HUE034460T2 - Szubsztituált tetrahidrokarbazol és karbazol karboxamid vegyületek, amelyek hasznosak kináz inhibitorokként - Google Patents

Szubsztituált tetrahidrokarbazol és karbazol karboxamid vegyületek, amelyek hasznosak kináz inhibitorokként Download PDF

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HUE034460T2
HUE034460T2 HUE14740094A HUE14740094A HUE034460T2 HU E034460 T2 HUE034460 T2 HU E034460T2 HU E14740094 A HUE14740094 A HU E14740094A HU E14740094 A HUE14740094 A HU E14740094A HU E034460 T2 HUE034460 T2 HU E034460T2
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mmol
formula
bromo
chloro
compounds
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HUE14740094A
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Joseph A Tino
Anurag S Srivastava
Soo Sung Ko
Michael A Galella
Charles M Langevine
George V Delucca
Qingjie Liu
Douglas G Batt
Scott Hunter Watterson
Qing Shi
Myra Beaudoin Bertrand
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Bristol Myers Squibb Co
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07B2200/07—Optical isomers
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    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • Plural Heterocyclic Compounds (AREA)
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  • Indole Compounds (AREA)

Claims (11)

  1. SZABADALMI IGÉNYPONTOK. }. Képiét (I) szerinti vegyület; «hol:
    a két .szaggatóit voltaikéi egyszeres vagy két kettős kötési teptezeiitálisak; Q' Rj K U, -ÜN, vagy-CH;;;
    Üv Cl vagy -CHj; R, -CCCl-LV'.OM vagy ·<.:Η;,α Μ)Η; R;( H vagy -CB'?; mindegyik Rj, luggetleníi! F, Cl -OL„ és/vagy -OC.Hv; és π nulla, 1, vagy 2.
  2. 2. Az í. igénypont szerinti vegyiiiet, amelynek szerkezete képlet (iA) szerinti:
  3. 3. Az 1-2. igénypontok bármelyike szerinti vegyülni, ahol; Q :
  4. 4. Az 1-3. igénypontok bármelyike szerinti vegyület. amelynek szerkezete képiét (1ΪΛ-Π szerinti:
    ahol'Rj >C(CH3)20H·.
  5. 5. Az !. Igénypont szerinti vegyfiler. amelynek szerkezek' képiét (IB) szerinti;
    fk Az 1. és 5. igénypontok bármelyike szerinti vegyälet, ahol: Q :
  6. 7. Az 1. és 5-6. igénypontok bármelyike szerinti vegyűlet, amelynek szerkezete képiéi (ITB-1) szerinti: ahol.R} -Í.XCMéhüH,
    S, Az 1. és 5-6. igénypontok bármelyike szerinti vegyűlet, amelynek szerkezete képlet (Ü1B-2) szerinti:
    ahol R; -C(Ci3():OH.
