NO328537B1 - Pyrazolforbindelser nyttige som proteinkinaseinhibitorer - Google Patents
Pyrazolforbindelser nyttige som proteinkinaseinhibitorer Download PDFInfo
- Publication number
- NO328537B1 NO328537B1 NO20032670A NO20032670A NO328537B1 NO 328537 B1 NO328537 B1 NO 328537B1 NO 20032670 A NO20032670 A NO 20032670A NO 20032670 A NO20032670 A NO 20032670A NO 328537 B1 NO328537 B1 NO 328537B1
- Authority
- NO
- Norway
- Prior art keywords
- amine
- pyrazol
- methyl
- quinazolin
- phenylsulfanyl
- Prior art date
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- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 5
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Description
Foreliggende oppfinnelse er i feltet for medisinsk kjemi og vedrører forbindelser av formel Ila som angitt i krav 1 og som er proteinkinaseinhibitorer, sammensetninger inneholdende slike forbindelser som angitt i krav 11 og anvendelse derav som angitt i krav 14 - 16. Mer spesielt vedrører denne oppfinnelse forbindelser som er inhibitorer av Aurora-2-proteinkinase samt GSK-3, -CDK-2 eller Src-aktivitet.
Oppfinnelsens bakgrunn
Letingen etter nye terapeutiske midler har blitt mye hjul-pet i de senere år gjennom bedre forståelse av strukturen til enzymer og andre biomolekyler assosiert med målsykdom-mer. En viktig klasse av enzymer som har vært målet for ekstensiv studie er proteinkinasene.
Proteinkinaser medierer intracellulær signaltransduksjon. De gjør dette ved å bevirke en fosforyloverføring fra et nukleosidtrifosfat til en proteinakseptor som er involvert i en signalbane. Det er en rekke kinaser og baner gjennom hvilke ekstracellulære og andre stimuli forårsaker at mange forskjellige cellulære responser skjer inne i cellen. Eksempler på slike stimuli inkluderer miljømessige og kjemis-ke stressignaler (f.eks. osmotisk sjokk, varmesjokk, ultra-fiolett stråling, bakterielt endotoksin, H2O2) , cytokiner (f.eks. interlevkin-1 (IL-1) og tumornekrosefaktor a (TNF-a)) og vekstfaktorer (f.eks. granulocytt makrofag-koloni-stimulerende faktor (GM-CSF) og fibroblast vekstfaktor
(FGF). En ekstracellulær stimulus kan påvirke en eller flere cellulære responser relatert til cellevekst, migra-sjon, differensiering, sekresjon av hormoner, aktivering av transkripsjonsfaktorer, muskelkontraksjon, glukosemetabo-lisme, kontroll av proteinsyntese og regulering av cellesyklusen .
Mange sykdommer er assosiert med abnormale cellulære responser utløst av proteinkinasemedierte hendelser. Disse sykdommer inkluderer autoimmune sykdommer, inflammatoriske sykdommer, nevrologiske og nevrodegenerative sykdommer, cancer, kardiovaskulære sykdommer, allergier og astma, Alzheimers sykdom eller hormonrelaterte sykdommer. Følgelig har det vært en betydelig anstrengelse innen medisinsk kjemi for å finne proteinkinaseinhibitorer som er effektive som terapeutiske midler.
Aurora-2 er en serin/treonin-proteinkinase som har blitt implisert i human cancer, slik som kolon, bryst og andre faste tumorer. Denne kinase er antatt å være involvert i proteinfosforyleringshendelser som regulerer cellesyklusen. Spesielt kan Aurora-2 spille en rolle i kontroll av den nøyaktige segregasjon av kromosomer under mitose. Feil-regulering av cellesyklusen kan føre til cellulær proliferasjon og andre abnormaliteter. I humant koloncancervev, har aurora-2-proteinet blitt funnet å være overuttrykket. Se Bischoff et al., EMBO J., 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771.
Glykogensyntasekinase-3 (GSK-3) er en serin/treonin-proteinkinase omfattet av a~ og p-isoformer som hver er kodet av distinkte gener [Coghlan et al., Chemistry&Bioloqy, 7, 793-803 (2000); Kim og Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK-3 har blitt implisert i forskjellige sykdommer inklusive diabetes, Alzheimers sykdom, CNS-forstyrrelser slik som manisk-depressiv forstyrrelse og nevrodegenerative sykdommer, og kardiomyocett hypertrofi [WO 99/65897; WO 00/38675; og Haq et al., J. Cell Biol.
(2000) 151, 117]. Disse sykdommer kan forårsakes av, eller resultere i, den abnormale operasjon av visse cellesignal-baner hvor GSK-3 spiller en rolle. GSK-3 har blitt funnet å fosforylere og modulere aktiviteten av en rekke regulato-riske proteiner. Disse proteiner inkluderer glykogensyn-tase som er det hastighetsbegrensende enzym nødvendig for glykogensyntese, mikrotubulen assosierte protein Tau, gentranskripsjonsfaktor |3-catenin, den translasjonsinitie- rende faktor elF2B, samt ATP citratlyase, aksin, varme-sjokkfaktor-1, c-Jun, c-Myc, c-Myb, CREB og CEPBa. Disse forskjellige proteinmål impliserer GSK-3 i mange aspekter av cellulær metabolisme, proliferasjon, differensiering og utvikling.
I en GSK-3-mediert bane som er relevant for behandlingen av type II diabetes, fører insulinindusert signalisering til cellulært glukoseopptak og glykogensyntese. Langs denne bane er GSK-3 en negativ regulator av det insulininduserte signal. Normalt forårsaker nærværet av insulin hemming av GSK-3-mediert fosforylering og deaktivering av glykogensyn-tase. Hemmingen av GSK-3 fører til økt glykogensyntese og glukoseopptak [Klein et al., PNAS, 93, 8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J. 299, 123-128 (1994)]. I en diabetespasient hvor insulin-responsen er svekket, mislykkes imidlertid glykogensyntese og glukoseopptak i å øke tross nærværet av relativt høye blodnivåer av insulin. Dette fører til abnormalt høye blodnivåer av glukose med akutte og langtidseffekter som til sist kan resultere i kardiovaskulær sykdom, renal svikt og blindhet. I slike pasienter mislykkes den normale insulininduserte hemming av GSK-3 å inntreffe. Det har også blitt rapportert at i pasienter med type II diabetes er GSK-3 overuttrykket [WO 00/38675]. Terapeutiske inhibitorer av GSK-3 anses derfor å være nyttige for behandling av diabetespasienter som lider av en svekket respons på insulin .
GSK-3-aktivitet har også blitt assosiert med Alzheimers sykdom. Denne sykdom erkarakterisert veddet velkjente P~amyloidpeptid og dannelsen av intracellulære nevrofibrillære knuter. De nevrofibrillære knuter inneholder hyper-fosforylert Tau-protein hvor Tau er fosforylert på abnormale steder. GSK-3 har blitt vist å fosforylere disse abnormale steder i celle- og dyremodeller. Videre har hemming av GSK-3 blitt vist å forhindre hyperfosforylering av
Tau i celler [Lovestone et al., Current Biology 4, 1077-86
(1994); Brownlees et al., Neuroreport 8, 3251-55 (1997)]. Derfor er det antatt at GSK-3-aktivitet kan fremme produk-sjon av de nevrofibrillære knuter og progresjonen av Alzheimers sykdom.
Et annet substrat av GSK-3 er p-catenin som degraderes etter fosforylering av GSK-3. Reduserte nivåer av p-catenin har blitt rapportert i schizofrene pasienter og har også blitt assosiert med andre sykdommer relatert til økning i nevronal celledød [Zhong et al., Nature, 395, 698-702
(1998); Takashima et al., PNAS, 90, 7789-93 (1993); Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997)].
Som et resultat av den biologiske betydning av GSK-3, er det for tiden interesse i terapeutisk effektive GSK-3-in-hbitorer. Små molekyler som hemmer GSK-3 har nylig blitt rapportert [WO 99/65897 (Chiron) og WO 00/38675 (SmithKline Beecham)].
For mange av de ovennevnte sykdommer assosiert med abnormal GSK-3-aktivitet har andre proteinkinaser også blitt gjort til mål for behandling av de samme sykdommer. Imidlertid virker de forskjellige proteinkinaser ofte gjennom forskjellige biologiske baner. For eksempel har visse kinazo-linderivater nylig blitt rapportert som inhibitorer av p38-kinase (WO 00/12497 til Scios). Forbindelsene rapporteres å være nyttige for behandling av tilstanderkarakterisertved økt p38-a-aktivitet og/eller økt TGF-p-aktivitet. Selv om p38-aktivitet har blitt implisert i en vid variasjon av sykdommer, inklusive diabetes, er p38-kinase ikke rapportert å være en bestanddel av en insulinsignalbane som regulerer glykogensyntese eller glukoseopptak. Derfor ville p38-hemming, forskjellig fra GSK-3, ikke være forventet å øke glykogensyntese og/eller glukoseopptak.
Det er et kontinuerlig behov for å finne nye terapeutiske midler for å behandle humane sykdommer. Proteinkinasene
Aurora-2 og GSK-3 er spesielt attraktive mål for oppdagel-sen av nye terapeutika på grunn av deres viktige roller i henholdsvis cancer og diabetes.
Beskrivelse av oppfinnelsen
Det har nå blitt funnet at forbindelser av denne oppfinnelse og farmasøytiske sammensetninger derav er effektive som proteinkinaseinhibitorer, spesielt som inhibitorer av Aurora-2. Disse forbindelser har den generelle formel Ila eller et farmasøytisk akseptabelt salt derav, hvori: Rx og RY tas sammen med pyrimidingruppen for å danne et quinazolin eller 5,6,7,8-tetrahydro-quinazolin hvor quina-zoinet er usubstituert eller eventuelt substituert i 7- eller 8-posisjonen med metoksy, hydroksyl, 3.morfolino-pro-poksy, 3-dimetyl-aminopropoksy, nitro, amino, hydroksyamino eller fluor; R<1>er en fenylring som kan være substituert med en eller flere substituenter valgt fra gruppen bestående av -Cl, - Br, -F, -CF3, -COOH, -COOMe, -NH2, -NHAc, -NHS02Me, - NHS02Et, NHS02(n-propyl), -NHS02(isopropyl), -NHCOEt, - NHCOCH2N(C02t-Bu) CH3. -NHCOCH2N (CH3) 2, -NHCO (cyklopropyl) , - NHCO(isopropyl), -NHCO(isobutyl), -NHCOCH2(morfolin-4-yl), -NHCOCH2CH2/morfolin-4-yl) , -NHCOCH2CH2CH2 (morfolin-4-yl) , - NHC02 (t-butyl) , -OMe, -0H, -CONHCH2CH2N (CH3) 2, - CONHCH2N (CH3) 2, -NHCOCH2N (CH3) 2, -NHCOCH2NHCH3, metyl og etyl; eller en naftalengruppe, 2-benzimidazolyl eller 1-metyl-2-imidazolyl,
R<2>er valgt fra H, cyklopropyl eller metyl og R<2>' er H eller R2 og R2' danner sammen med de tilstøtende atomer i pyrazol-ringen en benzoring.
Som anvendt heri, skal de følgende definisjoner gjelde med mindre annet er indikert. Frasen "eventuelt substituert" anvendes omvekslende med frasen "substituert eller usubsti tuert" eller med begrepet "(u)substituert." Med mindre annet er indikert kan en eventuelt substituert gruppe ha en substituent ved hver substituerbare stilling i gruppen, og hver substitusjon er uavhengig av den andre.
Med mindre annet er fastsatt er strukturer beskrevet heri også ment å inkludere alle stereokjemiske former av strukturen; dvs. R- og S-konfigurasjonene for hvert asymmetriske senter. Derfor er enkelte stereokjemiske isomerer samt enantiomere og diastereomere blandinger av de foreliggende forbindelser innenfor rammen av oppfinnelsen. Med mindre annet er angitt er strukturer beskrevet heri også ment å inkludere forbindelser som er forskjellige bare i nærværet av ett eller flere isotopisk anrikede atomer. For eksempel er forbindelser som har de foreliggende strukturer bortsett fra erstatningen av et hydrogen med et deuterium eller tri-tium, eller erstatningen av et karbon med et<13>C- eller<14>C-anriket karbon innenfor rammen av denne oppfinnelse.
Forbindelser med formel Ila eller salter derav kan formuleres i sammensetninger. I en foretrukket utførelse er sammensetningen en farmasøytisk sammensetning. I en utførelse omfatter sammensetningen en mengde av proteinkinaseinhibitoren effektiv for å hemme en proteinkinase, spesielt Aurora-2, i en biologisk prøve eller i en pasient. Forbindelser av denne oppfinnelse og farmasøytiske sammensetninger derav, som omfatter en mengde av proteinkinaseinhibitoren effektiv for å behandle eller forebygge en Aurora-2-mediert tilstand og en farmasøytisk akseptabel bærer, adjuvans, eller vehikkel, kan formuleres for administrasjon til en pasient.
Et annet aspekt av oppfinnelsen vedrører hemming av Aurora-2-aktivitet i en biologisk prøve, hvilken fremgangsmåte omfatter å kontakte den biologiske prøve med Aurora-2-inhibitoren med formel Ila, eller en sammensetning derav.
Et annet aspekt av oppfinnelsen vedrører hemming av GSK-3-aktivitet i en biologisk prøve, hvilken fremgangsmåte omfatter å kontakte den biologiske prøve med en GSK-3-inhibitor med formel Ila.
Et annet aspekt av oppfinnelsen vedrører hemming av CDK-2-aktivitet i en biologisk prøve.
Et annet aspekt av oppfinnelsen vedrører hemming av Src-aktivitet i en biologisk prøve, hvilken fremgangsmåte omfatter å administrere til prøven en forbindelse med formel Ila eller en sammensetning omfattende forbindelsen.
Et annet aspekt av oppfinnelsen vedrører hemming av Lck-aktivitet i en biologisk prøve, hvilken fremgangsmåte omfatter å administrere til prøven en forbindelse med formel Ila eller en sammensetning omfattende forbindelsen.
Begrepet "farmasøytisk akseptabel bærer, adjuvans, eller vehikkel" refererer til en ikke-toksisk bærer, adjuvans eller vehikkel som kan administreres til en pasient, sammen med en forbindelse av denne oppfinnelse, og som ikke øde-legger den farmakologiske aktivitet derav.
