe case of the SH-SY-5Y strain, and 24 hours after in the case of the SK-N-BE Bep 75 sttalu, hy ipsanb&amp;ation of the DNA bytópfesmic histones (cell death detection ELISA, Bodtdnger Mamfeoim, Germany), lie degrees of apoptosis ate expressed as amesnt of oligonncleosomes/lQ^ cells. Each value corresponds to tbe mean of f ekpernnettial points distributed over 3 Indejjentient experiments:,
Iho compounds of lormnia (I) exhibit: an initlbitory activity on NGF-indtieed apoptosis, with iCSl values which twnge lfom (θ'* io 10'*SM: for example, compounds No, 9 and 11: showed an lCSaof 0,72 nM and 4,46 nM, tespeclively.
Thus, the binding of the compounds accord®! fe th# invention to the p75NSR receptor results, on tbe one naná, ai: sh« blochetmoal: lavai, in: the inhibition of the diweri:mPon of the receptor índacaá fey mmroteophtos, or toéepfeubentiy of öle ligand, and, os the other land, M the cellular level, is thé jphtfetÄ of the proapoptetic effect mediated by the p?5N : &amp; receptor.
Thus, recording; to one of the §#JgctS of the present invention, Ée cetnpontsds of fofmuîâ: (I) exfcÉítá very advantageous activity of inhibition of the dimeriMhPn of the p75^:'S meeptor, independently of its ligand.
The compounds according to She invention can there lore fee used for ifee preparation: ©f Rijçdiestnsaris/te parileslar of medicameßht fer nse ip: preventing or treating asyr.piWogteal condition where toe p75N Λ receptor Is inypived, more paptepigrly those indicated hereistaifer.
The compounds according to the invention ess also be used lor: preventing or treating assy pathological condition where the f7SS ijX receptor is: involved, more particularly those indicated beretoafet.
Thus, aceordtug to another of its aspects, a subject ofthe invention is: ioedi^onehts which comprise a eOittpoutid of tormáid :(1¾ or m addition salt of the latter with a: pharmaceutically acceptable acid,
Thus, the compounds according to the invention cap fee need, in humans of in animals, in the tretouteht or prevention of various: p75Nfl!'”dep«ndem: conditions, such as central and: peripheral oethodegenritoive diseases, lor instance: senile dementia,; epilepsy,: Alzheimer’s disease, Parklnsorfs disease, Huntington’s chorea, Down’s: syndrome, prion diseases, amnesia, schizophrenia, depression, bipolar disorder; amyotrophic lateral sclerosis, multiple sclerosis; cardiovascular conditions, for instance post-ischaemic cardiac damage, c&amp;rdioptyopa'toies. myocardial infarction*, heart iaijure, cardiac ischaemia, cerebral infarction; peripheral penropathies (of diabetic, traumatic or iatrogenic oflgip’r, damage to the optic nerve and to the retins (retinal pigment degeneration, glaucomas retinal ischaemia; macniar degeneration; spinal cord traumas apd cranial traumas; atherosclerosis; stenoses; cicsirlzatkm disorders; aiopeeia.
The compounds according to the invention may also fee used in the treatment of pancreatitis ansi of hepatic fibrosis.
The compounds according to the invention may also .¾¾ used in the treatment of cancers, for instance long cancer, thyroid cancer, pancreatic cancer, prostate cancer, cancer of the stnaM mtestinc sod of the colon* or breast cancer, or in the treatment of tumours, of métastases and of leukaemias.
The compounds according to the; invention may also be used in the treatment of respiratory disorders, tor instance pulmonary inflammation, allergy, asthma and chronic obSirirCiiyé pulmonary disease.
The eompoithds according to the; Invention niay also be used Id Ée tmatment of cutaneous pain ( to the skin, the subcutaneous tissues ami the associated organs;!, somatic pam, viscera! pain (in the eireuiatory, mpirtoory, iashomtesbns! or mogeptaisy stent), and neurological pain:.
The eorupoundS: according, to the invention may fe©; used in tile: treatment of chronic osyropafeie aud inflammatory pain, and in the treatment of autoimmune diseases, such as rheumatoid arthritis.
The compounds according to the mvention may also be used to the heatment of diseases such as ahhyiosing spondylarthritis, psoriatic arthritis, or plaque psoriasis.
The compounds according to the invention may also be used in the treatment of botte fractures, or Is the treatment or pevenion of hose diseases such as osteoporosis.
According to aunthéf of its aspects, the present invention relates to pharmaceutical compositions comprising, as active ingredient, a compound according to the invention. These pharmaceutical compositions domain ait eietoiye: dose of at least one compound according to the invention, or a pharmaceutically acceptable salt of fold epmpoimd,; andiaiho at feast one pharmaceutically acceptable excipient,
Said excipients are chosen, according: 8* the plutrafoeeutica! form and Öné method of aèsktsir^icé: Éhbíed, :hbPffoe castbtbafy excipients which aie fotown to ilfose skilledin foe a:«.; lit the: ithaírtiacendeal compositions 0f Éé present invention for oral, sublingual, stfomhmteous, intrwwÂÉj intravenous, topical, local, intratracheal, mfomas-al, transdeomi or rectal administration, lis active ingfodisut of formula (1) above, or salt thereof, tnay be administered in unit administration form, as a mixture with conven'ioital pharatacmkai excipients, to animals and to human beings for the prevention or treatment of the disorders or of the diseases above.
The suitable unit administration forms comprise oral administration forms such as tablets, hard or sol gel capsules, powders, parades and oral solutions or suspensions, sublingual, buccal, ktnmashooh intraocular, mtra-aaticulsr and Intranasal administration forms, forms for adubnistratioh by fohaiatfon, topical administration forms, parenteral administration fmm» such as transderfoai, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms, and implants, For ΙορΟΟίνορ^Ιίΰβίϊοη, the compounds according to foe invention may be used in creams, gels, ointments or fotfons.
By way of example, a unit administration form of a compound according to the invention in tablet form may comprise foe following components:
Compound according to foe invention 50.0 mg
Mannitol 223-75 mg
Sodium croscaramellose 6.0 mg
Make starch 15.0 mg
Hydroxypropylrnethykeiiuiose 2.25 mg
Magnesium stearate: 321 mg
The dose of active ingredient administered per day may reaeh fobl to löö mg/kg, as one or more intakes, preferably 0.02 to 50 mgfkg. In general, foe daily dose of foe compound of the myehtlon will be foe lowest effective dose of the compound capable of producing a therapeutic effect.
There may be particular cases where higher or lower dosages are appropriate; such: dosages db hot depart: Stun the context of the invention. According: to the customary "pâtifoSè, foe dosage Suitable for each patient, is determined by the physician according to foe: method of administfatlon: and the weight: and response of said patient.
According to- another of its aspects, the present invention also relates to a method of treating the pathological conditions indicated above, which comprises foe administratipp, to a patient, of an effective dose of a compound according to she invention, or a pharmaceutically acceptable sait foe teof.