  7. 9. At 1. igdliiÿpônt sxetitrti -vegyidet 8l>o! -a vegyidet ki va« váisssdva a kou-iUvOk ko-'ui UM-(R)H3*(RV{8-0uor-l-ntetü-2<4-díoxo-l,2-díhidrokinazo!in-3(.4HH]-h2-!netíiíéiHl)-7-(2-bidroxjp«^>ájv2-il)* 9M-karbazo3-l-karboxamid (i ); '3«Jd^,'4-:®H3KS)*{S*fiuor*i-‘meti!*2<4-dioxo-K2-dihidtx>kraaxoim-3{4H)-ii}-2*inet:iîfenil)-7^(2-hk!.roxipïopà«-:i-ïl)-0H-kaffe;)Z()i· 1 •kaíhoxaaud (2); i*Mor-?~(2-hldroxiptoftón-'2-il)-4-(RW2-raeítiÍ-i3*(t:“fflfitii-2.4-<líox.o-l>2-dihidrökinaxoHni-3(4H}'-il}.renil)'9H“.k8íhazoí“l'karboxarajd (3); 3* klór'44.R}-(3-4l<8-dlmeti.l-2,4-áioxo-l,2'dit«drokinazoHn~3(4íí)41}'2rnK4ilieail}-?'(2'hídfoxipri)p3Jí--2-),l}· 9H*katbazoM -karboxamid .{4}; 3-k!ór-?-{2*hidfoxipropání-2l-.U)-4-(:R)-(3“('RH7-=melhDxv3~n«tíl-2,4-d«oxM-í ,2-dihidr'Okinazoíin-3(4li}-il)»2’tö©ti}'fenil-}-9l.i»karbíízol·l-ksrboxamid (3); 3>k!ót-?-(2^h:id«!SÍp:fopáR'2^ iS)-4 (Rp{:V(S)· i 7 «íeth<)\i d-rndíí-S^-dioxo-í J-dihidrokiöaKoliii-3(4i-l}-il}-2-n'>cti]íeíijl)-<)H-karba2oi“l· k&amp;tboxatnid (6); 3*kJór-7-(2-hidfo*ipröpán4241)-4-tRH3-tS-methöxi-l-meid*24-dksx.o-1-,2·- dilúdrt'kmazoiin-3(4H}-jl)-2-metilfenil)-9H-kart»8«)l' !-karix»xan»d (7); >-któr-4 (R)-(3-(6-duót- Î aieíil-2.4kííoxo-I í2-'dihidroklnaz<hin-3<4I4)-ti)--2-ix»ítiironí! )-7-(2-l»dyoxipíopáa-2-ií)-9}i-karbaKol~(-karlmxsiíöd (8): 3-k.lór-4-(Ri-(3-(7-iKiot-S -i'íR'tí!-2,4-dioxc-L2-ciihídrokííia7.oÍi«-3(4H}-ü)-2-ísetí{ten.il)-7-(2' hidroxipropán-2 - ü)--9H-karbami"Í-kar!x>xamid (9), 3-kíér-4-(R)^(3i-(6i8-dtt1«or^2,4-díoxo^ ! <2- díhidrokina/ohn- 3(4iÍV t])-2-melJlíejwÍ)*7-{2-h}droxjpfopsn-2~i3)-9H-karba2©l*:l-karboxamid ( í0); 3-klór-4-(S.)-(3-(S)· ( 8-fluor-1 -metil(dO-2,4-dtoxo-1,2-dihidroki»azoU»-3{4H>rt}-‘2-raelilfcíai0*7ií2;“hídroxÍpK]pá«‘ 2-ii)-9H-karbazo3-i-karboxamid (11); 3-klor-4-(R)~(3-(R)dS“naor-l-«Mäd.Uxl0v‘2.4'4H>xo-.L2- dihidrokinazolin-3(4H3-il)-2--tnetil fenil)- /-( 2--}udít»xipropán-2-ll)-9H-kafbazoM -karboxamid ( i 2): 3-kiór-4-(Κ}·(3··ί8··ΐ]ΐϋ>Γ··2,4··4!οχο- 3,2 dilbdrokmazo3hv3(4H)--íl)-2-!netiiien.i)}-7~(2~hídroxipropá«-2~il}-913-karbazol-1 -karboxamid ί 13); 3-klôr-4-(R H?