Begrepet "pasient" inkluderer humane og veterinære indivi-der .
Begrepet "biologisk prøve", som anvendt heri, inkluderer, uten begrensning, cellekulturer eller ekstrakter derav; preparater av et enzym passende for in vitro assay; biop-simateriale erholdt fra et pattedyr eller ekstrakter derav; og blod, saliva, urin, feces, sæd, tårer, eller andre kroppsvæsker eller ekstrakter derav.
En mengde effektiv for å hemme proteinkinase, for eksempel, Aurora-2 og GSK-3, er en mengde som forårsaker målbar hemming av kinaseaktiviteten når sammenlignet med aktiviteten av enzymet i fravær av en inhibitor. Enhver fremgangsmåte kan anvendes for å bestemme hemming, slik som, for eksempel, de biologiske testeksempler beskrevet under.
Farmasøytisk akseptable bærere som kan anvendes i disse farmasøytiske sammensetninger er generelt kjent i faget.
De inkluderer, men er ikke begrenset til, ionebyttere, alu-mina, aluminiumstearat, lecitin, serumproteiner, slik som humant serumalbumin, buffersubstanser slik som fosfater, glysin, sorbinsyre, kaliumsorbat, delvise glyseridblanding-er av mettede vegetabilske fettsyrer, vann, salter eller elektrolytter, slik som protaminsulfat, dinatriumhydrogen-fosfat, kaliumhydrogenfosfat, natriumklorid, sinksalter, kolloidal silika, magnesiumtrisilikat, polyvinylpyrrolidon, cellulosebaserte substanser, polyetylenglykol, natriumkar-boksymetylcellulose, polyakrylater, vokser, polyetylen-po-lyoksypropylen-blokkpolymerer, polyetylenglykol og ullfett.
Sammensetningene av den foreliggende oppfinnelse kan administreres oralt, parenteralt, ved inhalasjonsspray, topisk, rektalt, nasalt, bukkalt, vaginalt eller via et implantert reservoar. Begrepet "parenteralt" som anvendt heri inkluderer subkutane, intravenøse, intramuskulære, intra-artiku-lære, intra-synoviale, intrasternale, intratekale, intrahe-patiske, intralesjonelle og intrakranielle injeksjons- eller infusjonsteknikker. Fortrinnsvis administreres sammensetningene oralt, intraperitonealt eller intravenøst.
Sterile injiserbare former av sammensetningene av denne oppfinnelse kan være vandig eller oljeaktig suspensjon. Disse suspensjonene kan formuleres i henhold til teknikker kjent i faget ved å anvende passende dispergerings- eller fuktemidler og suspensjonsmidler. Det sterile injiserbare preparat kan også være en steril injiserbar løsning eller suspensjon i et ikke-toksisk parenteralt akseptabelt for-tynnings- eller løsningsmiddel, for eksempel som en løsning i 1,3-butandiol. Blant de akseptable vehikler og løsnings-midler som kan anvendes er vann, Ringers løsning og isoton natriumkloridløsning. I tillegg anvendes sterile, fikserte oljer konvensjonelt som et løsningsmiddel eller suspen-sjonsmedium. For dette formål kan enhver harmløs fiksert olje anvendes inklusive syntetiske mono- eller diglyseri-der. Fettsyrer, slik som oleinsyre og dens glyseridderiva-ter er nyttige i fremstillingen av injiserbare, som også naturlige farmasøytisk akseptable oljer er, slik som oli-venolje eller ricinusolje, spesielt i sine polyoksyetylerte versjoner. Disse oljeløsninger eller suspensjoner kan også inneholde et langkjedet alkoholfortynningsmiddel eller dis-pergeringsmiddel, slik som karboksymetylcellulose eller lignende dispergeringsmidler som vanligvis anvendes i for-muleringen av farmasøytisk akseptable doseringsformer inklusive emulsjoner og suspensjoner. Andre vanlig anvendte surfaktanter, slik som Tween-er, Span-er og andre emulge-ringsmidler eller biotilgjengelighetsøkere som vanligvis anvendes i fremstillingen av farmasøytisk akseptable faste, flytende eller andre doseringsformer kan også anvendes for formuleringsformål.
De farmasøytiske sammensetninger av denne oppfinnelse kan administreres oralt i enhver oralt akseptabel doseringsform inklusive, men ikke begrenset til, kapsler, tabletter, vandige suspensjoner eller løsninger. I tilfellet av tabletter for oral bruk inkluderer bærere vanligvis anvendt laktose og maisstivelse. Smøremidler, slik som magnesiumstea-rat, tilsettes også typisk. For oral administrasjon i en kapselform inkluderer nyttige fortynningsmidler laktose og tørket maisstivelse. Når vandige suspensjoner er krevd for oral bruk, kombineres den aktive ingrediens med emulger-ings- og suspensjonsmidler. Om ønsket kan visse søtemid-ler, smaks- eller fargestoffer også tilsettes.
Alternativt kan de farmasøytiske sammensetninger av denne oppfinnelse administreres i form av suppositorier for rektal administrasjon. Disse kan fremstilles ved å blande midlet med en passende ikke-irriterende eksipiens hvilken er fast ved romtemperatur, men flytende ved rektal tempe-ratur og derfor vil smelte i rektum for å frigi legemidlet. Slike materialer inkluderer kakaosmør, bivoks og polyety-lenglykoler.
De farmasøytiske sammensetninger av denne oppfinnelse kan også administreres topisk, spesielt når behandlingsmålet inkluderer områder eller organer lett tilgjengelige ved topisk applikasjon, inklusive sykdommer i øyet, huden eller det lavere intestinale system. Passende topiske formule-ringer fremstilles lett for hvert av disse områder eller organer.
Topisk applikasjon for det lavere intestinale system kan bevirkes i en rektal suppositorie formulering (se over) eller i en passende klystérformulering. Topisk-transdermale plaster kan også anvendes.
For topiske anvendelser kan de farmasøytiske sammensetninger formuleres i en passende salve inneholdende den aktive komponent suspendert eller løst i en eller flere bærere. Bærere for topisk administrasjon av forbindelsene av denne oppfinnelse inkluderer, men er ikke begrenset til, mineralolje, parafinolje, vaselin, propylenglykol, polyok-syetylen, polyoksypropylenforbindelse, emulgerende voks og vann. Alternativt kan de farmasøytiske sammensetninger formuleres i en passende lotion eller krem inneholdende de aktive komponenter suspendert eller løst i en eller flere farmasøytisk akseptable bærere. Passende bærere inkluderer, men er ikke begrenset til, mineralolje, sorbitanmo-nostearat, polysorbat 60, cetylestervokser, cetearylalko-hol, 2-oktyldodekanol, benzylalkohol og vann.
For oftalmisk bruk kan de farmasøytiske sammensetninger formuleres som mikroniserte suspensjoner i isoton, pH-justert steril saline, eller, fortrinnsvis, som løsninger i isoton, pH-justert steril saline, enten med eller uten et preservativ slik som benzylalkoniumklorid. Alternativt, for oftalmiske anvendelser, kan de farmasøytiske sammensetninger formuleres i en salve slik som petrolatum.
De farmasøytiske sammensetninger av denne oppfinnelse kan også administreres ved nasal aerosol eller inhalasjon. Slike sammensetninger fremstilles i henhold til teknikker velkjente i faget for farmasøytisk formulering og kan fremstilles som løsninger i saline, ved å anvende benzylalkohol eller andre passende preservativer, absorpsjonsfremmere for å øke biotilgjengelighet, fluorkarboner og/eller andre kon-vensjonelle oppløsnings- eller dispergeringsmidler.
Farmasøytisk akseptable salter av forbindelsene av denne oppfinnelse inkluderer de avledet fra farmasøytisk akseptable uorganiske og organiske syrer og baser. Eksempler på passende "syresalter inkluderer acetat, adipat, alginat, aspartat, benzoat, benzensulfonat, bisulfat, butyrat, cit-rat, kamforat, kamforsulfonat, cyklopentanpropionat, diglu-konat, dodecylsulfat, etansulfonat, format, fumarat, gluko-heptanoat, glyserofosfat, glykolat, hemisulfat, heptanoat, heksanoat, hydroklorid, hydrobromid, hydrojodid, 2-hydrok-syetansulfonat, laktat, maleat, malonat, metansulfonat, 2-naftalensulfonat, nikotinat, nitrat, oksalat, palmoat, pek-tinat, persulfat, 3-fenylpropionat, fosfat, pikrat, piva-lat, propionat, salisylat, succinat, sulfat, tartrat, tio-cyanat, tosylat og undekanoat. Andre syrer, slik som ok-salsyre, selv om de ikke i seg selv er farmasøytisk akseptable, kan anvendes i fremstillingen av salter nyttige som intermediater for å oppnå forbindelsene av oppfinnelsen og deres farmasøytisk akseptable syreaddisjonssalter.
Salter avledet fra passende baser inkluderer alkalimetall-(f.eks. natrium og kalium), alkalijordmetall- (f.eks. mag-nesium), ammonium- og N<+>(Ci_4alkyl) 4-salter. Denne oppfinnelse forutser også kvaterniseringen av alle basiske nitro-geninneholdende grupper av forbindelsene brakt for dagen heri. Vann eller oljeløslige eller dispersible produkter kan oppnås ved slik kvaternisering.
Mengden av proteinkinaseinhibitoren som kan kombineres med bærermaterialene for å frembringe en enkelt doseringsform vil variere avhengig av pasienten som behandles og den spesielle administrasjonsmåte. Fortrinnsvis bør sammensetningene formuleres slik at en dosering på mellom 0,01 - 100 mg/kg kroppsvekt/dag av inhibitoren kan administreres til en pasient som mottar disse sammensetninger.
Det bør også forstås at et spesifikt doserings- og behand-lingsregime for enhver spesiell pasient vil avhenge av mange forskjellige faktorer, inklusive aktiviteten av den spesifikke forbindelse anvendt, alderen, kroppsvekten, generell helse, kjønn, diett, administrasjonstid, ekskre-sjonshastighet, legemiddelkombinasjon, og den behandlende leges vurdering og alvorligheten av den spesielle sykdom som behandles. Inhibitormengden vil også avhenge av den spesielle forbindelse i sammensetningen.
Avhengig av den spesielle proteinkinasemedierte tilstand som skal behandles eller forebygges kan ytterligere terapeutiske midler, som normalt administreres for å behandle eller forebygge denne tilstand, administreres sammen med inhibitorene av denne oppfinnelse. For eksempel, i behandlingen av cancer kan andre kjemoterapeutiske midler eller andre anti-proliferative midler kombineres med de foreliggende forbindelser for å behandle cancer. Disse midler inkluderer, uten begrensning, adriamycin, deksametason, vinkristin, cyklofosfamid, fluorouracil, topotecan, taksol, interferoner og platinaderivater.
Andre eksempler på midler inhibitorene av denne oppfinnelse også kan kombineres med inkluderer, uten begrensning, midler for å behandle diabetes slik som insulin eller insuli-nanaloger, i injiserbar eller inhalasjonsform, glitazoner, alfa-glukosidaseinhibitorer, biguanider, insulin sensibili-satorer og sulfonylureaer; anti-inflammatoriske midler slik som kortikosteroider, TNF-blokkere, IL-1 RA, azatioprin, cyklofosfamid og sulfasalazin; immunomodulatoriske og im-munsuppressive midler slik som cyklosporin, takrolimus, ra-pamycin, mycofenolat mofetil, interferoner, kortikosteroi der, cyklofosfamid, azatioprin og sulfasalazin; nevrotro-fiske faktorer slik som acetylkolinesterase inhibitorer, MAO-inhibitorer, interferoner, anti-krampefremkallende midler, ionekanalblokkere, riluzol og anti-Parkinsonsmidler; midler for å behandle kardiovaskulær sykdom slik som beta-blokkere, ACE-inhibitorer, diuretika, nitrater, kalsiumka-nalblokkere og statiner; midler for å behandle leversykdom slik som kortikosteroider, kolestyramin, interferoner og antivirale midler; midler for å behandle blodforstyrrelser slik som kortikosteroider, anti-levkemiske midler og vekstfaktorer; og midler for å behandle immundefektforstyrrelser slik som gammaglobulin.
Disse tilleggsmidler kan administreres separat fra den pro-teinkinaseinhibitorinneholdende sammensetning, som del av et multippelt doseringsregime. Alternativt kan disse midler være del av en enkelt doseringsform, blandet sammen med proteinkinaseinhibitoren av denne oppfinnelse i en enkel sammensetning.
Forbindelser av denne oppfinnelse kan eksistere i alterna-tive tautomere former. Med mindre annet er indikert er re-presentasjonen av den ene eller den andre tautomer ment å inkludere den andre.
En forbindelse som er spesielt nyttige for behandling av Aurora-2-medierte sykdommer vedrører forbindelser med formel Ila:
eller et farmasøytisk akseptabelt derivat eller prodroge derav, hvori; Rx og RY tas sammen med pyrimidingruppen for å danne et quinazolin eller 5,6,7,8-tetrahydro-quinazolin hvor quina-zoinet er usubstituert eller eventuelt substituert i 7- eller 8-posisjonen med metoksy, hydroksyl, 3.morfolino-pro-poksy, 3-dimetyl-aminopropoksy, nitro, amino, hydroksyamino eller fluor; R<1>er en fenylring som kan være substituert med en eller flere substituenter valgt fra gruppen bestående av -Cl, - Br, -F, -CF3, -COOH, -COOMe, -NH2, -NHAc, -NHS02Me, - NHS02Et, NHS02(n-propyl), -NHS02(isopropyl), -NHCOEt, - NHCOCH2N(C02t-Bu) CH3. -NHCOCH2N (CH3) 2, -NHCO (cyklopropyl) , - NHCO(isopropyl), -NHCO(isobutyl), -NHCOCH2 (morfolin-4-yl) , -NHCOCH2CH2/morfolin-4-yl) , -NHCOCH2CH2CH2 (morfolin-4-yl) , - NHC02 (t-butyl) , -OMe, -0H, -CONHCH2CH2N (CH3) 2, - CONHCH2N (CH3) 2, -NHCOCH2N (CH3) 2, -NHCOCH2NHCH3, metyl og etyl; eller en naftalengruppe, 2-benzimidazolyl eller 1-metyl-2-imidazolyl,
R<2>er valgt fra H, cyklopropyl eller metyl og R<2>' er H eller R2 og R2' danner sammen med de tilstøtende atomer i pyrazol-ringen en benzoring.