Claims (5)

  1. Szabadalmi igénypontok í. (I) képlett! vegyllieí:
    Π) ahoi: - A jelentése a következő csoport:
    > U értéke 1 vagy 2; ra értéke 0 vagy I ; * ¥ féieníése szénatom, nitrogén-, :fcé« vagy oxigétratom vagy egyes vagy kötés kötés ; % Íí i és X2 jelentése nitrogén-·, kén vagy oxigénatom, aboi X, Kt és X2 legalább egyikének jelentése széaaíemtoi «Itéré; R és % jelentése, amelyek a fezzâfÂÉS pozíciók Mrmelyíkén Myezkeének el, egymástól függetlenül hiciregénatom, Wstgênatoin, {G3-C4}-ab£ticsopôrt5 (Cí-G4)»alkt)3cíes^ört, gerfuoraiktl-esoport, Míinernuösxi-csopork eianoesoportvagy COOM, C'OÖ-alkil, €014¾¾ vagy NMCÖR« csoport; vagy Rí jelentése a kíkvökeöl csoportok: közül választott:
    R megjttättezasa vátezatlp:;: Rj és K4 jelentése bármely pozícióban egymástól Rtogetfemti todrogénatom, baíögcnatom, alkílesopnrt, CCl-€4)-alkotdesoport, prfuomM^soport, triittotntotoxt-csopork cíanpcsopört; vagy 000¾ CÖO-alkíi, O0MRÄ vagy NMCDE, csoport; -W* leteníése sa aiibbíak közül váVasöott nittogántanálffiö beteroesklüS·
    - 14 értéke 1 vagy 2: í -3 értékelj: vagy 3; Rr jelentése a kővetkező képletü csoport:
    és 1¾¾ jfeleffrtëse bármely pozícióban egypiÉ#] fdggétlendl Éidrógénatömj lalögénatörp,: (C1-C4)-aíkilcsoport, (0-€4)*alkoxiesoport trifiuc«TBetíi-csoport. olfluormeioxi-csopórk maßbesPpöii Ví|gy COOH, COO-ailfÜ, COO-eikioalkil. SO-aikil. SOjalkiJ, CONH2. CONR.R., vagy MBGÖKj CSöpPit vagy R7 és R8 amely &amp; kővetkezők közül választott:
    Z jelentése oxigén- vagy kéöaíööl; R« és R.s jeleníése bkirogén vagy (Cl 'Cój-alkiicsoport; bázis vagy savval képzett adílscios sö íörmájábari. 2 Az l. igénypontszériáit vegyidet, aboi: W jeiemése az alábbi képletü csoportok közöl váksztoit:
    Rs és ü·, jeleplésc hjáSc^ésatOíP: vagy meïilesopofî; bázis vagy savval képzett addieiós só formájában. 3, áz; 1. vagy 2. igénypbit szerinti yegyölét, ahol b értéké 1; bázis vagy savval: képzelt addfcáös só formájában.
  2. 4, ÂZ: 1-3. Igénypontok bártbelyike: szerinti vegyüfek ahol: %jelentése:
    R? és : R« jeleoíéss bármely posfciöbao egymástól &amp;ggetienbi hidrogénatom, kaiogéRatöffij |Çt<;4b a&amp;fesopoit, tniimmtetii-esoporí, COW-cseporj: vagy CDCNilkilcsopórt; vagy RT és 8® egyikének jelemése beíérociklos, amely a következők közöl váláSzíptí;
    bázis vagy sawaj képzett addiciós sö formájában. S.Áz ML s^sypójstok Mrmelyiks sáerínó yegytüek ahol: Y jelentése niröggnato® vagy egyes vagy kettős kötés; Mm mgg savval képzett addkdós só formájában* &amp; Az Î-5. igénypontok bánnelyike szerinti vegyidet, ahöl; X, %s és Xj jelMiisé ssénaíöm. nitrogén- vagy Mnadïtn. ahol X, Xj és X* legalább egyikének jelentése szénaíonlöl: eltérő; bázis vagy savval képied addiciós só formájába#
  3. 7, Az 1-6. igénypontok bármelyike szerinti vegyidéi, áíiol: R és R, jelentésé Mrmely pozícióban egymástői íaggétlenöi fctàsgêM&amp;stt,Mlogdnatoi« vagy CG 1 -C4.j- aMtcsoport; vagy Rí jeileatése: a követkézé esősért:
    és R jelentése hidrogénatom; Rs és 3üt jelentése bármely paste iába n Iddmgénaimm hale^patom, 0Cl-C4)-alkoxiesoport vagy períluoralkii-csoport; bázis vagy savval képzett addiciós só formájában.
  4. 8. Az előző igénypontok bármelyike szerinti vegyidet, amely az alábbiak közül választott.: “ í. számú vegyit let: l-(6,:7~dihidro~4H4ienô[3,2-e]piridin~5-il!-2d:ÿ-(6-di)orp!rim:din-2-il)-3,8-dtazabicîklo-13.2.1 jokt-3-djetanon; ~ 2, számú vegyidet: 2-[BXő'<dtsö!bírítmdín»2“íl}-3,S^!azab!ciklöp;2.íjoké3dl}-Í-p-Íení}-65?--dibidrO''4H- diazolopX^ijpirÄ - 3. számú vegySlét: iA3rkiör-7,8-d5feidio-5M-[l,6]:nafttridm-6-i:i)-2i8-(5'-dörspritnidin-2-ll|-3,^diazäbieik-io|3.2.í jokí~3-i!]etanon; - 4. szám« vegyidet: 2-|8A5-Saorptrimid!R-2-il}-3,8-diaz;3bieikio:[3.2Jjokt-3-dj-í-(2-íenÍ-2,4,ői(7-íetrabid- topimzi>fo[4,3-e j prrtd in~5-i 1 )etam>n; - S, százéi végyakst:: i^|3rP^o^{2-lenji-6J-dikidm-4ki4ia^ldp.4mjp!rjdii-S4i)eiilj-3J'<iazabicikiO'· 13-2.1 jokt-8-r;}nikotifísav~metit-észter; - ő. szánét vegyül®: Í-{f3S,:gR)p;ő4Íjmeib4-|2-oxö-2A2riénd-6,3-dthtátzv4i4-pa2íd<i5,4-clpridmr5-í:{3- eti ijpipeoazirl·· 1-51} rt ikoti ttsa v; - 7. számi vegyük;·: ó-{3~[2-oxo-2~(2-fen3Í-6i?-dihid:rO“fH-tiazokíj5,4~cipiridí:r!