-(K )-(8-duor-2,4-dioxo- 1.S-diiudrokinazohn- 3(411) d i -2- iïæiiikmii)-7-('2-hidroxipropim-2-il)~9Îl~karbazol-l~karboxamid (14); 3-cyano-44$M3«<$«iiu»:Kv 1 -t»eld-2,4· dioxo-L2-dihidrokiiMzo3in-3(4H)-il3-2-nieti{fenil)--7-{2--hidroxiptopáB--2--Ü)-9H-karba*oM-kaibox8Hud 05 ès> 16); 3-íh:nr--44RM-MSdluor- i •••tnetii-Xví'-dioxo-l .2-ch.bk}roki»azi.'>liTi-3(4H)-}l)-2-n)et}(i:o»il 1-7-(2-hídmxipropan-2-Ü>-9H4aibazok I - karboxamid ( ί 7); 3-f3uor-4~(R)~(3~(S)-(S-t1uor-1 -metil-2.4-dioxo-l,2-<ldhdrok.inax.oHiv3(4H)'ii)-2-'fnau?fex!ÎI)'?'(2-hsdîoxipropàa-2-il)-3>H-kafbazo3-î-karboxatiikl OS); 3-fl8í>r-4--(R)--(3-(S)-(8-fluoi:“t-i«eîïl-2<4--dioxo-î<2-düiidfoki«azôlm-3(4H)-iî)^2-m«iilieni{)'7-(2^h}droxipfopâ»v2--il )-93í~karbazoM-karboxamid (39); 3-tluor-4-(R)d3-(8-i)yor-2,4-du)xo- i ,2-<h.i)idTokiiîazoi(n-3(4.H)-iî)--2-tneiiirani3)-742-iíidroxipropán-2-ií)-9}i karbazi>f-4 karbcixaniid (20); 3-i3uo)“4-(R)-(3-(R)--(8--duör--2,4- dioxo-3,2>dniidrokinazolin-3(4H)-i3)-:'2--H!iítilie»j!)--7-(2-bidr()xí|»:>;>pát)-;2-il)--9Ii--karbazí>i-l -karboxamid (23); .3-ilíK)t-4-(R)-í3-(S)48-naotv2,4-dioxf>-L2-dihídrökínazoiÍn-3(4T4)-il)-2-i«etii(bni3)-7-(2- bidroxípn>pát)--2-ii)-9FI-kaibaKo!-l-ka):bc>aa!«id (22); 3-klór-4-(R)-(3-(3-(4-í3víOí4m!{)'23>-dix>xtv2!3- díhídropirtm5dit)-l(6íi)-n)-2-meúlfeni{)-7-(2-hídroxipropím-2-rt)-9ii-k.arbazoí-['karboxaiiiid (23); 3-kîôr-4-(R)-(3'(3-(4-fíuorÍe(HÍ)-2,6-djoxO'2.3-dihidropiriu!Íc!n)-[((di)-ií)-3-niot!Íít'HÍi)-7-(2-hidTo>:ipropán-2-i!}-9H-karbazo 1-1-karboxamid (24); b-.kíór--3-(R)-í3-(S--i;]ru)í-.t>rne{ii--2.4-dios:í)-í .2-d}hídn>kit)azoiio-3(4M)-i!)-2-me{iUei)ií)-2-(S)-(2- hids'oxiixopá))-2-d)--2.3,4,9-teRahidro-iH-karbazoi-8-karboxafnid (25); 6-klór-5-(R)H'3-f S)--(8 -övior-1 · oieíil-2i4;-dioxo-1,2-dih.idrokinazo!in-3(4H)-il )*2*metiMeail)-2-(.S>>i2“hidroxipit)päft-2“iO-2.3.4.9 -«-Mtabkiio--1 H-karbazol-8-karböx.amk! (26); 6-ílyor-S--(R}-(3-<S)-(8-í3iior-!-n)éíi]-2!4-d!oxt>-L2- dibidrokiriazo3bi-3(4H)-ii)-2-metilfond)-2-(R)-(2-h:idroxipropati-2-ii)-2,3<4,9-tetrahidröi-iil-karbazol-8-käiboxamid (27); 6-fi«or-5-(RH3-(S)-{8· fluor-i-meti 3- 2,4-dioxo-J ,2-dihidrdfâtpæôUn- ?