Representative forbindelser med formel Ila er vist under i tabell 1.
I en annen utførelse tilveiebringer denne oppfinnelse en sammensetning omfattende en forbindelse med formel Ila og en farmasøytisk akseptabel bærer.
En annen fremgangsmåte vedrører å hemme Aurora-2-, GSK-3-, CDK2- eller Src-aktivitet i en biologisk prøve, hvilken fremgangsmåte omfatter å kontakte den biologiske prøve med Aurora-2-, GSK-3-, CDK2- eller Src-inhibitoren med formel Ila, eller en farmasøytisk sammensetning derav, i en mengde effektiv for å hemme Aurora-2, GSK-3, CDK2 eller Src.
Hver av de ovennevnte fremgangsmåter rettet mot hemmingen av Aurora-2, GSK-3, CDK2 eller Src, utføres fortrinnsvis med en foretrukket forbindelse med formel Ila, som beskrevet over.
Forbindelsene av denne oppfinnelse kan fremstilles ved generelle fremgangsmåter kjent for fagmannen for analoge forbindelser, som illustrert ved de generelle skjemaer I-VII, de generelle fremgangsmåter som følger og ved fremstil-lingseksemplene under.
Reagenser: (a) EtOH, Et3N, romtemperatur; (b) R<1->QH (Q = S, NH eller 0) eller R<1->CH2-M/katalysator (M er Al eller Mg eller Sn, katalysator=Pd<0>eller Ni<0>)
Skjema I over viser en generell rute for fremstillingen av de foreliggende forbindelser. Det diklorerte utgangsmateri-ale 1 kan fremstilles ved å anvende fremgangsmåter lignende de rapportert i J. Indian. Chem. Soc, 61, 690-693 (1984) eller i J. Med. Chem., 37, 3828-3833 (1994). Reaksjonen av 1 med aminopyrazol (eller aminoindazol) 2 på en måte som beskrevet i Bioorg. Med. Chem. Lett, 10, 11, 1175-1180,
(2000) eller i J. Het. Chem, 21, 1161-1167, (1984) gir det allsidige monoklorintermediat 3. Betingelser for å erstat-te klorgruppen i 3 med P^-Q vil avhenge av naturen til den Q-sammenbindende enhet og er generelt kjent i feltet. Se, for eksempel, J. Med. Chem, 38, 14, 2763-2773, (1995) (hvor Q er en N-link), eller Chem. Pharm. Bull., 40, 1, 227-229,
(1992) (S-link), eller J. Het. Chem., 21, 1161-1167, (1984)
(O-link) eller Bioorg. Med. Chem. Lett, 8, 20, 2891-2896,
(1998) (C-link) .
Reagenser: (a) P0C13, Pr3N, 110 °C; (b) EtOH, Et3N, romtemperatur .
Skjema II over viser en alternativ rute for fremstillingen av de foreliggende forbindelser. Utgangsmaterialet 4 kan fremstilles på en måte lignende den beskrevet for analoge forbindelser. Se Chem. Heterocycl. Compd., 35, 7, 818-820
(1999) (hvor Q er en N-link), Indian J. Chem. Sect. B, 22, 1, 37-42 (1983) (N-link), Pestic. Sei, 47, 2, 103-114
(1996) (O-link), J. Med. Chem., 23, 8, 913-918 (1980) (S-link) eller Pharmazie, 43, 7, 475-476 (1988) (C-link). Kloreringen av 4 gir intermediat 5. Se J. Med. Chem., 43, 22, 4288-4312 (2000) (Q er en N-link), Pestic. Sei, 47, 2, 103-114 (1996) (O-link), J. Med. Chem., 41, 20, 3793-3803
(1998) (S-link) eller J. Med. Chem., 43, 22, 4288-4312
(2000) (C-link). Erstatning av 4-Cl-gruppen i intermediat 5 med aminopyrazol (eller aminoindazol) 2 for å gi forbindelser av denne oppfinnelse kan utføres i henhold til kjente fremgangsmåter for analoge forbindelser. Se J. Med. Chem., 38, 14, 2763-2773 (1995) (hvor Q er en N-link), Bioorg. Med. Chem. Lett., 7, 4, 421-424 (1997) (O-link), Bioorg. Med. Chem. Lett., 10, 8, 703-706 (2000) (S-link) eller J. Med. Chem., 41, 21, 4021-4035 (1998) (C-link).
Reagenser: (a) POCI3; (b) EtOH, Et3N, romtemperatur; (c) Okson; (d) R<1->QH (Q = S, NH eller 0) eller R<1->CH2-M/katalysator (M er Al eller Mg eller Sn, katalysator = Pd° eller Ni°)
Skjema III over viser en annen alternativ rute for fremstilling av de foreliggende forbindelser. Utgangsmaterialet 6 kan kloreres for å gi intermediat 7. Erstatning av 4-klor-gruppen i 7 med aminopyrazol (eller aminoindazol) 2 gir intermediat 8 som, ved oksidasjon av metylsulfanylgrup-pen, gir metylsulfonen 9. Metylsulfonylgruppen i 9 kan enkelt erstattes med R<1->QH for å gi det ønskede produkt I.
Se J. Am. Chem. Soc, 81, 5997-6006 (1959) (hvor Q er en N-link) eller i Bioorg. Med. Chem. Lett., 10, 8, 821-826
(2000) (S- link).
Reagenser: (a) P0C13; (b) EtOH, Et3N, romtemperatur; (c) RY-H (R = S, NH eller 0); (d) okson; (e) R<1->QH (Q = S, NH eller 0) eller R<1->CH2-M/katalysator (M er Al eller Mg eller Sn, katalysator = Pd° eller Ni°)
Skjema IV over viser en generell rute for fremstillingen av de foreliggende forbindelser. Det startende 4,6-dihydrok-sy-2-metylsulfanylpyrimidin 10 kan fremstilles som beskrevet i J. Med. Chem., 27, 12, 1621-1629 (1984). Klorgrup-pene i intermediat 11 kan erstattes sekvensielt med aminopyrazol (eller aminoindazol) 2 og deretter med et annet amin (eller alkohol eller tiol) ved å følge prosedyrer lignende dem rapportert i US patent 2585906 (ICI, 1949) . Me-tylsulf anylgruppen i 13 kan deretter oksideres for å gi me-tylsulf onet 14. Erstatning av metylsulfonylgruppen i 14 gir det ønskede produkt II.
Syntesetransformasjonene vist i skjema I-IV over er ytterligere illustrert ved de følgende fremgangsmåter.
Skjema VI over viser en generell rute for fremstilling av arylguanidinintermediatet. Mono- eller bisalkyleringen av 19 i trinn (a) for å fremstille forbindelse 20 kan oppnås ved å anvende fremgangsmåter hovedsakelig lignende dem beskrevet av Jeffery, J. E., et al, J. Chem Soc, Perkin Trans 1, 1996 (21) 2583-2589; Gnecco, D., et al, Org Prep Proced Int, 1996, 28 (4), 478-480; Fedorynski, M. og Jonczyk, A., Org Prep Proced Int, 1995, 27 (3), 355-359; Suzuki, S, et al, kan J Chem, 1994, 71 (2) 357-361; og Prasad, G., et al, J Org Chem, 1991, (25), 7188-7190. Fremgangsmåten i trinn (b) for å fremstille forbindelse 21 fra forbindelse 20 kan oppnås ved å anvende fremgangsmåter hovedsaklig lignende dem beskrevet av Moss, R., et al, Tetrahedron Lett, 1995, (48), 8761-8764 og Garigipati, R., Tetrahedron Lett, 1990, (14), 1969-1972.
Arylguanidinintermediatene fremstilt i henhold til skjema VI kan deretter anvendes for å fremstille forbindelsene av denne oppfinnelse ved fremgangsmåtene beskrevet i skjemaene I-IV over og ved fremgangsmåter kjent for fagmannen. Skjema VII over viser en generell fremgangsmåte som kan anvendes for å fremstille forbindelser med formel II. Forbindelse 26 kan deretter anvendes for å fremstille de ønskede amino-pyrazolforbindelser ved å anvende fremgangsmåtene beskrevet over i skjema I trinn (b).
Metode E. En løsning av (2-klorkinazolin-4-yl)-(5-metyl-2ff-pyrazol-3-yl) -amin (200 mg, 0,77 mmol) og 4-acetamido-tiofenol (644 mg, 3,85 mmol) reflukseres i tert-butanol (3 ml) over en 20 timers periode. Dietyleter (10 ml) tilsettes til blandingen og et fast stoff dannes som samles ved filtrering. Dette faste stoff suspenderes i EtOH/H20 1 ml/3 ml), deretter tilsettes K2CO3(110 mg, 0,8 mmol) og suspensjonen omrøres i 2 timer ved romtemperatur. Et fast stoff dannes og samles og tørkes under vakuum for å gi pro-duktet [2-(4-acetamidofenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2if-pyrazol-3-yl) -amin.
For at oppfinnelsen beskrevet heri kan bli mer fullstendig forstått, fremsettes de følgende eksempler.
SYNTESEEKSEMPLER
De følgende HPLC-metoder ble anvendt i analysen av forbindelsene som spesifisert i synteseeksemplene fremsatt under. Som anvendt heri, refererer begrepet "Rt" til retensjonsti-den observert for forbindelsen ved å anvende den spesifi-serte HPLC-metode.
HPLC-metode A:
Kolonne: C18, 3 um, 2,1 X 50 mm, "Lighting" fra Jones Chro-matography.
Gradient: 100 % vann (inneholdende 1 % acetonitril, 0,1 % TFA) til 100 % acetonitril (inneholdende 0,1 % TFA) over 4,0 min, hold ved 100 % acetonitril i 1,4 min og retur til startbetingelser. Total kjøretid 7,0 min. Strømningshas-tighet: 0,8 ml/min.
HPLC-metode B:
Kolonne: C18, 5 um, 4,6 X 150 mm "Dynamax" fra Rainin
Gradient: 100 % vann (inneholdende 1 % acetonitril, 0,1 % TFA) til 100 % acetonitril (inneholdende 0,1 % TFA) over 20 min, hold ved 100 % acetonitril i 7,0 min og retur til startbetingelser. Total kjøretid 31,5 min. Strømningshas-tighet: 1,0 ml/min.
HPLC-metode C:
Kolonne: Cyano, 5 um, 4,6 X 150 mm "Microsorb" fra Varian.
Gradient: 99 % vann (0,1 % TFA), 1 % acetonitril (inneholdende 0,1 % TFA) til 50 % vann (0,1 % TFA), 50 % acetonitril (inneholdende 0,1 % TFA) over 20 min, hold i 8,0 min og retur til startbetingelser. Total kjøretid 30 min. Strømningshastighet: 1,0 ml/min.
HPLC-metode D:
Kolonne: Waters (YMC) ODS-AQ 2,0x50 mm, S5, 120A.
Gradient: 90 % vann (0,2 % maursyre), 10 % acetonitril (inneholdende 0,1 % maursyre) til 10 % vann (0,1 % maursyre), 90 % acetonitril (inneholdende 0,1 % maursyre) over 5,0 min, hold i 0,8 min og retur til startbetingelser. Total kjøretid 7,0 min. Strømningshastighet: 1,0 ml/min.
HPLC-metode E:
Kolonne: 50x2,0 mm Hypersil C18 BDS;5
Gradient: elusjon 100 % vann (0,1 % TFA), til 5 % vann (0,1 % TFA), 95 % acetonitril (inneholdende 0,1 % TFA) over 2,1 min, retur til startbetingelser etter 2,3 min. Strømnings-hastighet: 1 ml/min.