--5-d}etilj-3J'diázafeici:klO'· p.2.1 jokt- S-ií ) nikotinsav ; - S. S2ámi vegyidet: 6~j{3S,3R}-3.5-dirfmtii-4-j2-oxo-2-(2-ferlib6,7-dihidrö~4fl-tíazolo[S,i-ejpiridin~5-í1>- ei:iljpipera2in- í dl [nikotinsav; - 0. számé vegyijei;: 24(2S.6Rk2,6^dítnetiM*{54rifíuonpetdpÍridm-&amp;Í)piper3^n-l-iij-l-(2-&amp;nil-A,7- -dihidro-41'i-tk3ZoiöfS,4-cj{)ii'idin-5-il)eiai!Oii; - 10. számé vegyidet: 2-i(2S,6R)'2,6-d3met:il-4-f5-trii1iionnetiipiridffi-2-il}pipeniziri-I'-it]:-l-(2-!eRr!-2,4,6,7- - 1 1. számú vegyidet: à-p-oxo-S-p-ïesiî-ljJ-dífeKro-4|í-t|axotóÍSîïî^S^íOetsÍJ" 1 -(S-ISrt$úú«seti1pí# dsO“2-ii}pf|>erii2ï(j-2-0!K - I2> számú vegyidet:: l >-(2-ífení 1-6,7-tisfeiiä;rö^4i-ä-tiatjö3o [5^<í -g:]^írídín-il)-3~|4~(;5 -Sfíetfl^iiríÉÍIn-2-9)-píperazlm 1 4!}etaaöm * 13-: számú vegyidet: i--Ç3«í©í5il-2,4,6,74:öíjáíyd:röp£ráZöÍ9í4p4|Ráíúm4sal}^ pi peï-îï kís n -1 Ï letáKíííí ; μ î4, szàâîtô vegyitiet: .d^p^oxO'l-p-feiiíp^^s^-te^^hidr^a'aaofep^-'ejptridiíít-iS^i^etHI-l-p-íKiuormetd-pirÍ£Íinpr|Í^|peraa«p>-öú; - 15. számú yegylfet:: :25|(2S5éR>4'(5riuo^j:íÍÍ:rüdPtv2.-):l|P,S"tílmetilpípefa«ia-14:l|-l“{2-íen:ij^,7-diPidío^ 4íÍ4iázote[5J'-e)pmáiít'*S-il)efeHom - M. számú vegyidet: S-ipS^Rj^^-dimetll^^ptrimldiCT-S^il-piperazift·- ! zö!o[4,3-cJpiridín-5-!l|el&amp;8oö:;: - :J7, számú vegyidet: 2-({2.$,6R}-4-! 5-fluo^irrm!dm4Í«d)4!,6-dimeílipiperazin“l-il]-12· leníl-2,4,6,7-tetr«-lií sïro p ^£1201014,3 -ej p i r I d i n-5 - î i íarisún ; - 18. számú vegyidet: 2di2S>öR)-2J6-dimetii446-irill:iíöm3et|ip!ríQÍ:n'4Úl)pfperax&amp;^í-ill'l-p-®;úíi-6p-di:htd-ro4H-í:íazo]oí5.4-cjptridlív5“ii)etaf!on; - 19. számú: vegyidet: 643~[2"OKO-242-fenl!-2J4f6.7^feiTalidrop3r£Koto[4!3-c|plrMm4-®etll*3,S-dl8zafeieSc-loP>.2.i|olií~8"íi}rdkotiKsaV”ínet:Íi-észíef; * 20, számú vegyidet: 2-[{2S>úR)y2,6-din^etij'4'(64iáftmmtei%lrídm-34%tperazm-í:-ti|-H2-feí!l-2í4>úJ-4etmlyldrppira:zo)o[4.3-e]pirldin-?di)e;ïiîKiiî; - 21, számú vegyidet; 6-|(3S,5lt)4iS^dï8ï8tn4:'iP'-oxô»2'|2-fenï]--2,4Ji,7-teîrahîdrop3r3ZDlc5p2;-e^p:!ridîn-5' • il.jeííl]piperazin· i -is}nikotin»av; - 22, szarná vegyötet; l^pSyÚEl-SJ-átoeíM-pirímídin-S-ií-ptpmaivldlyvl^d-ÉRn-áP^dityrom}·^ 4Íazo!o[5,4-c)piridÍ8-5~i!}etanors; - 23. száma vegyölet;: ő--|0S,5RÍ4s5“dsm^d4‘p-8xo-242-fenll'2,4,Ú!74etmhídropsm5sslö|4:13-e|pHdm''5-dlJeiSJpipmitzm-'Í -0} rnkmiasav-rnstiiRészter; » 24. számú vegyüiet: S“t342'mx<^2ip#iÉI»2^4^^Âlàr<^«rà2S^4^3pWdm-5*il^iï|r3v8^%z^)»cik·'· Iop.2.]jokt-8-Í!}nikoti»sav; - 25. számú vegyidet: 6-|2^xe4-|2^xö22-P4sMúms7múúdr84M4úm9MS4^Úpí4Úte54Í|sSiU^>ípemzitt'l-41|níkotinsáv~tnetil-és2íer; · 2&amp; számú: vegyölet: 2-|R-p-fco^úimMffi-2-n|-3,^ái3zafc}eikloi344j#fc3-itJ“i-(s-feaíl-l,4mi7-tetrahí£Ú rí>pírazolo[4,3-c ]píridiö-5~si)etsinon; » 27. számú vegyidet: 142^^l-2,4.6.3^£mhädFöpjrazöm|4,3-c|prad5öP4t3^(4^ydfe34t|i4p^epaty'l:r •üjeianon; - 28. számó verölet: l-(2-tenit-2;44!.7-tetrahidRípírazolo[4;3*e]píridÍn-5-ir)-2'(8-pirídín-3~il-3íS-diaza8icík'· fep ,2.1 ]öktr3 úietmtííát - 29. számú vegyölet: l-{2~fealí-2,4/>.7-teí:rahidropifazoio[4>3“C'jpiridin'5'ii}~2-[8-i5-tiiíluormetilphí<:íín-2“íi)--3 J-dí3za|steiklöp>2> 1 ]ökí-4M i|e&amp;88&amp;;: « 3Ck számú vegyidet: l'P-í^iköpHáffetdm^kNíazolföpp^lpú'iám^úlpS^ú'pMdm 44í^.4'jdkzepú-í^ -í Metánon; 3L sä vegyüieí: ctklo[3.2. f jokt-3-ii)ctönon; - Ά számú vegÿSlei:: 2-[8~(5-i]uôrpttmidit^2-iî)-3>S~âîà28bicik!ôp;^l|ôà^3'itï"^"(2'4nstH-2!4tig,^8ifahid-^iiaEolo|4J~e|pndi«-S-i])i^ßön:; - 33, számú vsgyület: 6'{3-[2-os0-2-(2-fenfM56-dikidrop!Mk)[3,4'd]{>a2ol-5-'d)ei^l'“>>^^8za^e^®P·“-^1” okt-S-d } nikoiîrisav-meifl^észî^· - 34, szátó vegÿf&amp;fc 4-f2"P-P-metoxil«fíi1)”2,4,ö,7-|e{rafeídfopÍ5'a2oJ0|4,3"CJP^®*^"^"^‘ÖXOe,:*^"^"í^'· 4rid«QHri0ílÍpirid:ia^241;jpiperazÍR-2”Oíí; .- 3$. számú -ysgyifet: 4-pHP^4-#a0rfeö}í)-2,4J,74etrabídropÍ!ías!;0foí4,3'<;.l;P*r^’íí'^"'*:y^'exoe^^“^~Í5'w -ÍPÍÍa0naeííÍpyd3S-2d3)píperazis-2:-0s; - 36. számú vegyüie;. 2-|'S-f5-ßuor{>hi»ddifi-2-ii)-3s8'4iazab:c!kio[3.2. !]oki--3-ií]-i-(2-íRedl-'6,7-dihidr0-'4H- 4ía®oí0|5s4-elpiFÍds>5--ll)etaíion; - 37. számú vegyüieí: 6-C>-P-P-(4-nuúosif'envS)-6,7<iúiíd)O-4}i-t;a7f)lí>|'5,4--cip!rsdin-S-il]-2-öxoetiS}-3J-.^i^&amp;fc%!^3láJ]sy“^iJ)n{kotiriisav-itneál-&amp;5zien - 38. számú vegyidet: 643-{2-f2-vWluortenilKJ-d?Tiidr^il»i^te|S,4^1jp»^t^^i^2-»xo{«Ä|-:3^8-<fesEBah' bícíkkfí3.2. l}oki-8di)nikotinsiiv-tneiii-eszter; - 39. számú vegyüieí: 6-(3-{2-c«ío-2-[2-(5-ixifhíontiéídpridmP-í^~2}4,é,74etmiúdr0p«^o}©(43'C3pB'ídiía-S--iíjelil} -3J-diazabieiklo[3.2. i Jokt-8-ií jnikotinsav-otöílkiészíer, - 40. számú vég v üiet: 2-{·8-(.5-Λ«(^Λ^0)-έ-%·3:»^4ί2Ζ8&amp;.»