>(4H)-i'i-2- meulíetríi)’2-(S}-(2-híd!Oxipropán-2~il:)-3,3v4,íi-ietrahidro-lH-karba2öí^-karboxars«d (28): 4-(R)-(34SHS-floor· j •«®uf-214-dioxO'i,2^dihKiroköiaxo3in^3(4H)-is^2-m(;(:ilfenilV7-i(2~hidro.Kipropäti'-2-il)-3-JBetil-9M-karbazoW -kurboxrmdd (29); 4~(RHMS^klór-M^ioxo-i H~piridô[ Î >2-cjpirimkijn-2(3IO-in-2-J«etjlfe!iilk 3-i]vu>^7-(2-lűdt'<>xipropárt-2-ií)-9H-karbaaoi-í -karboxartüd (30 és 3!}; 3-klófr4^RH WRHS-felór- 1.3-dioxo-llkfy(rid6p...2-e]{>iiimid:in-2(jH)dÍ)'2r'metiífsínii)--7*(2d!ÍdröXÍpf«pá!i'2-ií)'-9Fkkatbaxol“l* karboxamid (32); 3-klór~4-(R)d3-(S)-(5-k]6r-í,3-dioxí»-lii-pir!de[í,2->c|ptrííiiidia~2(3ki}-li)-2'metilÍeíiíl)-”-(2-hidToxÍprppáív2-d)-9H-karbaxoí'l-k3rboxa}uid (33); 3-!dór'4-(R)-(3'(5-iluc«vl»3-dioxO'IM- ρΪΓΚ:!ο[1 J<jpíröntdin-2(3H)-ii)v2>medlfeTiiO“7-(2-4Pdroxipropán-2--ij)-9H-karbaxol- b-kíirb^xandd (34); 3-kjár-4"( R)*(3"(5 -fluor* I I H»pmdaf l:<2*ejpirimidin--2(^H:Hl)*2“metÍl.fetní)*?<2“hídK)xipropán-2-ii)'· 9H-karbazol-i-karboxamid (35 és 36); 3-klór-7-(2r-hídroxipmpáii-2-ii)-4-(.R)-(3-(5-tnethoxi-l,3-dloxo- 1M-pjrido[l,2'G]pmmídtn'2(31d}~iii-2~me{íifbnil)>-9H>-karbazöl-Likafboxan}id (37); 3H-diiazoiop,2<]pímnidib-6(7Hpil)-2-met}ifcnií)~742-hitóxipmpán--2-}l)-9H-karbazPl-i--karboxamíd (3f 39); 3*fluor*4--{R)<(3.'(5-0uord:i3-’dk»xo-dH*pirido[l:2"c)pmmidffi*2(3H)“d)-2'<nieii.lfeai} )-7-(2- bidioxipropán· 2-íi)-9H-karbazof-d“karboxamid (40. as 41); 3--klór-4 •(R)-(2-kiór-3-( 1 -motii-2,4·ακ>χο· i ,2-díbid.fókibaz.c)lÍH-3{4)it-d)feí«l)-:-7-{2-!ti<lroxipR)pán-2“il}4>H-karbaz(>{--.í--k<írbox<in5í(í (42), 4-kint-4 (R)-{2-kiór-3'(R)-( i -metií-2,4-dioxo~l,2-dilúdrokinazoíííK3í4H)d])ténd)~?-(2-)ndímipropáö-2~íi)-91i-kartxs;?.ol-4 -karboxa-níd (43 ): 3-kiöt -4-(R)-(2-kk'ir-3-(8- fluor! -metíi-2,4 -dioxo- S ,3'dihidrokiiiazo!is)--3(4H)4))íbní))-7-(? htvifox-pjopaxi-241)-911 ka)ba*M-t-kaíbuwuud (44); 3-'kiór-4--(R)-(2''kl(P--3-(R)-(k-í1u0r- ! -tnetii-2,4-díoxo-:;2-díh!drokinazo]m-3{4tí)-ii)(énil)-7~(2'íudn'ixípfopáti-2-i])-9H-karbazol-l-k^ft)<>xa}Qid (45); 4~(R>-(2-klór-3-(8-íluor~ 1'tnetiI~2.4-dioxfv i ,2-djhídrokínazohíi-3(4H)-il tiénii)--3--f]uor-7~(24wdîojdprçpàPs24):b 9H-karbazoi-1 -karboxanúd (46): 3-klor-4-( R)42-kkn--3-(S4)uor-2.4--dioxo-k2-dähädtpkinäXö{ip-'3(4H k il)ten!l)-?--(2-hidim!propái:-2-il)-9n-katbazul -1 - katboxatnid (47):
  8. 10. As L igénypont szerinti vegyulet. amelynek szerkezete
  9. 11. Az {. igánypöftt fiserinti vegyüfct^melysisk szerkezete