Eksempel 1 (5-metyl-2ff-pyrazol-3-yl)-(2-fenylsulfanyl-kina-zolin-4-yl)-amin (IIa-1): Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt gult fast stoff, smp >300 °C (dek.);<*>H NMR (DMSO) 8 2,07 (3H, s), 5,54 (1H, s), 7,38 (1H, m), 7,56-7,45 (4H, m), 7,65 (2H, m), 7,73 (1H, m), 8,55 (1H, d), 10,43 (1H, s), 12,05 (1H, br s); IR (fast) 3259, 3170, 3109, 1618, 1594, 1565, 1525, 1476; MS 334,0 (M+H)<+>
Eksempel 2 [2-(4-klorfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-2): Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt gult fast stoff, smp 259-260 °C;<*>H NMR (DMSO) 5 2,12 (3H, s), 5,40 (1H, s), 7,60 (1H, t) , 7,64 (2H, d) , 7,76 (3H, d) , 7,92 (1H, t), 8,70 (1H, d) 11,50 (1H, br s); IR (fast) 1627, 1606, 1557, 1484, 1473, 1433, 1400, 1339, 1286, 1219; MS 368,0 (M+H)<+>
Eksempel 3 [2-(2,4-diklorfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-3): Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt gult fast stoff, smp 258-259 °C;<1>R NMR (DMSO) 8 2,12 (3H, s), 5,40 (1H, s), 7,54 (1H, t), 7,63 (1H, m), 7,68 (1H, d), 7,86 (1H, t), 7,92 (1H, d) , 7,96 (1H, d) , 8,66 (1H, d) 11,20 (1H, br s); IR (fast) 1623, 1610, 1551, 1488, 1435, 1410, 1339, 1284, 1217; MS 402,0 (M+H)<+>
Eksempel 4 [2-(4-metoksyfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin (IIa-4): Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt gult fast stoff, smp 264-268 °C;<1>H NMR (DMSO) 5 2,04 (3H, s), 3,85 (3H, s), 5,43 (1H, s), 7,12 (2H, d), 7,53 (1H, t), 7,61 (3H, d), 7,84 (3H, t), 8,63 (1H, d), 11,09 (1H, br s), 12,30 (1H, br s); IR (fast) 1622, 1598, 1552, 1492, 1404, 1340, 1292, 1249, 1219, 1171, 1161; MS 364,1 (M+H)<+>
Eksempel 5 [2-(2-etylfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-5): Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt gult fast stoff, smp 205-208 °C;<1>H NMR (DMSO) 8 2,05 (3H, s), 5,19 (1H, s), 7,38 (1H, t), 7,52-7,64 (3H, m), 7,68 (2H,
d), 7,90 (1H, t), 8,68 (1H, d); IR (fast) 3262, 2967, 1632, 1605, 1558, 1492, 1434, 1403, 1344, 1294, 1224, 1162; MS
362,1 (M+H)<+>
Eksempel 6 {2-[2,4-bis(trifluormetyl)fenylsulfanyl]-kinazo-lin-4-yl}-(5-metyl-2fT-pyrazol-3-yl) -amin (IIa-6) : Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt gult fast stoff, smp >300 °C;<X>H NMR (DMSO) 8 1,98
(3H, s), 5,37 (1H, s), 7,50 (1H, t), 7,59 (2H, d), 7,84 (1H, d), 8,32 (1H, s), 8,40 (2H, s), 8,66 (1H, d) , 10,73 (1H, br s); IR (fast) 1628, 1603, 1577, 1548, 1512, 1493, 1448, 1417, 1354, 1275, 1196, 1124; MS 470,1 (M+H)<+>
Eksempel 7 [2-(2-klorfenylsulfanyl)-kinazolin-4-yl]- (5-metyl-2ff-pyrazol-3-yl)-amin (IIa-7): Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt gult fast stoff, smp 262-263 °C;<1>H NMR (DMSO) 8 2,05 (3H, s), 5,35 (1H, s), 7,52 (2H, t) , 7,65 (2H, m) , 7,74 (1H, d) , 7,83 (1H, t) , 7,88 (1H, d) , 8,62 (1H, d) , 10,97 (1H, br s) ; IR (fast) 1621, 1603, 1569, 1544, 1491, 1448, 1400, 1376, 1336, 1288, 1208; MS 368,0 (M+H)<+>
Eksempel 8 [2-(2,3-diklorfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin (IIa-8): Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt gult fast stoff, smp >300 °C;<X>H NMR (DMSO) 8 2,05 (3H, s), 5,34
(1H, s), 7,50 (2H, m), 7,60 (1H, d), 7,75 (1H, t) , 7,88 (2H, m), 8,62 (1H, d), 10,72 (1H, br s); IR (fast) 1632, 1609, 1561, 1532, 1492, 1432, 1400, 1380, 1345, 1298, 1228, 1162, 1125; MS 402,0 (M+H)<+>
Eksempel 9 [2-(3-klorfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-9): Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt gult fast stoff, smp 248-249 °C;<1>R NMR (DMSO) 8 2,05 (3H, s), 5,42 (1H, s), 7,55 (2H, m), 7,66 (3H, m), 7,81 (1H, s), 7,85 (1H, t), 8,62 (1H, d), 11,10 (1H, br s); IR (fast) 1628, 1611, 1551, 1487, 1432, 1410, 1341, 1292, 1217, 1165; MS 368,0 (M+H)<+>
Eksempel 10 [2-(l-metylimidazol-2-ylsulfanyl)-kinazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin (IIa-10): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 255-256 °C;<X>H NMR (DMSO) 8 2,19 (3H, s), 3,59 (1H, s), 5,51 (1H, s), 7,18 (1H, s), 7,45 (1H, t) , 7,57 (1H, s), 7,59 (1H, d) , 7,77 (1H, t) , 8,57 (1H, d) , 10,57 (1H, s), 12,13 (1H, br s); IR (fast) 1628, 1565, 1550, 1532, 1492, 1430, 1376, 1333, 1292, 1278, 1211; MS 338,2 (M+H)<+>
Eksempel 11 [2-(2-hydroksyfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-11) : Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt gult fast stoff, smp 273-275 °C;<X>H NMR (DMSO) 8 2,06 (3H, s), 5,41 (1H, s), 6,99 (1H, t) , 7,07 (1H, d) , 7,50 (1H, t) , 7, 57-7, 62 (2H, m) , 7,73 (1H, d) , 7,94 (1H, t) , 8,71 (1H, d) , 10,29 (1H, br s), 11,66 (1H, br s); IR (fast) 1623, 1597, 1552, 1485, 1442, 1404, 1354, 1341, 1289, 1221, 1165;
MS 350,1 (M+H)<+>
Eksempel 12 [2-(2,4-difluorfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-12): Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt gult fast stoff, smp 256-258 °C;<X>H NMR (DMSO) 2,10 (3H, s), 5,41 (1H, s), 7,33 (1H, t), 7,51-7,58 (2H, m), 7,65 (1H, d) , 7,82-7,91 (2H, m), 8,63 (1H, d), 11,06 (1H, br s) ; IR (fast) 1626, 1608, 1556, 1482, 1409, 1341, 1288, 1270, 1219, 1162, 1140; MS 370,1 (M+H)<+>
Eksempel 13 [2-(3,4-dimetoksyfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin (IIa-13): Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt gult fast stoff, smp 229-232 °C;<X>H NMR (DMSO) 8 2,05 (3H, s), 3,70 (3H, s), 3,85 (3H, s), 5,39 (1H, s), 6,95 (1H, d) , 7,30 (2H, d) , 7,60 (1H, t) , 7,77 (1H, d) , 7,94 (1H, t), 8,72 (1H, d), 11,66 (1H, br s); IR (fast) 1625, 1607, 1551, 1503, 1436, 1404, 1342, 1290, 1254, 1237, 1218, 1161, 1137; MS 394,1 (M+H)<+>
Eksempel 14 [2-(3-metylfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin (IIa-14): Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt gult fast stoff, smp 249-250 °C;<1>H NMR (DMSO) 8 2,06 (3H, s), 2,36 (3H, s), 5,31 (1H, s) , 7,45 (2H, d) , 7, 48-7, 58 (3H, m) , 7,61 (1H, d) , 7,88 (1H, t) , 8,68 (1H, d) , 11,66 (1H, br s); IR (fast) 1617, 1587, 1558, 1496, 14414, 1387, 1341, 1283, 1221, 1162, 1140; MS 348,1 (M+H)<+>
Eksempel 15 [2-(2-metoksyfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-15): Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt gult fast stoff, smp 237-239 °C;<X>H NMR (DMSO) 8 2,07 (3H, s), 3,71 (3H, s), 5,35 (1H, s), 7,12 (1H, t), 7,23 (1H, d), 7,55 (1H, t), 7, 60-7, 67 (3H, m) , 7,87 (1H, t) , 8,66 (1H,
d) , 11,20 (1H, br s); IR (fast) 1632, 1606, 1561, 1480, 1430, 1405, 1344, 1292, 1276, 1251, 1224; MS 364,1 (M+H)<+>
Eksempel 16 [2-(2-naftalenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin (IIa-16): Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt gult fast stoff, smp 267-270 °C;<1>H NMR (DMSO) 8 2,05 (3H, s), 5,09 (1H, s), 7,57 (1H, t), 7,62-7,75 (4H, m), 7,90 (1H, t), 8,07 (3H, t), 8,40 (1H, s), 8,66 (1H, d), 11,28 (1H, br s); IR (fast) 1624, 1606, 1550, 1487, 1435, 1407, 1341, 1285, 1216, 1158; MS 384,1 (M+H)<+>
Eksempel 17 [2-(2,6-diklorfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-17) : Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt brunt fast stoff, smp >300 °C;<X>H NMR (DMSO) 5 2,11 (3H,
s), 5,49 (1H, s), 7,49 (1H, t), 7,59-7,67 (2H, m), 7,76 (2H, d) , 7,81 (1H, d) , 8,60 (1H, d) , 10,60 (1H, s) ; IR (fast) 1618, 1599, 1565, 1533, 1486, 1424, 1401, 1361, 1344, 1285, 1246, 1216, 1188, 1172; MS 402,0 (M+H)<+>
Eksempel 18 [2-(3,4-diklorfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-18): Fremstilt på en måte lignende den over beskrevne metode E for å gi et blekt gult fast stoff, smp 268-272 °C;<X>H NMR (DMSO) 5 2,11 (3H, s), 5,47 (1H, s), 7,56 (1H, t), 7,68-7,72 (2H, m), 7,83 (2H, d) , 7,88 (1H, t) , 8,05 (1H, d) , 8,66 (1H, d) ; IR (fast) 1628, 1607, 1556, 1488, 1436, 14412, 1399, 1367, 1341, 1288, 1216, 1166; MS 402,0 (M+H)<+>
Eksempel 19 [2-(benzimidazol-2-ylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-19): Fremstilt på en
måte lignende den over beskrevne metode E for å gi et blekt grått fast stoff, smp 192-196 °C;<X>H NMR (DMSO) 5 1,60 (3H, s), 5,48 (1H, s), 7,44 (2H, m) , 7,53 (1H, t) , 7,69 (2H, d) , 7,76 (2H, m), 7,85 (1H, t), 8,64 (1H, d), 10,79 (1H, s); IR (fast) 1618, 1606, 1569, 1537, 1487, 1411, 1395, 1369, 1343, 1288, 1273, 1170; MS 374,1 (M+H)<+>
Eksempel 20 [2-(2-aminofenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-20): Fremstilt på en måte lignende den over beskrevne metode E for å gi et lyst gult fast stoff, smp 257-259 °C;<1>R NMR (DMSO) 8 2,11-2,30 (3H, 2xbr s), 6,10 (1H, br s), 7,10-7,80 (7H, m), 8,60 (1H, br s), 9,80 (1H, br s), 10,80 (1H, br s); IR (fast) 1623, 1591, 1567, 1538, 1496, 1483, 1410, 1351
Eksempel 21 (5-cyklopropyl-2H-pyrazol-3-yl)-(2-fenylsulfanyl-kinazolin-4-yl)-amin (IIa-21): Fremstilt på en måte lignende den over beskrevne metode E for å gi et gult fast stoff, smp 233-236 °C;<X>H NMR (DMSO) 8 0,89 (2H, d) , 0,98 (2H, d) , 1,67 (1H, m) , 5,48 (1H, s) , 7, 54-7, 73 (7H, m) , 7,89 (1H, t), 8,68 (1H, d), 11,60 (1H, br s); IR (fast) 1629, 1606, 1577, 1546, 1509, 1484, 1438, 1413, 1370, 1291, 1219; MS 360,3 (M+H)<+>
Eksempel 22 (5-cyklopropyl-2ff-pyrazol-3-yl)-[2-(3-metoksy-karbonylfenylsulfanyl)-kinazolin-4-yl]-amin (IIa-22): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 224-225 °C;<X>H NMR (DMSO) 8 0,52 (2H, m), 0,86 (2H, m), 1,67 (1H, m), 3,86 (3H, s) , 5,60 (1H, s), 7,45 (1H, t) , 7,56 (1H, d) , 7,66 (1H, t) , 7,76 (1H, t) , 7,93 (1H, d) , 8,10 (1H, d) , 8,18 (1H, s) , 8,57 (1H, d), 10,48 (1H, br s), 12,07 (1H, br s); IR (fast) 1724, 1617, 1593, 1567, 1526, 1478, 1432, 1400, 1361, 1343, 1283, 1260, 1218, 1169, 1128; MS 418,3 (M+H)<+>
Eksempel 23 (5-cyklopropyl-2H-pyrazol-3-yl)-[2-(3-metylfe-nylsulfanyl)-kinazolin-4-yl]-amin (IIa-23): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 241-243 °C;<X>H NMR (DMSO) 8 0,55-0,63 (2H, m) , 1, 87-1, 97 (1H, m) , 1, 67-1,79 (1H, m), 2,35 (3H, s), 5,72 (1H, s), 7,30-7,60 (6H, m), 7,68-7,78 (lH,m), 8,50-8,60 (1H, d), 10,38 (1H, s), 12,02 (1H, s); IR (fast) 1617, 1594, 1568, 1529, 1480, 1401, 1344, 1287, 1176, 758, 665,656; MS (M+H)<+>