ίί^ί^332.1 jokt-S-ilJ-í-P^Svtriíkiormeílpíridm-^-^)-2,4,^,:74^3^^.0^^^10^4,3"G]píí:iiíim5“iÍ|eÍ8ítefú - 41 · számú vegyidéi: 4"|2“öso-2-(2“feßi!-7,S-dj}ddFO-5li-pmdö[4J-d]pirímtdin-6-i)etilj-I~{5~tt4flú0j5!:Heiipi- ddíú-2-iÍápipsrazfe2~mi;, - 42. számú vegyüieí: 4- p-oxa-2^{2-iÍoi®R-3-íi-6,7-di3íídfö-4íl~i:iazöte|5,4 -c]pííidiEk5-i!)eti}- l-(5“trif1uor-tBeiiipiödm-2-íl)pi|ísrítzin-2-0n; - 43:. száOíú vegyüieí: 2“p"CS"fluo^irimid.bí-2-íl3“3i:8-diazabíeíMep.2,|)0kt-3:-íÍ^Í-[2-(4-«ietöX!Éidl)·· -Sid^őp-ieírshidföpirsZOlűIdíS-dÍpírídin-S-irisítffiop; - 44:, számú vegyüieí: 6-P-p-öxoP4MroSmP4É-ú,?-dftíéO-4?4^ cikío[3.2.i ]ökt-8-ii}iítkotlnsav; - 45. számú vegyüieí: 2~|S-(5-flaß^!SiKidl!t'2-l)-3,8piaza|dk&amp;feP J- I Júki-íM:}^ j -f} -(2,2,2-trifliioreií|>--4)5,6J-Seímbidtx)-4í:i-feáa2ol-5-3ileíanöH;; - 46. számú vegyüieí: 2~P-(S-fi0ö{pmimdis-2~Si-^ -|l-(4-meíoxifesíii>· -1,4s6,74eí nütidröpúazoiopp^elpif idm-5-ii]eta»oai ·< 47, számú vegyüei; 2-|S^5-iuoíp5FÍmi:dm-2-íi)-3,8'iiazsbMk1ö[3.:2.vl]iakí-3-}|]»i:43,4,6,7-teírabidtppiraz0>-Í0[4,3-ejpiridia~5-il}e5anoti; - 48. számé vegyütei:: 6~{3~P-oxo-2~(l-fedk fop.2J]<4d»8~i|sik0tmsav-metn-észíer; - 49. számú végyfc 6-{3-|2-oxo-2-(i 4*míM4&amp;?-k4rahti^^ ϊορ.2. i |idít-8-t}) mlotiasgv; - Sík számú vegyüieí: í4í:-tefe-bmil-í,4,6574eí!‘akidr0pírazsd0[4p-e;|p:irídöi-5-ii):-2-{|-{5-fkiorpirímidin-2-il|- -3,84*aimbicikiop.2.l]okt-3-i}jetatK>n. * 5).: számi vegyül«: Í -(1 -(4- fioorfenih-1 ^.ö^^leinAiiirQpimzofeHJ-cIpmdänrS-ilj-Ä-lS^S-iöorpsrhMidin--2-il)«3,S*djazabicik!o[3.2 î jokî-3-Πjeíanon, - 52. számú vegyidet: 6-{(2R.5S)-2,5-dimeúi-'t-p-o^-2^(|:^íeKÍ3-2,4I6;i;7-Mr8kí<Sn>piíaKö(o|4í3”ei|piriílfm5:-· ~ii)eii!]piperazin~ i -iH nicotlnonitril; - 53. számú vegyidet;: 6:*|(2S.,5:$)-2s5-dií8etít--4'-|2'-os*i^2^p-feH:i3"2>4?;§,;74etraMdríípirszöfef4,3-cí|p}ríáiííí:-5^ -illeti! jptperazín-1 -31 |tdtetmsa v;, - 54, számú vegyidet 2:-{8-(5-fiüOTpirimMin-2>il}*3J-diszafeieikfo[3,2-l}ökt‘3“i]“l-(:2*leftät4,7-<d5i|dfO“5II--duorj2,3-cjpind':n-6-i])et;mon; - 55, számi vegyidéi: 2-p-(5-iüöipirimtdiß-2-ii^33*däaÄ8ibtcJklö[3.2J]oi:tH3--ili-i -(S-íeúil-1,4,5,7-tetráh!d-:FOplrrolöP:3-e|plri{lm'S-iS)etappp;: - SB. számi vegyiiM:: i*{8--|2-öxö-2^(2-fend-Öi7-diti3ro-4M-tíszp!p[5/[-c]ptfíáffi-5~tl)etl]-:3ySÍ-ája2aÍ3íeiki:o-· [3.2.1]okt-3-ii}nikotínsav-metií-észrer; - 57. számi vegyidet 6-{8-P-oxo-2-(2-fe-íi]~23ií6í74et:niúdFc^tt*úfc[43--e]p|i(|4sn--5^lí}4íd]>*3:tÍ-diáza|ieÉ^ lo|3:,2:, 1 ]okt-3-íl) nikotinsav-metíl-évaer. - 58, számú vegyül«; 2-i8-(5-Α«ϋφίπ^ίύί^2#ΡJ4iaza6ieÉ&amp;i3,2J]:ôki~3-f ~0*azolo[4,5-c]pírí<lín--5-ií)etanon; - 59. számú vegyüíet: 6-'((2R,5SJ'23"4imetSl-'4~|2^öspP-{2«íeúi!Py7"d®íáfo--4fi-tkzoÍö|5,4-cjpindm-5-íl}-erll (piperazin- - 60. számú vegyülik 2-|8:-|5-pmie:tjl-|l,2í4|oxááiazol-3-í:!)pi:rídnv2-iS5-3.8-díazabieMöp.2.11ökt-3--il|--l---(2-^15:1-6,7"d&amp;idiö4l4!azölep4j^pn3dtm5-{l3etartö8; - 61. számú vegyüíet: {í-(S-[2~oxo-2~(2~fenll-2,4,6,74etrahid:ropin(zoÍQ[4,3-c| pír id in-5 - í i )et ü 1 -3,8-d laxabic ík-ísp.2.1 Jokt-S-ií} nikotmsav; - 62. számú vegyidet: 6-(8-[2-oxi)-2-(2-refiil-6,7-£iihidro-4l:l-tfazok>(5,4--c]piridin~5-il)etii]-3,8-dja>:abicikki--[3.2j]okí-3-in íákotamy; - 63, számú vegyüíet: 6-|pR,5S|-2,54inmíií4-P-öXö-2-P~fen:il-6,7-dibfdz<4ÍP-4|ázofo(5,4-c|ptrídm-5^li}-etüjpiperazitt-1 -sí) mkoíinsav; - 64, számi vegyüíet: '2Hii^5iÄ^äi^im24l)^3,S-^mzabfciklop.2J'^kt#4}^|-(2'firidto4-8-6J-di'·- - 65. számi vegyüíet: 4-p-ms<v-2--p-(5-íriBuormetíípind:ímá-il^2,4:vá,74etíiffiídik>píráz6tö[4,3^CÍptd:áf6-5-dI·' etíij- í -(S-:ú41iuotmetí:lptrídííí-2-í l)p:ipetazk-2-öü; - 66. számú vegyüM: 4-(2--cso-2--{I--(2pp--Îïillsieretil|-l;,4s6,:7-®d;aJii<iropî5-azpîO: |4.43-ο|ρΜί«-5-»!]βΐΗ}-1* -(5-p'ÍÍua:reietiípí:dd3n-2:-d)p:iperazln-2-on;: * 63:. száiM vegyüfet 248"P"%<^ÍdtmdÍa»24i^3,Mk2aí)ieil:lo{3.2, í ]okt-3-tí|~ í -(2-fet5i-7J--:áí]t5dí'0“5ií--p Í!4dpp,;3;-d]piámíd:ÍB-6'-íl3etaBon; - 68. számú vegyidet: 3-(6-(3-[2~oxo-2~(2-íémi-2,4,öp-tettaltidropirazplöpp-e] fíridm4-:i}etii|-3,8®iazsb?-· dkiöp.!2 J 36kt-8-d| piridii- 3~íl}*4í-í4 Î ,2:,4|exadî azöl-S-ei;: - 69. számi vegyüíet: 2-(8-(5-11ϋθφίπΐΓ1ί0ίΓΐ'2-ΐί)-3J-disza6ieäkiöp.2.r]okt--3-iiJ--l-(2-fenii--3,4,6,7-ietr®id-roú«íd3z.o|-1.5“e|pírídin--5~i!)etanün; - 70. számi vegyüíet: 34p-p~p4xoP-p-®nt!