    12. Λ:< 1. igénypont szerinti vegyül« t; ahol a vegyület: 3 -k iör- 4 - í ií.)-( 3-í S ) ^- ( S -i- ií í · irséii Ï > 2- - cl it>x ö - ;l... 2 -ti i ls i eimfcííiírxíí tín-3 {-ΪΙΕ'Χ)-il ) - 2 - me í ílf felit i) - 72 - iridrox!propáíí-2~í])'l)H-karbazol'-í^irboxaíXí!d kristály alakban M-t. ahogy az alább felsorolt töredék atotnk'oonlináíákkal van jelientezve. Körülbelül 203 K hőmérséklete«számítva; Atomkoordinâlâk txU'/’)
    3><:kíÔI^{R)'(^:''{S>-(·î5'·fl»OΓ“í-raetίl(ds)“¾4'dioxQ-i.,·2^l^hidΓokâla2oli»‘·3í4HVt^)*'2ilnetüf¾î!Í>·?‘ (24»d«vcipropáB~2-iíb9H-karbazok1 karboxamkl kristály alakban H-l ,..ahogy az alább fglsemk töredék atonikoordinátákkai van jetieniezye, igÂhéînérsékîetea tsyiMtvgjl^bpkoöídMták ιχίοή).
    ? klót-4-iR).(i.(S)-f8-niu«r· 1 -mc'uRd,)-2.-1-uíoxo-}.’-dihidiokuia-íOlin-JHH^íDO-meiilfeml)-?-(2*hidr»>Ätpn?pan-2*}i).QH.k8rhdÄol-l*karbt)xa«ncl knasái} alakban M-í . ahngy .u alább felsöjok (orMék a i ( > n ík ot ! rd i náíák ks I van jellemezve, Svefeabömérsékletcii számítva: Aiinnkoordináták (xíO4)
    6-iiuor-5'íH fíöOi-}-n*.iMt1-?,4 diow 1^•ddndKdanaA.ám-IH'-UiMl)~2~nietíSfemíV2-(S}~ (2d>KÍroxipropán~2 -)0-7,3,4.9-ϊί-t'anuiro· 1 fï Litb-3/pi-8 kaüx-vm.id kmtáh o.äakban M2-1 . ahop> a/ alabb felsorolt töredék aftf mköimlútstákkaí van jellemezve. Körülbelül 173 K hőtncrsékk-ica számiiva; Atomkcwdmáiák (x 1 04}
    vagy liîdrosipK'ipàn-;!-iO-VÏ(-karb;i^ol· !-katbosjüiiid kristály alakban M?-i , ahogy tu alább fehoroií Rlnjáék íaorakoordinátákkai van jellemezve. Körülbelül 1.73 k. hőmérsékleten számítva: AtomkcKmlináták tx IÖ'1)
  10. 13, Gyógyszerészeti köínpozició. ataely íartalrnazza az Í.-I2, igénypontok bániiéiyike szerinti vegyöletetés győgyszerészetiieg eUbgadható vívóauyagöt, 14 > Az 1-12. igénypontéit hamtelyike szerinti végySM ieíhaszrtálásra terápiában.
  11. 15. Az Ml. igénypontok MmieMke ssaerittti vegyßiet tblhasxnálásra terápiában ainoiísnuat betegség vagy krónikus gyaliadásös betegség kezdésére;
HUE14740094A 2013-06-25 2014-06-25 Szubsztituált tetrahidrokarbazol és karbazol karboxamid vegyületek, amelyek hasznosak kináz inhibitorokként HUE034460T2 (hu)

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