Eksempel 24 (5-cyklopropyl-2H-pyrazol-3-yl)-[2-(3-metoksyfenylsulfanyl)-kinazolin-4-yl]-amin (IIa-24): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 232-234 °C;<X>H NMR (DMSO) 8 0,55-0,62 (2H, m) , 0,88-0, 97 (2H, m), 1,70-1, 80 (1H, m), 3,79 (3H, s), 5,79 (1H, s), 7,08 (1H, d), 7,22-7,29 (2H, m), 7,40-7,50 (2H, m) , 7,60 (1H, d) , 7,79 (1H, t) , 8,57 (1H, d) , 10,40 (1H, s), 12,04 (1H, s); IR (fast) 3100, 1618, 1592, 1567, 1527, 1477, 1402, 1345, 1284, 1246, 1231, 1171, 1041, 1001, 969, 826, 761, 692, 667; MS (M+H)<+>
Eksempel 25 (5-cyklopropyl-2H-pyrazol-3-yl)-[2-(3,4-dime-toksyfenylsulfanyl)-kinazolin-4-yl]-amin (IIa-25): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 250-252 °C;<X>H NMR (DMSO) 8 0,54-0,60 (2H, m), 0,83-0,91 (2H, m), 1,68-1,77 (1H, m), 3,79 (3H, s), 3,85 (3H, s), 5,79 (1H, s), 7,10 (1H, d), 7, 20-7,26 (2H, m) , 7,45 (1H, t) , 7,57 (1H, d) , 7,77 (1H, t), 8,55 (1H, d), 10,45 (1H, s), 12,04 (1H, m); IR (fast) 1617, 1593, 1567, 1530, 1504, 1479, 1457, 1439, 1398, 1364, 1347, 1288, 1269, 1250, 1232, 1181, 1169, 1138, 1037, 1020, 997, 972, 882, 846, 804, 764, 750; MS (M+H)<+>
Eksempel 26 [2-(3-karboksyfenylsulfanyl)-kinazolin-4-yl]-(5-cyklopropyl-2ff-pyrazol-3-yl)-amin (IIa-26): Fremstilt fra IIa-22 i henhold til metode G for å gi et gult fast stoff, smp >300 °C;<X>H NMR (DMSO) 8 0,53 (2H, d), 0,86 (2H, d) , 1,65 (1H, m) , 5,37 (1H, s) , 7,55 (1H, t) , 7,68 (1H, t) , 7,81 (1H, d), 7,88 (1H, t), 7,95 (1H, d) , 8,15 (1H, d) ,
8,15 (1H, s), 8,71 (1H, d), 11,32 (1H, br s); IR (fast) 1702, 1626, 1609, 1559, 1490, 1412, 1355, 1293, 1222, 1170; MS 404,7(M+H)<+>
Eksempel 27 (5-cyklopropyl-2ff-pyrazol-3-yl)-[2-(naftalen-2-ylsulfanyl)-kinazolin-4-yl]-amin (IIa-27): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 285-288 °C;<X>H NMR (DMSO) 8 0,25 (2H, br s), 0,52 (2H, br s), 0,87 (1H, m), 5,54 (1H, br s),
7, 42-7, 77 (4H, m) , 8,00 (3H, m) , 8,30 (1H, br s) , 8,56 (1H, br d) , 10,42 og 11,88 (1H, 2 x br s); IR (fast) 1615, 1592, 1562, 1527, 1476, 1398, 1366, 1287, 1240, 1216, 1167, 1158, 1142, 1128, 996, 965; MS 410,7(M+H)<+>
Eksempel 28 (5-cyklopropyl-2H-pyrazol-3-yl)-[2-(2,4-difluorfenylsulfanyl)-kinazolin-4-yl]-amin (IIa-28): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 250-253 °C;<X>H NMR (DMSO) 8 0,61 (2H, m), 0,91 (2H, m), 1,74 (1H, m), 5,67 (1H, m), 7, 24-7,28 (1H, m) , 7,44-7, 48 (3H, m), 7,53-7,81 (2H, brm), 8,55 (1H, m), 10,47 og 12,10 (1H, 2 x br s); IR (fast) 1614, 1598, 1565, 1525, 1479, 1423, 1398, 1366, 1345, 1285, 1267, 1243, 1213, 1168, 1143, 1114, 1026, 995, 968; MS 396,6(M+H)<+>
Eksempel 29 (5-cyklopropyl-2H-pyrazol-3-yl)-[2-(naftalen-2-ylsulfanyl)-5,6,7,8-tetrahydrokinazolin-4-yl]-amin (Ila-29): Fremstilt på en måte lignende den over beskrevne metode F for å gi et hvitt fast stoff, smp 244 °C;<X>H NMR (DMSO) 8 0,13 (2H, s), 0,45 (2H, s), 0,79 (1H, s), 1,73 (4H, s), 2,42 (2H, s), 2,58 (2H, s), 5,28 (1H, s), 7,58 (2H, d) , 7,61 (2H, d) , 7,97 (3H, d) , 8,23 (1H, s), 8,56 (1H, s), 11,63 (1H, s); IR (fast) 1594, 1561, 1514, 1477, 1423, 1333, 1279, 1251, 990, 808, 744, 657, 651; MS 414,7(M+H)<+>
Eksempel 30 (5-cyklopropyl-2H-pyrazol-3-yl)-[2-(2,3-diklor-fenylsulfanyl) -kinazolin-4-yl] -amin (IIa-30): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 250-252 °C;<X>H NMR (DMSO) 8 0,60 (2H, d) , 0,93 (2H, d) , 1,70 (1H, m) , 5,54 (1H, s), 7,47 (2H, m) , 7,57 (1H, d) , 7,76 (1H, t) , 7,86 (2H, d) , 8,57 (1H, d) , 10,48 (1H, s), 12,04 (1H, s); IR (fast) 1616, 1601, 1570, 1528, 1486, 1432, 1400, 1367, 1335, 1285, 1246, 1210, 1159, 1146, 1051, 1033, 1021, 997; MS 428,6(M+H)<+>
Eksempel 31 [2-(3-klorfenylsulfanyl)-kinazolin-4-yl]-(5-cyklopropyl-2ff-pyrazol-3-yl)-amin (IIa-31): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 235-238 °C;<X>H NMR (DMSO) 8 0,58 (2H, d) , 0,92 (2H, d) , 1,75 (1H, m) , 5,71 (1H, s) , 7,44 (1H, t) , 7, 50 - 7, 63 (4H, m) , 7,73 (1H, s) , 7,75 (1H, t) , 8,57 (1H, d) , 10,46 (1H, s), 12,08 (1H, s); IR (fast) 1616, 1593, 1562, 1528, 1479, 1456, 1406, 1367, 1343, 1286, 1244, 1216,
1176, 1067, 1051, 997; MS 394,7(M+H)<+>
Eksempel 32 [2-(2-klorfenylsulfanyl)-kinazolin-4-yl]-(5-cyklopropyl-2ff-pyrazol-3-yl)-amin (IIa-32) : Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 255-257 °C;<X>H NMR (DMSO) 5 0,59 (2H, d) , 0,91 (2H, d) , 1,71 (1H, m) , 5,62 (1H, s) , 7,45 (2H, m) , 7,57 (1H, m) , 7,69 (1H, d) , 7,75 (1H, t) , 7,85 (1H, d) ,
8,56 (1H, d), 10,43 (1H, s), 12,03 (1H, s); IR (fast) 1619, 1596, 1564, 1529, 1480, 1446, 1398, 1370, 1343, 1289, 1246, 1218, 1165, 1148, 1089, 1054, 1030, 997; MS 394,7(M+H)<+>
Eksempel 33 (5-cyklopropyl-2H-pyrazol-3-yl)-[2-(3,4-dime-tylfenylsulfanyl)-kinazolin-4-yl]-amin (IIa-33): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 255-256 °C;<X>H NMR (DMSO) 5 0,56 (2H, m), 0,90 (2H, m), 1,67 (1H, m), 2,26 og 2,29 (6H, 2 x s), 5,75 (1H, br s), 7,26 (1H, m), 7,35-7,55 (4H, m), 7,74 (1H, m), 8,54 (1H, br s), 10,44 og 12,06 (2H, 2 x br s); IR (fast) 1617, 1596, 1569, 1526, 1479, 1459, 1404, 1366, 1343, 1287, 1243, 1218, 1167, 1145, 1017, 996, 966; MS 388,3(M+H)<+>
Eksempel 34 [2-(benzimidazol-2-ylsulfanyl)-kinazolin-4-yl]-(5-cyklopropyl-2ff-pyrazol-3-yl)-amin (IIa-34): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 201-203 °C;<X>H NMR (DMSO) 5 0,44 (2H, m), 0,71 (2H, m), 1,17 (1H, m), 5,72 (1H, m), 7,23 (2H, m) , 7,51-7,81 (5H, m), 8,59 (1H, m), 10, 59, 12, 06 og 13,17 (3H, 3 x br s); IR (fast) 1617, 1601, 1572, 1532, 1485, 1402, 1374, 1341, 1290, 1273, 1209, 1168, 1024, 1010, 965; MS 400,2(M+H)<+>
Eksempel 35 (5-cyklopropyl-2H-pyrazol-3-yl)-[2-(4-metoksy-karbonylfenylsulfanyl)-kinazolin-4-yl]-amin (IIa-35): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 245-246 °C;<X>H NMR (DMSO) 8 0,47 (2H, br s), 0,80 (2H, br s), 1,62 (1H, m), 3,85 (3H, s), 5,69 (1H, br s), 7,46 (1H, m), 7,58 (1H, m) , 7,76-7,81 (3H, m) , 8,02-8, 05 (2H, m), 8,57 (1H, m), 10,48 og 12,11
(2H, 2 x br s); IR (fast) 1721, 1712, 1616, 1596, 1572, 1564, 1523, 1481, 1435, 1404, 1360, 1346, 1277, 1181, 1114, 1106, 996, 971; MS 418,2(M+H)<+>
Eksempel 36 [2-(4-acetamido-fenylsulfanyl)-kinazolin-4-yl]-(5-cyklopropyl-2lT-pyrazol-3-yl)-amin (IIa-36) : Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 239-241 °C;<X>H NMR (DMSO) 8 0,57 (2H, m), 0,83 (2H, m), 1,69 (1H, m), 2,02 (3H, s), 5,73 (1H, br s), 7,41 (1H, m), 7,53-7,57 (3H, m), 7,73-7,75 (3H, m), 8,54 (1H, m), 10,18, 10,39 og 11,98 (3H, 3 x br s); IR (fast) 1665, 1618, 1607, 1586, 1572, 1564, 1529, 1482, 1387, 1343, 1320, 1287, 1243, 1221, 1162, 1005, 968; MS 417,2(M+H)<+>
Eksempel 37 (5-cyklopropyl-2H-pyrazol-3-yl)-[2-(naftalen-1-ylsulfanyl)-kinazolin-4-yl]-amin (IIa-37): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 271-273 °C;<X>H NMR (DMSO) 8 0,46-0,47 (2H, m) , 0,87-0, 89 (2H, m), 1,57 (1H, m), 5,01 (1H, m), 7,42 (1H, m), 7,52-7,54 (3H, m), 7,64 (1H, m), 7,75 (1H, m), 7,98 (1H, m), 8,06 (1H, m), 8,17 (1H, m), 8,28 (1H, m), 8,50 (1H, m), 10,29 (1H, br s), 11,84 (1H, br s); IR (fast) 1615, 1592, 1567, 1528, 1483, 1401, 1362, 1343, 1285, 1242, 1219, 1173, 998, 963; MS 410,2(M+H)<+>
Eksempel 38 [2-(4-acetamidofenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-38): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 268-271 °C;<1>E NMR (DMSO) 8 2,02 (3H, s), 2,09 (3H, s), 5,56 (1H, s), 7,40 (1H, t), 7,55 (3H, m), 7,75 (3H, d), 8,55 (1H, d), 10,21 (1H, s), 10,40 (1H, s), 12,03 (1H, s); IR (fast) 1662, 1620, 1599, 1572, 1531, 1438, 1397, 1370, 1358, 1341, 1323, 1312, 1278, 1265, 1245, 1216, 1161, 1006, 966; MS 391,2(M+H)<+>
Eksempel 39 [2-(4-metansulfonylamino-fenylsulfanyl)-kinazo-lin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-39): Frem stilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 219-222 °C;<X>H NMR (DMSO) 5 2,15 (3H, s), 2,61 (3H, s), 5,84 (1H, s), 6,91 (2H, d), 7,22 (2H, d) , 7,36 (1H, s) , 7,52 (1H, d) , 7,69 (1H, s) , 8,53 (1H, d), 10,31 (1H, s), 11,96 (1H, s); IR (fast) 1621, 1602, 1584, 1567, 1528, 1486, 1351, 1287, 1253, 1207, 1179, 1102, 1091, 983; MS 427,0(M+H)<+>
Eksempel 40 [2-(4-acetamidofenylsulfanyl)-7-metoksy-kinazo-lin-4-yl] - (5-metyl-2fT-pyrazol-3-yl) -amin (IIa-40) : Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 291-293 °C;<X>H NMR (DMSO) 8 2,01 (3H, s), 2,09 (3H, s), 3,87 (3H, s), 5,55 (1H, s), 6,96 (1H, s), 6,99 (1H, d) , 7,55 (2H, d) , 7,73 (2H, d) , 8,45 (1H, d), 10,21 (1H, s), 10,23 (1H, s), 11,99 (1H, s); IR (fast) ; MS 421,2(M+H)<+>
Eksempel 41 [2-(4-acetamidofenylsulfanyl)-8-(3-morfolin-4-yl-propoksy)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-41): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 262-264 °C;<X>HNMR (DMSO) 5 1,94 (2H, kvint.), 2,03 (3H, s), 2,09 (3H, s), 2,38 (4H, s), 2,45 (2H, t) , 3,58 (4H, s) , 4,11 (2H, t) , 5,60 (1H, s), 7,24 (1H, d) , 7,30 (1H, t) , 7,57 (2H, d) , 7,73 (2H, d), 8,07 (1H, d), 10,20 (1H, s), 10,24 (1H, s), 12,02 (1H, br s); IR (fast) 3245, 3045, 2954, 2918, 2845, 1663, 1609, 1586, 1527, 1468, 1391, 1332, 1268, 1254, 1159, 1136, 1114, 1054, 995, 823; MS 534,4(M+H)<+>
Eksempel 42 [2-(4-metoksykarbonylfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-42): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 257-260 °C;<X>H NMR (DMSO) 5 1,95 (3H, s), 3,89 (3H, s) , 5,51 (1H, br s) , 7,39 (1H, br s) , 7,51 (1H, br s), 7,70 (1H, br s), 7,81 (2H, d), 8,04 (2H, d) , 8,51 (1H, br s), 10,48 (1H, br s), 12,03 (1H, br s); IR (fast) 1718, 1618, 1599, 1568, 1531, 1481, 1434, 1395, 1362, 1342, 1286, 1247, 1216, 1156, 1116, 1018, 1003, 968; MS 392,2(M+H)<+>Eksempel 43 [2-(4-karboksyfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-43): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 263-265 °C;<X>H NMR (DMSO) 5 1,98 (3H, s), 5,50 (1H, s), 7,46 (1H, t) , 7,60 (1H, d) , 7,78 (3H, m) , 8,02 (2H, d), 8,58 (1H, d), 10,58 (1H, s), 12,50 (1H, br s); IR (fast) 1623, 1605, 1574, 1560, 1533, 1490, 1401, 1349, 1318, 1285, 1249, 1216, 1174, 1131, 1088, 1018; MS 378,2(M+H)<+>