-6,7-difeídK^4kí-tiazoío(5,4-c|pí:ridÍ8-5-íi3«ÍÍ3-3,8-6mz3bieik-· Iop.2.1 ]ökí-^ajpmfe-3-ü)-4H-[ 1,2,4joxadíszel-S-9B; - ’> i. szám« vegyület: :^[S(541iJorpirsmkHïr2-íi}-3,8-diΐîzabkíl:íö[3.2,l)okε-3-iIj-l-(2-fbsîl-6,?-díhídro-4H--ttazoío^S-cjpiridin-S · il ietanots; - 12. számú vsgydM; 2-|(3S,5R)-3.5-dmietii-4-P-DX9-2-(24eail-6J^!iiiHdro^4H-iiaBokif554-c]piridiK--5-i:l}-et üj pi pe.razm- í -il} plrsmidme-S-karbonsav; - 73. számé vegyidet; 1ï jdr<ï-4ϊ-ί-í Saxcí 1 öf 5,4-c j ρ ir ídíys-r 5-1 í}e&amp;í non ; - 74, számé vegyijei: ! '-C2-'fei3l1-ő,7~dí^3drO'-4H~tía^öío|S>4-c|pí:ríd^m-'5-íí}-2-{S-t5~f lí-I~tetrazc>!--5~íi)piruts«-2---i!)-3,8-diazabicík soi 3.2. i ]okt-3~í!} ciánon ; - 75. számi vegyület: 2-b^3S,3R)-:k5-.c]iü^cv;ii~4'i2-®xó.-2-(2-fenj!>2,4,6;,7-í:e&amp;a!ií4ro:píraz0lo|43'c!pkidíp-5- -il)etií]piper3zÍR- l-if}pirirn(dine-s-isarbons.av; - ló- számú vegyült: 6-G-{2-[2-(4-niK>rfeaií)-{í;7~dikídí'o-41:btia2olöf5í4-e];píí3dÍK'5-ií|-2-oxóéirI}.-3,.8-dlsK).“ bkiklö[3.2.. I jokt-8~i Dnicot i non irri 1 ; - 77. számú vegyület: 6-{.>-[2-oxo-24:’2-fe8il-2,4,6,74etebid)Opfe^lö[4(3-<:!|>sridin-54!}etilj”3,8“di:azäbk'3k-Ío|3.2.i|okí:-8-il}iiiiXHÍnoniírii; - 78. számú vegyük:·: 4-[2-oxo-2-(2-.f«ííil-3t4<é<?“í«irabUlrtíim:sddzof4,5-c|piridjs-5~sl)etil]-ii-(5-írif!Uonseti:l· pindín-2-í l'ipíperazin- 2~on; - 79. számé vegyület: ö-{(3S,5RV:x5'dimetil-4-P-öxo-2-(2-le«:il-2,456J-kirshkiröp!razöfe[43-c|pmdfc-5- -il}etH]pípef8zlé--|-íí|»ikotmsav etil-észter; - 8ü. számú vegyidet: l-f2-(4-il«orfeHíl>6.7-dihidrö-4H:-t:i;mdo[5,4-clp:iriáin-5-i31-2--[8-(5-lluorpirimÍdm-2- 'Sl}-3,S"difiz:abieí:kl9|3.2:.íjökt-3-il]«iaitoíí:; - 81. számú vegyidet: 2-|'S-(S-fluo5'piriml<l3n-2~í!)'-3í8-d:is?:aMeikío|:3.2.d]öifct--3-ilj- Î [2 (4-ïi)*toxifëfïil>'-ô^7·' -dihidro-4H-iia&amp;dof5,4-cjpindin-5-iijer&amp;fion; - 82. számú vegyidet. 4-[2~px<H2.-(2.-iè«ii-d,?-.dihideô-414-;tiàZDloi4J-e]pindin:-5-d}etiî|-l-(5-iridviprmetïlpM-dm-2-ilipiperszb-2-oú; - 83, számú vegyület: 4-|2'Oxo~2-(2“fenil'ő,7'd!:k!:dro-4:H-oxazoIo[4,5-c]plridm'S-íÍ)eíií|-í-(5-trifltiormetílpi-ridin-2-!l )pípení/in-2-on : - 84. számú vegyidet: 4~[2~o>:o-2-{2-piísdir!--3-!l-á,7^á:lkk1i9.-4B.-í:íazok)|5g'bcl:pírldin'-5~il)eiíí|~l-(5-íriíI«&amp;r- medlpirldm-2-íl>piperazm-2-öi); - 85. számú vegyület: 2-í8-[5-i.2-roetií-2H-{e{razoi-5-U}pír)á)R-2dIj-3,é-áiaz8bíclklé [3.2.1]okí-3-l]}-l-{2- ~íenil-2g1,ú.7-té1ralúdfoplrazoio[4,3-.c|pirld!n-l;-.!lk:anon: - 84. számé vegyidet: 2-{{2S.6R}-2,6-dimeí11-4-15-( 1-tnesd- iH-le-razoi-S-ií't-piridin-2-iljpiperazin-i-i]}-i-(2--&amp;rdit-2s4,ú,7-Íetnsüi{lröplrazolo[4,3-e.jpindm-5-5l}etaí5e8; - 87. számé vegyidéi: 2-{{2S,őR)-2.6-dimeti!~4-|5-(2-öieút5~21l4ek;t2ól-S-íl)-pindin.-2-:il]plpep)zip-1-11)--1-(2-4mä-2ASy7-t«sAi^<^>irazolo[4,3-cjp'lrldin-5-i)eismo8; - 88. számé vegyidet: 2-[8-(5-fluorpir)mldln-2-11)-3.8-diazabiçiklof3.2.1 jokt-3d!}-1~[ i~(4-triílupnRetlife)t:d}--l,4,6,7-Mrábldróplr4Z9k)í4,3-ejpiriditt-5-iljetanon; - 89. számú vegyület: 2-^(2S.úR)-2,6-dimd.il~4-{5-(5-ínéüfí,2,4]öxadiazol-3-il}-pindín-2-líjpipefa2m-Í-ít)--!“(3“i%íHl-2.4,6,7-íetrahidrop!raz0lö[4,3~e]pírid!H-5~íl)etantm; - 9Θ. Számú vegyidet: 2-ί:(28,6^~2,6-άί:Πΐ0ΐί1-4-(5-[33/1]0Χ34:ΐ3Ζθ1-2-·11ρΐΐ4:ά1ίν2-·11)|)ΐρβταζ5^1-0]-1-(2-1«ήί1- - 4L számi vegyölet: 2-^2«3Ε)-2:,δ-9ίθ^ί(1-4-[5-{3-οί8ΐί1~[13,4]οκ^ϊ8^9·-5-·ίΪ)·'|5θ%1Ι«-·2-ίΙ]ρ3ρ6Γ3χί0-!·-Ι1^ -l-p-l«ai!H23,4;74etrafei^ro|simoloi43~e^ifisS®-5-ö}ota!3oa; - 92. számú vegyúlet: ö--{{3S:.5:R)-4-P-3.-1;6f32-bí4íL13íös?4etráydí'0píra^olóP34^|3ífldÍft-S“9|^O3í<>8Íl|^ -3:,5-d3me91jji;peraKîo-:l-iî]) oíkotiosav-íoetíl-ésxter; - 93. számi- vegyülei; 6-[(3S,5l^4:“P~34erC“feôtil“3,:43,7“îeîrÊèidmplraâîote:[43-ej^ind|fl^5-iiii*2:-oxoenl1--SJ-dimeiilpipefaziP- 141) mkotlnsav; * 94> számú vegyüld: 6-(3'[2~(!-íerc4>úíi^:l:3sÖ,74etfsh:y5-^lrazó)ó|4,3-cjpirl:dlR-ö-il>-2--öxöeíll|‘-3,8"díaza-HiÄp.2.1 ]okt-8-iJ }nikotínáav;: * II»: szäÖÄ vagyaiét: 2-:S-(5>>Í^|)lí3!«íílm-2:40P>l4Ísazal>soíkÍö:[3.2.1)<íkí-341^1-í2"feoll-6,7-díhíd!'o-4H--ox'a2olo[5,4"C|púidin-5"ii)etanon; - 94. szúrni Vegyülei 4-[2~oxo^2-p>lmil-6!7-di!iidro-414-oxazolof5,4-c]pi:d(l;o-5-41)eiil];-l-{5-!rf.0t!oraie{il:pi" ddin^-i^plperaziB^-ôn; - 97. számú vegyölet: 2-^(23,6R)-3s4“dimelil-4-(3-tri:9«omteiilpirklH5-2-il)plporazöt-·^4-9)-1 -{2-fenií-4,7--di3íidre--51-l-fluerP;3--c)píridÍ3-í-ő"íÍ)etaííosr; - W·. szá»ú vegyitek 6-)(38,5R)“3,5-dlmötil-4-t2-oso-2-f2“fe:oil-2,4,6J-töiTah:idropirazoIol'4,3-c'|:pi:ridin-5~ -il^diljpipesrazHS- 3 -il) nikoimav-izepropi í-észter; - 99t spátnű vegyölet: l-(2-oieiil-2,4,6,7-teöahidreptrazoiof4,3-c|pirtdiH-S41)»3^P-(S-lrtlloormeiiipisdlß43r -13>-33-diazaöicikloP:.2.1|okt-3~í:iÍetanöö:; - 19Ö. számú vegyölet: 2y|lpSi6!