Eksempel 4 4 [2-(4-acetamidofenylsulfanyl)-8-metoksy-kinazo-lin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-44): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 247-249 °C;<X>H NMR (DMSO) 1,99 (3H, s), 2,10 (3H, s), 3,93 (3H, s), 5,40 (1H, s), 7,31 (1H, d) , 7,38 (1H, t) , 7,57 (2H, d) , 7,76 (2H, d) , 8,11 (1H, d), 10,28 (1H, s), 10,61 (1H, s), 12,11 (1H, br s); IR (fast) 3234, 3052, 2938, 1673, 1618, 1591, 1536, 1481, 1459, 1390, 1372, 1345, 1317, 1267, 1249, 1158, 1058, 985, 830; MS 421,2(M+H)<+>
Eksempel 4 5 [2-(4-acetamidofenylsulfanyl)-7-(3-morfolin-4-yl-propoksy) -kinazolin-4-yl] - (5-metyl-2ff-pyrazol-3-yl) -amin (IIa-45): Fremstilt fra IIa-74 ifølge metode I for å gi et offwhite fast stoff, smp 153 °C (dek.);<X>H NMR (DMSO) 8 2,02 (3H, s), 2,09 (3H, s), 2,29 (2H, kvint.), 3,16 (2H, m), 3,36 (4H, m), 3,57 (4H, m), 4,11 (2H, m), 5,58 (1H, s), 7, 22-7,29 (2H, m) , 7,55 (2H, d) , 7,76 (2H, d) , 8,07 (1H,
d) , 10,26 (1H, br s), 10,35 (1H, s), 12,06 (1H, br s); IR (fast) 1673, 1614, 1591, 1532, 1486, 1391, 1336, 1254,
1109, 1063, 995; MS 534,2(M+H)<+>
Eksempel 4 6 [2-(4-bromfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2fT-pyrazol-3-yl) -amin (IIa-46) : Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp >300 °C;<*>H NMR (DMSO) 8 2,15 (3H, s), 5,63 (1H, br s), 7,44 (1H, m) , 7, 55-7, 62 (3H, m), 7, 69-7, 77 (3H, m), 8,56 (1H, m), 10,47 og 12,12 (2H, 2 x br s); IR (fast) 1615, 1597, 1565, 1525, 1478, 1396, 1362, 1339, 1285, 1218, 1158, 1034, 1009, 967 ; MS 412,1/414,1(M+H)<+>
Eksempel 47 [2-(3-bromfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-47): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 280-281 °C;<1>H NMR (DMSO) 8 2,12 (3H, s), 5,54 (1H, br s), 7,46 (1H, m), 7, 55-7, 68 (3H, m) , 7,75-7,88 (3H, m), 8,81 (1H, m), 10,49 og 12,11 (2H, 2 x br s); IR (fast) 1617, 1600, 1567, 1530, 1483, 1399, 1362, 1342, 1282, 1200, 1168, 1054, 1034, 1005, 967; MS 412,2/414,2(M+H)<+>
Eksempel 48 [2-(4-isopropansulfonylamino-fenylsulfanyl)-ki-nazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-48): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 294-297 °C;<*>H NMR (DMSO) 8 1,26 (6H, d), 2,13 (3H, s), 5,75 (1H, s), 7,34 (2H, d), 7,41 (1H, t), 7,54 (1H, d) , 7,59 (2H, d) , 7,73 (1H, t) , 8,53 (1H, d), 10,16 (1H, s), 10,42 (1H, s), 12,07 (1H, br s); IR (fast) 1613, 1593, 1560, 1530, 1482, 1384, 1364, 1346, 1320, 1290, 1265, 1243, 1216, 1169, 1141, 1084, 1056, 1019, 999, 969, 916; MS 455,2(M+H)<+>
Eksempel 4 9 [2-(4-isobutyrylamino-fenylsulfanyl)-kinazolin-4-yl] - (5-metyl-2ff-pyrazol-3-yl)-amin (IIa-49) : Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 285-287 °C;<X>H NMR (DMSO) 8 1,12-1,13 (6H, m), 1,99 (3H, s), 2,64 (1H, m), 5,52 (1H, br s), 7,41 (1H, m), 7, 54-7, 57 (3H, m) , 7, 72-7,77 (3H, m), 8,54 (1H, m) , 10,12, 10,41 og 12,04 (3H, 3 x br s); IR (fast) 1704, 1680, 1617, 1590, 1566, 1516, 1481, 1395, 1358, 1341, 1286, 1247, 1214, 1155, 1052, 1032, 1006, 969; MS 419,3(M+H)<+>
Eksempel 50 (5-metyl-2ff-pyrazol-3-yl)-[2-(4-propionylamino-fenylsulfanyl)-kinazolin-4-yl]-amin (IIa-50): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 281-282 °C;<X>H NMR (DMSO) 8 1,11-1,13 (3H, m), 1,98 (3H, s), 2,33 (2H, m), 5,51 (1H, br s), 7,41 (1H, m), 7, 55-7, 57 (3H, m) , 7,71-7,78 (3H, m), 8,54 (1H, m) , 10,11, 10,41 og 12,04 (3H, 3 x br s); IR (fast) 1654, 1621, 1599, 1571, 1527, 1476, 1398, 1358, 1341, 1286, 1244, 1216, 1155, 1006, 969; MS 405,3(M+H)<+>
Eksempel 51 [2-(4-cyklopropankarbonylamino-fenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-51): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 300-303 °C;<*>H NMR (DMSO) 8 0,82-0,84 (4H, m), 1,83 (1H, m), 2,01 (3H, s), 5,55 (1H, br s), 7,39-7,41 (2H, m) , 7, 53-7,57 (2H, m), 7,72-7,77 (2H, m), 8,53-8,55 (2H, m), 10,40, 10,46 og 12,03 (3H, 3 x br s); IR (fast) 1664, 1614, 1591, 1560, 1526, 1480, 1432, 1390, 1344, 1288, 1240, 1194, 1177, 1152, 997; MS 417,2(M+H)<+>
Eksempel 52 [2-(4-acetamido-fenylsulfanyl)-8-hydroksykina-zolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-52): brun-gult fast stoff, smp 258-259 °C;<*>H NMR (DMSO) 8 1,99 (3H, s), 2,09 (3H, s), 5,45 (1H, s), 7,10 (1H, d), 7,22 (1H, t), 7,57 (2H, d) , 7,75 (2H, d) , 7,95 (1H, d) , 9,35 (1H, s) , 10,22 (1H, s), 10,26 (1H, s), 12,00 (1H, br s); IR (fast) 3295, 3272, 3181, 3109, 1654, 1591, 1527, 1482, 1459, 1386, 1368, 1314, 1268, 1141, 1077, 991, 814; MS 407,2(M+H)<+>
Eksempel 53 [2-(4-acetamido-fenylsulfanyl)-7-nitrokinazo-lin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-53): Fremstilt på en måte lignende den over beskrevne metode E for å gi et gult fast stoff;<*>H NMR (DMSO) 8 2,02 (3H, s), 2,09 (3H, s), 5,54 (1H, s), 7,58 (2H, d), 7,75 (2H, d), 8,08 (1H, d), 8,22 (1H, s), 8,80 (1H, d), 10,24 (1H, s) , 10,85 (1H, s), 12,15 (1H, s); IR (fast); MS 436,2(M+H)<+>
Eksempel 54 (5-metyl-2ff-pyrazol-3-yl)-{2-[4-(propan-l-sul-fonylamino)-fenylsulfanyl]-kinazolin-4-yl}-amin (IIa-54): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 272-273 °C;<X>H NMR (DMSO) 8 0,95 (3H, t), 1,71 (2H, m), 2,13 (3H, s), 3,18 (2H, t), 5,70 (1H, s), 7,31 (2H, d) , 7,41 (1H, t) , 7,52 (1H, d) , 7,58 (1H, d) , 7,73 (1H, t) , 8,55 (1H, d) , 10,16 (1H, s) , 10,42 (1H, s), 12,07 (1H, s); IR (fast) 1615, 1594, 1563, 1530, 1481, 1389, 1362, 1346, 1325, 1291, 1245, 1147, 969; MS 455,2(M+H)<+>
Eksempel 55 [2-(4-etylsulfonylamino-fenylsulfanyl)-kinazo-lin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-55): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 279-280 °C;<*>H NMR (DMSO) 8 1,28 (3H, t), 2,19 (3H,s), 3,25 (2H, m), 5,76 (1H, s), 7,36 (2H, d) , 7,48 (1H, t) , 7,53 (1H, d) , 7,65 (1H, d) , 7,80 (1H, t), 8,61 (1H, d), 10,23 (1H, s), 10,49 (1H, s) , 12,13 (1H, s); IR (fast) 1615, 1597, 1564, 1532, 1506, 1485, 1455, 1388, 1361, 1347, 1323, 1294, 1218, 1150, 1033, 1016, 998, 968, 918; MS 441,2(M+H)<+>
Eksempel 56 [2-(4-acetamido-fenylsulfanyl)-7-hydroksyamino-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-56): Fremstilt fra IIa-53 ifølge metode J for å gi et gult fast stoff;<*>H NMR (DMSO) 8 1,97 (3H, s), 2,11 (3H, s), 5,19
(1H, s), 6,88-6,91 (2H, m) , 7,65 (2H, d) , 7,85 (2H, d) , 8,44 (1H, d) , 9,27 (1H, br s), 10,49 (1H, s) , 11,38 (1H, s), 14,58 (1H, br s); IR (fast); MS 422,2(M+H)<+>
Eksempel 57 [2-(4-isobutankarbonylamino-fenylsulfanyl)-ki-nazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin (IIa-57): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 281-282 °C;<*>H NMR (DMSO) 8 0,95-0,97 (6H, m), 2,00 (3H, s), 2,12 (1H, m), 2,23-2,25 (2H, m) , 5,56 (1H, s) , 7,41 (1H, m) , 7, 54-7, 57 (3H, m) , 7,72-7,78 (3H, m), 8,54 (1H, m), 10,14, 10,41 og 12,03 (3H, 3 x br s); IR (fast) 1737, 1658, 1618, 1599, 1566, 1530, 1483, 1432, 1394, 1364, 1343, 1313, 1287, 1242, 1216, 1167, 1151, 1003, 967; MS 433,2(M+H)<+>
Eksempel 58 [2-(4-tert-butoksykarbonylamino-fenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-58): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 243-246 °C;<*>H NMR (DMSO) 8 1,50 (9H, s), 1,97 (3H,s), 5,40 (1H, s), 7,07 (2H, br s), 7,36 (1H, br s), 7,47 (2H, d), 7,58 (2H, d), 8,12 (1H, br s), 9,58 (1H, s), 11,24 (1H, br s); IR (fast) 1701, 1593, 1559, 1515, 1482, 1396, 1365, 1346, 1308, 1288, 1237, 1154, 1051, 1020, 969; MS 449,2(M+H)<+>
Eksempel 59 [2-(4-acetamido-fenylsulfanyl)-7-aminokinazo-lin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-59): Fremstilt fra IIa-53 ifølge metode K for å gi et offwhite fast stoff, smp 264-265 °C;<*>H NMR (DMSO) 8 1,99 (3H, s), 2,09 (1H, s), 5,53 (1H, s), 5,97 (2H, s), 6,47 (1H, s), 6,68 (1H, d) , 7,52 (2H, d) , 7,71 (2H, d) , 8,15 (1H, d) , 9,83 (1H, br s), 10,19 (1H, s), 10,87 (1H, br s); IR (fast); MS 406,2(M+H)<+>
Eksempel 60 (5-metyl-2ff-pyrazol-3-yl)-{2-[4-(2-morfolin-4-yl-acetylamino)-fenylsulfanyl]-kinazolin-4-yl}-amin (IIa-60): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 266-267 °C;<X>H NMR (DMSO) 8 2,03 (3H, s), 2,57 (4H, m), 3,23 (2H, s), 3,69 (4H, m) , 5,58 (1H, s) , 7,40 (1H, t) , 7, 55-7, 62 (3H, m) , 7,75 (1H, t), 7,80 (2H, d ), 8,54 (1H, d), 10,02 (1H, s), 10,41 (1H, s), 12,03 (1H, s); IR (fast) 1686, 1598, 1564, 1533, 1515, 1484, 1387, 1362, 1348, 1291, 1113, 868, 801, 773; MS 476,4(M+H)<+>
Eksempel 61 (5-cykloprpyl-2ff-pyrazol-3-yl)-[2-(4-metylsul-fonylamino-fenylsulfanyl)-kinazolin-4-yl]-amin (IIa-61): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 235-238 °C;<*>H NMR (DMSO) 8 0,61 (2H, s), 0,92 (2H, d) , 1,82 (1H, br s) , 2,98 (3H,s), 5,90 (1H, s), 7,23 (2H, d) , 7,41 (1H, t) , 7,54 (3H, m) , 7,72 (1H, t), 8,55 (1H, d), 10,16 (1H, br s), 10,38 (1H, s), 11,99 (1H, s); IR (fast) 1621, 1605, 1573, 1532, 1494, 1455, 1375, 1342, 1316, 1290, 1232, 1143, 1113, 985, 972; MS 453,3(M+H)<+>
Eksempel 62 [2-(4-amino-fenylsulfanyl)-kinazolin-4-yl]- (5-metyl-2H-pyrazol-3-yl)-amin (IIa-62): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp >300 °C;<*>H NMR (DMSO) 5 2,16 (3H, s), 5,58 (1H, s), 6,78 (2H, d) , 7,36 (2H, d) , 7,64 (2H, m) , 7,94 (1H, t), 8,74 (1H, d), 11,82 (1H, br s); IR (fast) 1615, 1591, 1561, 1532, 1495, 1480, 1387, 1363, 1344, 1288, 1244, 1148, 966; MS 349,2(M+H)<+>
Eksempel 63 [2-(4-acetamido-fenylsulfanyl)-kinazolin-4-yl]-(2ff-pyrazol-3-yl)-amin (IIa-63): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff,<*>H NMR (DMSO) 5 2,11 (3H, s), 5,93 (1H, s), 7,31-7,68 (8H, m), 8,54 (1H, s), 10,17 (1H, s), 10,54 (1H, s), 12,38 (1H, s); IR (fast); MS 377,4(M+H)<+>
Eksempel 64 (5-metyl-2ff-pyrazol-3-yl)-{2-[4-(4-morfolin-4-yl-butyrylamino)-fenylsulfanyl]-kinazolin-4-yl}-amin (IIa-64): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 240-243 °C;<*>H NMR (DMSO) 5 1,77 (2H, m) , 2,00 (3H, s), 2,31-2,38 (8H, m) , 3,57 (4H, m) , 5,54 (1H, s) , 7,39-7, 76 (7H, m) , 8,53 (1H, br m) , 10,15 (1H, s), 10,41 (1H, s), 12,00 (1H, br s); IR (fast); MS 504,3(M+H)<+>
Eksempel 65 (5-metyl-2ff-pyrazol-3-yl)-{2-[4-(2-morfolin-4-yl-etylkarbamoyl)-fenylsulfanyl]-kinazolin-4-yl}-amin (Ila-65): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 246-248 °C;<X>HNMR (DMSO) 8 1,97 (3H, s) , 2,43 (4H, br s), 3,30 (2H, s), 3,42 (2H, m) , 3,58 (4H, br s) , 5,52 (1H, s) , 7,43 (1H, t) , 7,55 (1H, d) , 7,76 (3H, m) , 7,97 (2H, d) , 8,56 (2H, m) , 10,45
(1H, s), 12,05 (1H, br s); IR (fast) 1637, 1618, 1596, 1568, 1530, 1484, 1396, 1362, 1343, 1286, 1247, 1216, 1159, 1116, 1006, 967; MS 490,3(M+H)<+>