í3P:,4-ditöed:M-(5-í:dtooro:tetiÍpiridio-2rll)|ííp^^|^|-i3|-:lrt2^ntetM,4,öv3-4etrahtdröpimzolö[4:,3-eJpiráiiív5-iheta.ri-:>f!; - ÍÖ4., számú vegyilet:: í-(2-lend-4.7-dihiáro-5íl-ÍÍúöpp,3-e)pii-ldlö-?6~tl)-2:-|Ö-(5-írífl!mnnetiípiridto-2-:9)- -3,S~di:azahi:eiklö|3i2, ! )ökí-3-il jetanon; - iö2. szántó vegyülei:; 6-G-{2-[2-t'4-dtíorfeod3d,7vd:tliidí'0-4íÍ4íáZ0lo{S,4-«Í: plrídm--3-ílJ-2-o?!:óelil|-3,S- -diazafelcikioi3.2.11ökt-8-li)ni.kolinsav; « !Ö3.: számi vegyúlet; 2-[(2S,6R)-2,6-dimetil-4-(5~trlÍoon:Heíd:pÍrtd:m-2HÍi)p!pera£ZÍR-l-tl]i-l-P-{5-tríl1uő^ iúeíÍfpifiílÍó-2-il)-2,4,6,7-tetraitldínpirazolö|4,3-cjp!3-jdift-5-:íl|eía80ö:; - ÍÖ4. számi vegyölet: 2'i8-(5-tnll:ootntetilpiridin-2-il)-3;,8"diazableikl:0:t3.2,t3okt-3-i:ll-1 “pH5-t?lileerm«8Í-pMd:ín-2:'-il)l-'S^^y7-tietrah:sdropí3'a^:cíi:o^4>3-'Cjplr!<3Í3n-5~il!eíasís>ítt; - i 05. szánni vegyúlet: 6-{:(2S,5R)4vp-(2-tefe-butíl-2,4,S,;7-tetralÍÍdtopírazofe[4,3-c)piridisí;-5--ií)-2:-exöetíl)- -3,S-din-ætilpiperà2iôvÎvil|ïd|ôî5psay( 106. szán-iá vegyüld: 2-(8-piridin-3~il-3,8-dÍ3zab;cikjd[3,2,i)ídít-3-il):-I-{2-(5-triflúorotedlptridíO:-2:-'iÍ)·- •2,4,6,7-íet:ahidropirazolo!4.3-ejplridin-5'líjetanon: > 107. számú vegyüld: 2-|5-(6»trifiuora^iîpiridazin-3-U>2,5^teÉl5dfel!ô|!2,2.Î.I bept-2-i|-í:"f24:S-tri0aöt· inetiípifldip-2--ií)“2,4,ó,7-!.etrí!hidropirazo}o|'4,3-ej psridm-5-iîjetanon; - 10S. számú vegyülét' 2~(6'-i3dr-2,3,5,64etrahidfo[ 1,2'jbipirazioi|~4-íl)-Í"[2-(5-teifliíotKíeiilpsndio-2-ll)-^2J,i,7^tt3h)dropärazolo(4J-e)pmdia-S-ilJetanoH; - 109. számú vegyidet: S-(2-feoii-3,4,o;7-tetrahidroinndazoi4,S-c]piridin-5-il)-2-48-(5-tT50oor;oeti]piridin'2- -t{3-3:,S-diazafeíeiklöpG. i ]oki-3-il|etaoöpi - ! If, számú vegyület; 2y)(2S,úllQ4>64úneliM-(3-íril3uttteíi!pindinv2vd)piper3zm-1 -·ί1|-ίν(2»&amp;ίύ1-3,4,6,7- -Setnshidroimidazo[4>5-c|piridin-5-ii)etanon; - I l I. számú vegvület: 24PS,5R)-3sS-dlmeti!~2í3í5,6-teiföhidfó|:l din^41i-24^^4etr^tdroplrazolö|4,3~e|pirsdlß-5-ll]etafton; - 11:2. számú vegyidet: 2*|pS,6l^4“(S-klóípírí<i:m~24í^sú"dtmeti1pipefa2Ífí-í41|-l-p-(54rífíüö3%eii;%an-díö-t-úJ-S^^^etndíidmpiniz^lold^^ptríúm-S'illetapeB; 113 . számú vegyület: 2"[4<7-feleddnoÍ!8-4~ti3píperazin-14{j-l-(2-íeRjl^,4,6^4ed-aÍ5idropirazolo:[4.3'e]púl-d«5-5-il}etsnon; - 114. számú vegyület: din-S-li}etanon; - 115. számú vegyidet: ! 42-pjrídíiy4.'d.6,?-ddúúro-4{i-tíazok>[54<]pmdh^-5“ÍS}-248-(5úTÍ!1uomK“öip!rídin--24í}-3,§-<tiazabic!kk>|'3.2.1 ]okt~3-iljeianon; » 11&amp; számú vegyület: .é-liJSLSRl-J^.^il^PÏ-P'^xô^rCIrfèRtl-SAé^tôJëafeïiBiàiaÂzold^-olp-itiâmrS·' -ií)etiS]píperazin-l-ií}nikotínsay; - 117. számú vegplet: dm~2d0“3 J"dlázabietklo|3 j,l3okíú3úl|elmíöí{5 - 115. Szálú® vegyület: 2-ÍpS,W-2iú^dlm^il-4-(5-trillaöríBetí}píí'ídí8-2-ii}plperaziml-(í|“i-(2-pirídm‘-2úl- - 119. számú vegyidet: 4-p-ox^2^(2-prúlím2ÚI-2>4>ú,7^eó^sdröpinizoÍoi4.3-d| plridln^-ll|etlii|~i-(5- -í3í:fiuo:nmetúpiridínH2"ii3ppgfazm42-ost; - 12Ú. számú vegyidet: 4Γίύ®ί^36ίΐ1ρ1πάκ^2ύ1ί)ρίρ6Γ3ζ1β'·2^0ίΐί - 121. számú vegyidet: 248-pmdin-3dl~3.8'diazabk-lklo[3,2, Î ]okK>-il>- 1 -(2-púidin-2-il'2,4,6,7-íetrahtdropí' razo!o[4.3-ejpiîidin-5-tl)et<âî>ttn; - 122, számú vegyidet: îô^iî^irÎïIsîÎ^^îl^^^S^^^biGtklÎîfâ.^.ïIokÉ^-ilJéËââîôns - í 23. számú vegyidet: 1 lokï~3 -il]máúOíi; - 124. US vegyidet: 2-|(2SJR}~2,6-dimetii4l^5~triS®05medlpindm42dl)piperazm-l-ill-i-[2-'(4-d«eirfemly--3,4>ú174etrahidroiraidazo|4.5~cipú'idie-5--jl|eia!3on; - 125. számú vegyidet; 4-(2-i>xo~2-d2-{2,2,2-;rîlluoreijl)-2,4,6.?-tetï'ah:<irop!razo;o [4,3 -e]píridm-5 · il Jetii) - ! - ~ Í26. számú vegyület: í'-ltPSpSRl^.ií-dín'iettM-iS-n'iiluormetilpíridin-SúDpIperaztr.-l-iíl-f 42-(2.2,2- 4ridítöi®tll|-2plJ,7iieúahidmpirazpíp|4p--e|píridtn^Ú13étagún; ~ Î27. számú vegyüld: -d)-2,S-diazabscik!o[2,2. í )hepí-2-ílfeiam>n; * 125. számú vegyület: ^{34á-#x^Í4(^^Í>2AM;ií^áfeíd^H>S^ú1o[4,34é^l3rídia-5*il|iS^e3?^dta2afet> eik!ö[3.2. i jokt-8~íi}mkotmsav cikkslMstli-észter; - 12&amp; számú vegyület: 2-((2S,6R>^,ù^dt3«eiiM-kmoim-2--dp!pemziîï--îdi}--i:--p--lei3i14î,4,i,74etiiSlidtop:sFazo^ kti4,3-c]piridt!