Eksempel 66 [8-metoksy-2-(4-metylsulfonylamino-fenylsulfanyl) -kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-66): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 275-277 °C;
<*>H NMR (DMSO) 8 2,10 (3H, s), 3,07 (3H, s), 3,89 (3H, s), 5,58 (1H, s), 7,24 (1H, d), 7,26-7,36 (3H, m), 7,60 (2H, d), 8,07 (1H, d), 10,13 (1H, s), 11,26 (1H, s), 12,03 (1H, s); IR (fast) 3379, 1622, 1595, 1531, 1481, 1467, 1344,
1326, 1271, 1248, 1143, 1061, 993, 975, 924, 829; MS 457,2(M+H)<+>
Eksempel 67 {2-[4-(2-dimetylamino-etylkarbamoyl)-fenylsulfanyl]-kinazolin-4-yl}-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-67): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 192-193 °C;<*>H NMR (DMSO) 8 1,99 (3H, s), 2,20 (6H,s), 2,42 (2H, t), 3,40 (2H, q) , 5,56 (1H, s) , 7,43 (1H, t) , 7,57 (1H, d) , 7,77 (3H, m), 7,92 (2H, d), 8,56 (2H, m), 10,44 (1H, s), 12,04 (1H, br s); IR (fast) 1650, 1618, 1593, 1561, 1525, 1481, 1419, 1395, 1361, 1337, 1287, 1247, 1214, 1165, 1004, 969; MS 448,3(M+H)<+>
Eksempel 68 { 2-[4-(2-dimetylamino-acetylamino)-fenylsulfanyl]-kinazolin-4-yl}-(5-metyl-2H-pyrazol-3-yl)-amin (IIa-68): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 241-243 °C;<*>H NMR (DMSO) 8..2,00 (3H, s), 2,33 (6H, s), 3,14 (2H, s), 5,60 (1H, s), 7,40 (1H, t), 7,58 (3H, m ), 7,77 (1H, t ), 7,76 (2H, d), 8,58 (1H, d), 10,04 (1H, s), 10,42 (1H, s), 11,99 (1H, s); IR (fast) 1707, 1617, 1601, 1571, 1509, 1485, 1420, 1397, 1365, 1304, 1290, 1243, 1215, 1161, 970, 847, 813, 765, 716, 683, 656; MS 434,3(M+H)<+>
Eksempel 69 [8-hydroksy-2-(4-metylsulfonylamino-fenylsulfanyl) -kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-69): blekt grønt stoff, smp 291-293 °C;<X>H NMR (DMSO)
8 2,10 (3H, s), 3,09 (3H, s), 5,57 (1H, s), 7,11 (1H, d), 7,24 (1H, t) , 7,31 (2H, d) , 7,62 (2H, d) , 7,96 (1H, d) , 9,32 (1H, s), 10,16 (1H, s), 11,28 (1H, s), 12,02 (1H, s); IR (fast) 3256, 1596, 1531, 1460, 1392, 1317, 1334, 1296, 1267, 1146, 993, 968, 931, 824; MS 443,2(M+H)<+>
Eksempel 70 {2-[4-(3-dimetylamino-propylkarbamoyl)-fenylsulfanyl]-kinazolin-4-yl}-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-70): Fremstilt på en måte lignende den over beskrevne metode E for å gi et rosa fast stoff, smp 210-213 °C;<1>H NMR (DMSO) 8 1,48 (2H, m), 2,01 (3H, s), 2,24 (6H, s), 2,38 (2H, br s), 2,93 (2H, s), 5,57 (1H, s), 7,48 (1H, t) , 7,62 (1H, d), 7,80 (3H, m), 8,02 (2H, d), 8,61 (1H, d) 8,74 (1H, s), 10,50 (1H, s), 12,15 (1H, br s); IR (fast) 1682, 1618, 1595, 1567, 1528, 1484, 1400, 1361, 1344, 1285, 1247, 1219, 1172, 1084, 1006, 969; MS 462,3(M+H)<+>
Eksempel 71 { 2-[4-(3-dimetylamino-propionylamino)-fenylsulfanyl] -kinazolin-4-yl} - (5-metyl-2fT-pyrazol-3-yl) -amin (IIa-71): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 280 °C (dek.);<1>H NMR (DMSO) 8..2,09 (3H, s) , 2,60 (6H, s), 2,93 (2H, m), 3,10 (2H, m), 5,64 (1H, s), 7,47 (1H, t), 7,59-7,70 (3H, m), 7,80-7,87 (3H, m), 8,61 (1H, d), 10,47 (1H, s), 10,48 (1H, s), 12,15 (1H, s).; IR (fast) 1670, 1619, 1598, 1586, 1571, 1534, 1515, 1481, 1397, 1364, 1348, 1286, 1178, 1162, 764; MS 448,4(M+H)<+>
Eksempel 72 [2-(4-acetamido-fenylsulfanyl)-8-metoksy-kina-zolin-4-yl]-(5-cyklopropyl-2ff-pyrazol-3-yl)-amin (IIa-72): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 265-268 °C;<X>HNMR (DMSO) 8 0, 49-0,56 (2H, m) , 0,79-0, 83 (2H, m) , 1,55-1,70 (1H, m), 2,06 (3H, s), 3,89 (3H, s), 5,61 (1H, s), 7,25 (1H, d) , 7,33 (1H, t) , 7,56 (2H, d) , 7,74 (2H, d) , 8,07
(1H, d) , 10,17 (1H, s), 10,26 (1H, s) , 11,94 (1H, br s); IR (fast) 3250, 1671, 1617, 1595, 1536, 1480, 1460, 1396, 1373, 1335, 1254, 1160, 1131, 1071, 1011, 984, 869, 815; MS 447,4(M+H)<+>
Eksempel 73 [2-(4-acetamidofenylsulfanyl)-8-(3-dimetyla-mino-propoksy)-kinazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin (IIa-73): Fremstilt på en måte lignende den over beskrevne metode E for å gi et offwhite fast stoff, smp 170-172 °C;<1>E NMR (DMSO) 5 1,91 (2H, kvint.), 2,03 (3H, s), 2,09 (3H, s), 2,17 (6H, s), 2,40 (2H, t), 4,10 (2H, t), 5,59 (1H, s), 7,23 (1H, d) , 7,30 (1H, t) , 7,57 (2H, d) , 7,73 (2H, d), 8,06 (1H, d), 10,20 (1H, s), 10,24 (1H, s), 12,02 (1H, br s); IR (fast) 3234, 3108, 1675, 1614, 1592, 1531, 1484, 1395, 1371, 1338, 1316, 1253, 1161, 1137, 1062, 1038, 994, 958, 823; MS 492,4(M+H)<+>
Eksempel 74 [2-(4-acetamidofenylsulfanyl)-7-hydroksy-kina-zolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-74): Fremstilt fra IIa-40 ifølge metode H for å gi et offwhite fast stoff, smp 246-248 °C;<*>H NMR (DMSO) 5 2,00 (3H, s), 2,08 (3H, s), 5,52 (1H, s), 6,78 (1H, s), 6,87 (1H, d), 7,54 (2H, d) , 7,72 (2H, d) , 8,37 (1H, d) , 10,06 (1H, s) , 10,17 (1H, s), 10,37 (H, s), 11,95 (1H, br s); IR (fast) 1661, 1633, 1594, 1572, 1539, 1492, 1420, 1389, 1359, 1298, 1223, 1176, 1148, 1087, 1026, 1010, 965; MS 407,4(M+H)<+>
Eksempel 75 [2-(4-acetamidofenylsulfanyl)-7-(3-dimetyla-mino-propoksy)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl)-amin (IIa-75): Fremstilt på en måte lignende den over beskrevne metode I for å gi et offwhite fast stoff, smp 249-250 °C;<*>H NMR (DMSO) 8 1,90 (2H, kvint.), 2,01 (3H, s), 2,09 (3H, s), 2,19 (6H, s), 2,42 (2H, m), 4,12 (2H, t), 5,55 (1H, s), 6,93 (1H, s) , 6,98 (1H, d) , 7,55 (2H, d) , 7,73 (2H, d), 8,43 (1H, d), 10,21 (1H, s), 10,23 (1H, s), 11,98 (1H, br s); IR (fast) 3272, 1677, 1615, 1571, 1558, 1530, 1501, 1434, 1420, 1394, 1344, 1320, 1292, 1263, 1222, 1168, 1048, 1034, 1005, 967, 864, 844; MS 492,4(M+H)<+>Eksempel 76 (2-{4-[2-(tert-butoksykarbonyl-metyl-amino)-acetylamino]-fenylsulfanyl}-kinazolin-4-yl)-(5-metyl-2ff-py-razol-3-yl)-amin (IIa-76): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 228-229 °C (dek.);<X>H NMR (DMSO) 8..1,37 (3H, s), 1,40 (3H, s), 2,02 + 2,03 (3H, 2xs), 2,88 + 2,90 (3H, 2xs), 4,01 + 4,02 (2H, 2xs), 5,52 + 5,57 (1H, 2xs), 7,47 (1H, t), 7,55-7,63 (3H, m), 7,75-7,80 (3H, m), 8,60 (lH,d), 10,28 + 10,30 (1H, 2xs), 10,45 (1H, s), 12,08 (1H, s).; IR (fast) 1698, 1683, 1653, 1617, 1594, 1559, 1538, 1532, 1507, 1488, 1457, 1418, 1397, 1364, 1346, 1307, 1287, 1246, 1151, 842, 827, 759; MS 520,4 (M+H)<+>
Eksempel 77 {2-[4-(2-metylamino-acetylamino)-fenylsulfanyl]-kinazolin-4-yl}-(5-metyl-2H-pyrazol-3-yl)-amin (IIa-77): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 242-244 °C;<*>H NMR (DMSO) 8.2,01 (3H, s), 2,34 (3H, s), 3,32 (2H, s), 5,58 (1H, s), 7,45 (1H, t), 7,50-7,60 (3H, m), 7,75 (1H, t), 7,80 (2H, d), 8,55 (1H, d), 10,10 (1H, br s), 10,42 (1H, s), 12,02 (1H, s); IR (fast) 1674, 1619, 1598, 1570, 1525, 1483, 1417, 1363, 1345, 1298, 1285, 1247, 1160, 966, 827, 804, 784, 763, 712, 670, 653; MS 420,4 (M+H)<+>
Eksempel 78 [2-(4-acetamidofenylsulfanyl)-8-fluor-kinazo-lin-4-yl] - (5-metyl-2fT-pyrazol-3-yl) -amin (IIa-78) : Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff, smp 257-259 °C;<*>H NMR (DMSO) 8.2,01 (3H, s), 2,09 (3H, s), 5,49 (1H, s), 7,42 (1H, t), 7, 57-7, 68 (3H, m) , 7,75 (2H, d) , 8,40 (1H, d) , 10,28 (1H, s), 10,75 (1H,s);19F NMR (DMSO) 8. IR (fast) 1690, 1670, 1637, 1609, 1588, 1543, 1519, 1493, 1456, 1434, 1395, 1366, 1332, 1315, 1289, 1254, 1242, 1032, 838, 829, 808, 744; MS 409,4(M+H)<+>
Eksempel 79 (lH-indazol-3-yl)-(2-fenylsulfanyl-kinazolin-4-yl)-amin (IIa-79): Fremstilt på en måte lignende den over beskrevne metode E for å gi et hvitt fast stoff.<1>H NMR
(DMSO) 8 7, 07 (m, 3H) , 7,19 (t, 1H) , 7,37 (d, 2H) , 7,39 (t, 1H), 7,52 (dd, 1H), 7,54 (t, 1H), 7,55 (d, 1H) , 7,56 (t, 1H), 7,83 (t, 1H), 8,53 (d, 1H), 10,71 (s, 1H), 12,85 (s, 1H); MS 370,1 (M+H)<+>
BiologiSK Testing
Forbindelsenes aktivitet som proteinkinaseinhibitorer kan undersøkes in vitro, in vivo eller i en cellelinje. In vitro assayer inkluderer assayer som bestemmer hemming av enten fosforyleringsaktiviteten eller ATPase-aktiviteten av den aktiverte proteinkinase. Alternativt kvantifiserer in vitro assayer inhibitorens evne til å binde til proteinkinasen. Inhibitorbinding kan måles ved radiomerking av inhibitoren før binding, isolering av inhibitor/proteinkinase-komplekset og bestemmelse av mengden med radiomerke bundet. Alternativt kan inhibitorbinding bestemmes ved å kjøre et konkurranseeksperiment hvor nye inhibitorer inku-beres med proteinkinasen bundet til kjente radioligander.
Biologisk testeksempel 1
Kj- bestemmelse for hemmingen av GSK- 3
Forbindelser ble undersøkt for sin evne til å hemme GSK-3P (AA 1-420) aktivitet ved å anvende et standard koblet enzymesystem (Fox et al. (1998) Protein Sei. 7, 2249). Reaksjoner ble utført i en løsning inneholdende 100 rtiM HEPES (pH 7,5), 10 mM MgCl2, 25 mM NaCl, 300 uM NADH, 1 mM DTT og 1,5 % DMSO. Endelige substratkonsentrasjoner i assayet var 20 uM ATP (Sigma Chemicals, St Louis, MO) og 300 uM peptid (HSSPHQS(P03H2)EDEEE, American Peptide, Sunnyvale, CA). Reaksjoner ble utført ved 30 °C og 20 nM GSK-3p. Sluttkonsentrasjoner av komponentene av det koblede enzymesystem var 2,5 mM fosfoenolpyruvat, 300 uM NADH, 30 ug/ml pyruvatkinase og 10 ug/ml laktatdehydrogenase.
En assaystambufferløsning ble fremstilt inneholdende alle reagensene listet over bortsett fra ATP og testforbindelsen av interesse. Assaystambufferløsningen (175 yl) ble inkubert i en 96 brønnplate med 5 yl av testforbindelsen av interesse ved sluttkonsentrasjoner som strekker seg over 0,002 yM til 30 yM ved 30°C i 10 min. Typisk ble en 12-punkts titrering utført ved å fremstille serielle fortyn-ninger (fra 10 mM forbindelsesstamløsninger) med DMSO av testforbindelsene i datterplater. Reaksjonen ble initiert ved tilsetningen av 20 yl ATP (sluttkonsentrasjon 20 yM). Reaksjonshastighet ble oppnådd ved å anvende en Molecular Devices Spectramax plateleser (Sunnyvale, CA) over 10 min ved 30 °C. Ki-verdiene ble bestemt fra hastighetsdataene som en funksjon av inhibitorkonsentrasjon.
De følgende forbindelser ble vist å ha Ki-verdier mindre enn 0,1 uM for GSK-3: IIa-2, IIa-3, IIa-8, IIa-9, IIa-11, IIa-12, IIa-17, IIa-18, IIa-21 til IIa-24, IIa-26, IIa-28, IIa-30 til IIa-32, IIa-39, IIa-43, IIa-46, IIa-47, IIa-61.