í-5-ií)eU3ni>r:; - 1M. számú vegyüld: Ú»-|pSjSR}--3,5klúfieiil--4^í»to-2-{2-fe-íii-2;4,6.7-'teirahldrepí3'azöío[4:,3-cJpiridm"S-· î î}« î ü I pi pera>: ttî-1 -il ; nikoíinsav etil -észter; - 1.11. számú vegyük!:: 2-f<2$,6R}<4'(5-í«e!aí!es«]pÍk*fiilpÍríklÍ:ö'2-3lV2,6-'dímetíipiperaziö~ i-5Ïj-l-(1~îemk .?4,ő,?^i:éÍíghidropíraxoÍo[4,.í<]píridiív-5-il}e^öTi'v - 132. számit vegyüleí: 2-[(2S,6R}-4-{S-fÍuorpirMái:á’'á4|)r2,6~dímetílpiperazhí~l-ii]~ I -P~(4^meío}díéml}-*6,7-dihicfrö^4H-dazok'>j; 5,4-c | pirldin-S-s ! jeianon; ~ î|3. számú: vegyüleí: I-f2~(á-metox!Íb!»il}-fíí7^dlftídi>0^lktwolö[5,4-i:]páidb-5"i:]l-2-{5454ríllaönseíiipí- ndin"2á]>-23i:áazabieiklo[2.2.r)hept-2-l]]«tanon; - 134, számú vegyüleí: 1J~dfcidm-4íf4iazolöp:.4<]pddk~5-i:i)-2- {4-[542H-pirszv)l:-3:-il)ipkidt3!-'2» -öjpiperazin-1 -illmnon; 135 . számú vegyüleí: 2:4|2Si,6R>-2*Mfe^t44^SdlamÎ424îpirÂ-2-I)p*pemz&amp;5-1-41} - ! -(2 -^13-2,4017^:-rabidippö'azoio|4j3~e|piryii!-5-s!}etamm; - 136. számú vegyük*: í-P--feiíi-6j7--díhidm-41í-iiazofe[5!4-cjptricím-5-ii)-2-[8-(5-íiazel-2-ÍÍpí:rttlB-2--t3i-3^-••d3azabiclklof3,2,l|ofeí-2"i3]«tano«:; - 137. számú vegyüleí: 2~[8-{5-i ! .2í4Joxarí'ía^ö!-'3^íípirMin-2->i!>-3.S--e1í:íi^ab}cík!o |3,2,3|pkk34'l|4342rfeöl--2,4,6,7-tetTahjdropirazo!o[4,3-t: jpiridín-5-fneíatKm; - 138- számú vegyüleí: í-(2-eúl“2.4.ö.?-ieírahldroplrazoleÍ4J^c|p3sdm~5-iÍ)-2-[S-(54!‘íll4efmeiilpíí1díá-2~i:l|--3,§41zzabiclklo[3.2.1 jokl-3-ii jetanon; - 139, számú vegyüleí: 2-j(2S,6R)-2.6-dmK:íiM-(5-[i.2,4]iíx:adkláúl-$-l3plrldlp~2-ll}pm^ 4,4,6,?-ietrahidroplrazolo|4.3-c]plrí<fia-5-il)etanm; - 140. szártiű vegyüleí· 6-l(3S.5R}-3>5-dime!il-‘l-[2-oxo4-(2:'p3fyiii4:-d4,4,:di?-tgtrahyTppo-azol0[4,3-eJpirl-· din-5-i!k4iS]p;perazm-3-il}n;koumas': - 141. számú vegyüleí: 24(2S>6R)4,64mieiil-4-pirldiß-3-ilpipeimiiB·· ί-0>'1·'(2-ρίΓΪθ!!ΐ-4-Η4,4J,7-letrÄld-ropirazolof4,3-cipindin-5-îlk?ani>n; - 142, számú vegyüleí; 2·'((28,6Ε)··2,δ4ΰΐ3«ίΐ]“4-ρ1ηΰώ-3-3{ρ1ρ6ΓΖζΐΒ~ 1-11)-1-(2-(5-31110^11111^4-11)-2,4^6,7-4íú:rabldróplrimolídl:,34]plridin-5-tÍ)eíánt>Tí; - 143, számú vegyüleí: 2-((2:8:,6R)4,6-áimetiM-píridlí^3-llpípemzm-!l-il)-l-12-(5-írlilitmmeti:lpífldÍH4“13)-4,4,6,7-^0-31^4^^1^^10(4,3-elplridm-5-íl]etaiiön; - 344. számú vegyüleí:: ú-|(3S,SR>-3,5-díme!Í!-4-Pm!io-2-{2^lridm-2-sÍ-2,4,ú,7-íelrahldí:öpímzölöb4)3-e)piri-. dm-5-31)eíli]pipemKl«:-;I-11} iííkolínsav-metil-észíer; - 345. számú vegyüleí;: 2-(pS>6R)-2!6-dSme3í3-4-p:irídm-3-íÍpilperazm-l-d)-l-(2-íetiíl-3t4J,7-tstraÉídr0ímida-:Z0f4,54}pffldlm3"ll)«íamm; - 34|, Számú vegyüleí: 2-[(2S.6R)-2,6 -dlmetik4-(S-ki®:tie«53ettipiîidlR-2-tl3piperazl!):-1 -il}-3 -p^smd&amp;zlm-l-ll-4)4,6s7-íettabidrop!raz.oloi4,rv-clpiricllmS-íl)e:tan0n; - 347, számú Vegyüleí.; 2-[(2S,6R)-2!ö-dfmeili^»(54riil«ötmeSlplrldm4-il)piperazm-l-iij-3-(3-sil34,4542- - 348, SZáiPá vegyüleí; 4-P-(2-stll-2:,4,d,7-íetrímldrtm!^^mí4,3-e|p3rldiH-5-il}-2-oxoeú!}-l-(5-íríf3a<íímíSl3-p3rjdm4-ll)piperazm-2-oti:; - 349. számú vegyüleí: 6-((3S,5R)-3,S-dsmetií-4-12-oxo-2-(.?.-reíiil-2.4,6,7-telfahldropi:r£fzolö[4Jre|p£ridÍp~S--i!}etiT]píperazln- í -13} nlkoíi «sav; - 350- számú vegyüleí: 6-f(3S,5R)-3,5rdímeíí3-4-[2~öxo-2~(2-fém34,4>6;7-íelrahldroplrazo!o}4,3-e)pÍTÍdlri-5- fcá4sí vagy sávval képzett asldicsès só forókpiiam % Az l *?, ‘0^ρ^φ^ bánnsiy&amp;« $m$k$ verölet, amely a -kOvtskezO
  5. 10. Αχ előző Igéæypmtok bármelyike szerimi vegyület, amely 0-1(38,51^)-3^^-0(01^0-4-(2-0^0-2-(2--i‘eail~2.42>,7-tőrrah3dmpi.raxoio[4,3-ejpiridln'5-ll}eíii]pi|Xírazifj-í ·ϊΙ}ηί1ί.οΙΐη8δν. 11· Eljárás az 1-1Ö. igénypontok bármelyike szerinti (!) képleíü vegyüld előállítására, azzal Jellemezve, íiogy egy 00 képié® yegyöletet
    cm akd Y, X X,, X, R1, R., rt és m jelenése az 1-1Ö. IgépypíSBíök bármelyike szerint;aiögk:aÄP®it9 és HaljeiesMése h&amp;lögéoaíöm,; reá aá íta t lírik £íl) általános képié® vegl®^6*· ahoi: W és ^jelentése az i-H). igénypontok bármelyike szerbit meghatározott. Í2i (II) képié® vegySÍeí::
    i'm aliűl Y X Xv. x, R, '% p és m iél®ó®se az. I -10, igê}5ypoîoR lÄelylke mannt meghatározsatU és Hal jelentése halogénatom; bázis vagy savval képzett addiciós só formájában. i£ Gyógyszer,; stzzal jellemezve, hogy MO: igénypontok bármelyike sárnál vegyPetet tartalmaz, vagy Ï-Ιδ. igénypontok bánneiyike szerinti vegyüiet gyógyászatit elfogadható .savval képzett addiciós sóját tartalmazza, Î4, öyógyászaíí feészitméay, azzal jellemezve, hegy I4J, :|gé»5|»öt}$ök b&amp;m^Ni MWfaâ vsgyiietét tartalmaz, vagy annak gyógyászatiéi: elfogadható sóját tartelmám, továbbá legalább égy gyÓgyászat|fag: elfogadható segédanyagot tartalmaz, IS. Az M#* igénypontok bármelyike szerinti vegyül« mim gyógyszer. IS. ÁZ i~10. igénypontok bármelyike szerinti vegyület a kővetkezők megelőzésében vagy kezeiésébéh történj alkalmazásra szolgáló gyógyszer eSö&amp;Uiiására: központi és perifériás neurodegeneraflv betegségek, időskort détseaéla, epilepszia, A izheimer-betegség, Parkinson-betegség, Muntington-kér, Böwrt-szmát’óuía,, prion betegségek^: amnézia, szkizofrénia, depresszió, bipoláris zavar, amioírófiás laterálist szklerözis, szklerozis mu!íiftiék,: szlv^érrendszert rendellenességek, poszt-iszkémiás szivkárosoáás, kardiotniöpaiiäk, :szi#iíarkfos, szivélégiéiénség,: kardiáliis íszkémia, eerebrálís ia&amp;tkías; perifériás nésropátiák, látóideg; és retina Mrosodssá, retipapigment-tlegaßeräslö, glaukóma, retmáüs ischaemia, makuladegeneraeió, gerincvélóí iramnál, kopőnyateumák, ateroszklerézis, szűkületek, bégesedés! rendellenességek, hajljülte teavalnriíígy-gyadadás, ntápferözia, rák, tantorok, áttétek, lenkémiák, légzési rendellenességek, pahnonári! gyulladás, sifetrgia, asztma, krónikás obstenkiv pütmonárisr betegség, Ä szomatikus, zsigeri és neurológiai fojdátem, krónikus nenropátiás éa gytiliadásós 1|i;dá|om, ámöibmtun: betegségek, reumatold ártritisz, spondylitis: ankylopoetíca., pszpriázisos artriifísz, plakkos pszoriázis, csonttörések, esöntheíegségek és efipntritkolás. Í7, Az 140. igénypofttok bármelyike szerinti vegyöíet alkalmazása, a kclvetkezök kezelésében es megelőzésében aStalmazott gyógyszer előállítására: központi és perifériás neuredegenerativ betegségek, időskori detnsncia, ;epitepszia, Airiteimer Jetégség, Párkmson-betegség, Henüngfon-kor, öntvmsrindrómte prion betegségek, atnpézia, szkizofrénia, depresszió, bipoláris zavar, amiotrofiás laterális szkleróKÍS, SZklérózis moltipíex, sziv-éczendszen rendellenességek, poszt-iszkémiás szivkárüsodás. kardíomíopáfiák, szfomforkfos, szívelégtelenség, kardiába iszkémia, eerebrálís Inforktus; perifériás neuropáilák. látóideg és retina károsodása, zetinapigtnest-degeneraoiö, giankőma, retináiig isébaepiia, makuiadegeneráció, gerincvelól traumák, koponyafeamnák, ateroszkicrózis, szöknleíck, hegesedési rendellenességek, hajhullás, hastiyáhnirigy-gynliadáS, mápferőzis, rák, testőreik, áttétek, leukémiák, légzési tenddlertességek, ptiimonáris: gyulladás, allergia, asztma, krónikus obstruktiv plmonáris betegség, kután, szomatikus, zsigeri és neurológiai fájdalom, krónikus paaropáíiás és gyalladásos fájdalom, autoimmun betegségek, reumatoid ariritisz, spondylitis; artkylopoetiea, pszoriázisos ariritisz, plakkos pszoriázis, esotiböréssk, csontbetegségek és csontritkulás.
HUE10801662A 2009-12-14 2010-12-13 Új (heterociklusos/kondenzált piperidin)-(piperazinil)-1-alkanon vagy (heterociklusos/kondenzált pirrolidin)-(piperazinil)-1-alkanon-származékok és alkalmazásuk P75 inhibitoraként HUE024988T2 (hu)

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RU2010140613A (ru) * 2008-03-05 2012-04-10 Таргасепт, Инк. (Us) Амиды диазабициклоалканов, селективные в отношении подтипа никотиновых ацетилхолиновых рецепторов
CN101284838B (zh) * 2008-06-06 2011-05-04 天津药物研究院 含噻吩并吡啶的哌嗪类衍生物、其制备方法和用途
FR2932482B1 (fr) 2008-06-13 2010-10-08 Sanofi Aventis Nouveaux derives de (phenyl-3,6-dihydro-2h-pyridinyl)- (piperazinyl ponte)-1-alcanone et leur utilisation comme inhibiteurs de p75
FR2932481B1 (fr) 2008-06-13 2010-10-08 Sanofi Aventis Derives de 4-{2-°4-phenyl-3,6-dihydro-2h-pyridin-1-yl!-2- oxo-alkyl}-1-piperazin-2-one, leur preparation et leur application en therapeutique.
FR2953839A1 (fr) * 2009-12-14 2011-06-17 Sanofi Aventis Nouveaux derives d'(heterocycle-piperidine condensee)-(piperazinyl)-1alcanone ou d'(heterocycle-pyrrolidine condensee)-(piperazinyl)-1alcanone et leur utilisation comme inhibiteurs de p75
FR2953836B1 (fr) * 2009-12-14 2012-03-16 Sanofi Aventis Nouveaux derives (heterocycle-tetrahydro-pyridine)-(piperazinyl)-1-alcanone et (heterocycle-dihydro-pyrrolidine)-(piperazinyl)-1-alcanone et leur utilisation comme inhibiteurs de p75

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