De følgende forbindelser ble vist å ha Ki-verdier mellom 0,1 og 1,0 uM for GSK-3: IIa-1, IIa-4, IIa-5, IIa-7, Ila-14, IIa-15, IIa-20, IIa-29, IIa-34 til IIa-36, IIa-38, Ila-41, IIa-42, IIa-48, IIa-54, IIa-55, IIa-62, IIa-63, IIa-66, IIa-69, IIa-78.
De følgende forbindelser ble vist å ha Ki-verdier mellom 1,0 og 7,0 uM for GSK-3: IIa-10, IIa-13, IIa-25, IIa-40, IIa-45, IIa-49, IIa-50 til IIa-52, IIa-64, IIa-65, IIa-67, IIa-68, IIa-71, IIa-72, IIa-74, IIa-76, IIa-77.
Biologisk testeksempel 2
Kj- bestemmelse for hemmingen av Aurora- 2
Forbindelser ble undersøkt på den følgende måte for sin evne til å hemme Aurora-2 ved å anvende et standard koblet enzymassay (Fox et al (1998) Protein Sei 7, 2249) .
Til en assaystambufferløsning inneholdende 0,1 M HEPES 7,5, 10 mM MgCl2, 1 mM DTT, 25 mM NaCl, 2,5 mM fosfoenolpyruvat, 300 mM NADH, 30 mg/ml pyruvatkinase, 10 mg/ml laktatdehydrogenase, 40 mM ATP og 800 yM peptid (LRRASLG, American Peptide, Sunnyvale, CA) ble en DMSO-løsning av en forbindelse av den foreliggende oppfinnelse tilsatt til en sluttkonsentrasjon på 30 yM. Den resulterende blanding ble inkubert ved 30 °C i 10 min. Reaksjonen ble initiert ved tilsetningen av 10 yl Aurora-2-stamløsning for å gi en sluttkonsentrasjon på 70 nM i assayet. Reaksjonshastighetene ble oppnådd ved å overvåke absorbans ved 340 nm over en 5 minutters avlesningstid ved 30 °C ved å anvende en BioRad Ultramark plateleser (Hercules, CA). Ki-verdiene ble bestemt fra hastighetsdata som en funksjon av inhibitorkonsentrasjon.
De følgende forbindelser ble vist å ha Ki-verdier mindre enn 0,1 uM for Aurora-2: IIa-1 til IIa-18, IIa-21 til Ila-64, IIa-66, IIa-68, IIa-69, IIa-71 til IIa-78.
De følgende forbindelser ble vist å ha Ki-verdier mellom 0,1 og 1,0 uM for Aurora-2: IIa-20, IIa-65, IIa-67, IIa-70.
De følgende forbindelser ble vist å ha Ki-verdier mellom 1,0 og 10,0 uM for Aurora-2: IIa-10.
Biologisk testeksempel 3
CDK- 2- hemmingsassay
Forbindelser ble undersøkt på den følgende måte for sin evne til å hemme CDK-2 ved å anvende et standard koblet enzymassay (Fox et al (1998) Protein Sei 7, 2249).
Til en assaystambufferløsning inneholdende 0,1 M HEPES 7,5, 10 mM MgCl2, 1 mM DTT, 25 mM NaCl, 2,5 mM fosfoenolpyruvat, 300 mM NADH, 30 mg/ml pyruvatkinase, 10 mg/ml laktatdehydrogenase, 100 mM ATP og 100 yM peptid (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale, CA) ble en DMSO-løsning av en forbindelse av den foreliggende oppfinnelse tilsatt til en sluttkonsentrasjon på 30 yM. Den resulterende blanding ble inkubert ved 30 °C i 10 min.
Reaksjonen ble initiert ved tilsetningen av 10 yl CDK-2/Cyclin A-stamløsning for å gi en sluttkonsentrasjon på 25 nM i assayet. Reaksjonshastighetene ble oppnådd ved å overvåke absorbans ved 340 nm over en 5 minutters avlesningstid ved 30 °C ved å anvende en BioRad Ultramark plateleser (Hercules, CA). Ki-verdiene ble bestemt fra hastighetsdata som en funksjon av inhibitorkonsentrasjon.
De følgende forbindelser ble vist å ha Ki-verdier mindre enn 1^M for CDK-2: IIa-14, IIa-36.
De følgende forbindelser ble vist å ha Ki-verdier mellom 1,0 og 20,0 uM for CDK-2: IIa-38, IIa-40, IIa-44, IIa-52 og IIa-54.
Biologisk testeksempel 6
Src- hemmingsassay
Forbindelsene ble evaluert som inhibitorer av human Src-kinase ved å anvende enten et radioaktivitetsbasert assay eller spektrofotometrisk assay.
Src- hemmingsassay A: Radioaktivitetsbasert assay
Forbindelsene ble undersøkt som inhibitorer av full-lengde rekombinant human Src-kinase (fra Upstate Biotechnology, kat. nr. 14-117) uttrykket og renset fra baculovirale celler. Src kinase-aktivitet ble overvåket ved å følge inkor-poreringen av<33>P fra ATP inn i tyrosinet av et vilkårlig poly Glu-Tyr-polymersubstrat med sammensetning, Glu:Tyr = 4:1 (Sigma, kat. nr. P-0275). De følgende var sluttkon-sentras j onene av assaykomponentene: 0,05 M HEPES, pH 7,6, 10 mM MgCl2, 2 mM DTT, 0,25 mg/ml BSA, 10 yM ATP (1-2 yCi<33>P-ATP per reaksjon), 5 mg/ml poly Glu-Tyr og 1-2 enheter av rekombinant human Src-kinase. I et typisk assay ble alle reaksjonskomponentene bortsett fra ATP forhåndsblandet og delt i like deler i assayplatebrønner. Inhibitorer løst i DMSO ble tilsatt til brønnene for å gi en endelig DMSO-konsentrasjon på 2,5 %. Assayplaten ble inkubert ved 30 °C i 10 min før initiering av reaksjonen med<33>P-ATP. Etter 20 min reaksjon ble reaksjonene stanset med 150 yl 10 % trikloreddiksyre (TCA) inneholdende 20 mM Na3P0-j. De stan-sede prøver ble deretter overført til en 96-brønns filterplate (Whatman, UNI-filter GF/F Glass Fiber Filter, eat no. 7700-3310) installert på en filterplate-vakuummanifold. Filterplater ble vasket fire ganger med 10 % TCA inneholdende 20 mM Na3P04og deretter 4 ganger med metanol. 200 yl scintillasjonsvæske ble deretter tilsatt til hver brønn. Platene ble forseglet og mengden av radioaktivitet assosiert med filtrene ble kvantifisert på en TopCount scintilla-sjonsteller. Radioaktiviteten inkorporert ble plottet som en funksjon av inhibitorkonsentrasjonen. Data ble tilpasset til en konkurranse- hemmings kinetikkmodell for å få Ki for forbindelsen.
Src- hemmingsassay B: Spektrofotometrisk assay
ADP produsert fra ATP av den humane rekombinante Src kinase-katalyserte fosforylering av poly Glu-Tyr-substrat ble kvantifisert ved å anvende et koplet enzymassay (Fox et al
(1998) Protein Sei 7, 2249). I dette assay oksideres ett molekyl NADH til NAD for hvert molekyl ADP produsert i ki-nasereaksjonen. Forsvinningen av NADH kan beleilig følges ved 34 0 nm.
De følgende var sluttkonsentrasjonene av assaykomponentene: 0,025 M HEPES, pH 7,6, 10 mM MgC12, 2 mM DTT, 0,25 mg/ml poly Glu-Tyr og 25 nM rekombinant human Src-kinase. Slutt-konsentras joner av komponentene av det koblede enzymsystem var 2,5 mM fosfoenolpyruvat, 200<y>M NADH, 30 yg/ml pyruvatkinase og 10 yg/ml laktatdehydrogenase.
I et typisk assay ble alle reaksjonskomponentene bortsett fra ATP forhåndsblandet og delt i like deler i assaypla-tebrønner. Inhibitorer løst i DMSO ble tilsatt til brøn-nene for å gi en endelig DMSO-konsentrasjon på 2,5 %. Assayplaten ble inkubert ved 30°C i 10 min før initiering av reaksjonen med 100 yM ATP. Absorbansendringen ved 340 nm med tid, reaksjonshastigheten, ble overvåket på en molecular devices plateleser. Hastighetsdataene som en funksjon av inhibitorkonsentrasjonen ble tilpasset til konkurranse-hemmingskinetikkmodell for å få Ki for forbindelsen.
De følgende forbindelser ble vist å ha en Ki-verdi på <100 nM på SRC: IIa-8, IIa-21, IIa-23, IIa-24, IIa-27, IIa-28, IIa-30 til IIa-33.
De følgende forbindelser ble vist å ha en Ki-verdi på mellom 100 nM og 1 uM for SRC: IIa-1, IIa-2, IIa-7, IIa-9, IIa-12, IIa-14, IIa-22, IIa-25, IIa-26, IIa-29, IIa-34 til IIa-42, IIa-46, IIa-47, IIa-49 til IIa-52, IIa-56, IIa-57, IIa-59, IIa-61, IIa-62, IIa-66, IIa-67, IIa-69, IIa-72, IIa-73, IIa-75.
De følgende forbindelser ble vist å ha en Ki-verdi på mellom 1fiM og 6 uM for SRC: IIa-13, IIa-20, IIa-44, IIa-45, IIa-48, IIa-54, IIa-55, IIa-63, IIa-65, IIa-68, IIa-70, IIa-71, IIa-74, IIa-77, IIa-78.
Claims (16)
1. Forbindelse med formel Ila:
eller et farmasøytisk akseptabelt salt derav, hvori;
Rx og RY tas sammen med pyrimidingruppen for å danne et quinazolin eller 5,6,7,8-tetrahydro-quinazolin hvor quina-zoinet er usubstituert eller eventuelt substituert i 7- eller 8-posisjonen med metoksy, hydroksyl, 3.morfolino-pro-poksy, 3-dimetyl-aminopropoksy, nitro, amino, hydroksyamino eller fluor;
R1 er en fenylring som kan være substituert med en eller flere substituenter valgt fra gruppen bestående av -Cl, - Br, -F, -CF3, -COOH, -COOMe, -NH2, -NHAc, -NHS02Me, - NHS02Et, NHS02(n-propyl), -NHS02(isopropyl), -NHCOEt, - NHCOCH2N (C02t-Bu) CH3. -NHCOCH2N (CH3) 2, -NHCO (cyklopropyl) , - NHCO(isopropyl), -NHCO(isobutyl), -NHCOCH2 (morfolin-4-yl) , -NHCOCH2CH2/morfolin-4-yl) , -NHCOCH2CH2CH2 (morfolin-4-yl) , - NHC02 (t-butyl) , -OMe, -0H, -CONHCH2CH2N (CH3) 2, - CONHCH2N (CH3) 2, -NHCOCH2N (CH3) 2, -NHCOCH2NHCH3, metyl og etyl; eller en naftalengruppe, 2-benzimidazolyl eller 1-metyl-2-imidazolyl,
R2 er valgt fra H, cyklopropyl eller metyl og R<2>' er H eller R2 og R2' danner sammen med de tilstøtende atomer i pyrazol-ringen en benzoring.
2. Forbindelse ifølge krav 1, hvori forbindelsen har ett eller flere trekk valgt fra gruppen bestående av: (a) Rx og RY tas sammen med pyrimidingruppen for å danne et quinazolin (b)R<1>er en fenylring som kan være substituert med en eller flere substituenter valgt fra gruppen bestående av -Cl, -Br, -F, -CF3, -COOH, -COOMe, -NH2, -NHAc, -NHS02Me, - NHS02Et, NHS02(n-propyl), -NHS02(isopropyl), -NHCOEt, - NHCOCH2N(C02t-Bu) CH3. -NHCOCH2N (CH3) 2, -NHCO (cyklopropyl) , - NHCO(isopropyl), -NHCO(isobutyl), -NHCOCH2 (morfolin-4-yl) , -NHCOCH2CH2/morfolin-4-yl) , -NHCOCH2CH2CH2 (morfolin-4-yl) , - NHC02 (t-butyl) , -OMe, -0H, -CONHCH2CH2N (CH3) 2, - CONHCH2N (CH3) 2, -NHCOCH2N (CH3) 2, -NHCOCH2NHCH3, metyl og etyl; (c) R<2>er H, metyl eller cyklopropyl og R2 er hydrogen; ellerR<2>ogR<2>' tas sammen for å danne en eventuelt substituert benzoring.
3. Forbindelse ifølge krav 2, hvori: (a) Rx og RY tas sammen med pyrimidingruppen for å danne et quinazolin (b)R<1>er en fenylring som kan være substituert med en eller flere substituenter valgt fra gruppen bestående av -Cl, -Br, -F, -CF3, -COOH, -COOMe, -NH2, -NHAc, -NHS02Me, - NHS02Et, NHS02(n-propyl), -NHS02(isopropyl), -NHCOEt, - NHCOCH2N(C02t-Bu) CH3. -NHCOCH2N (CH3) 2, -NHCO (cyklopropyl) , - NHCO(isopropyl), -NHCO(isobutyl), -NHCOCH2 (morfolin-4-yl) , -NHCOCH2CH2/morfolin-4-yl) , -NHCOCH2CH2CH2 (morfolin-4-yl) , - NHC02 (t-butyl) , -OMe, -0H, -CONHCH2CH2N (CH3) 2, - CONHCH2N (CH3) 2, -NHCOCH2N (CH3) 2, -NHCOCH2NHCH3, metyl og etyl; (c) R<2>er H, metyl eller cyklopropyl og R<2>' er hydrogen; ellerR<2>ogR<2>' tas sammen for å danne en eventuelt substituert benzoring.
4. Forbindelse ifølge krav 1, hvori forbindelsen har ett eller flere trekk valgt fra gruppen bestående av: (a) Rx og RY tas sammen for å danne en quinazolin-gruppe, (b)R<1>er naftalenylgruppe, 2-benzoimidazolyl eller 1-metyl-2-imidazolyl; og (c) R<2>er H, metyl eller cyklopropyl og R<2>' er hydrogen; ellerR<2>ogR<2>' tas sammen for å danne en eventuelt substituert benzoring.
5. Forbindelse ifølge krav 4, hvori: (a) Rx og RY tas sammen for å danne en benzoring, (b)R<1>er l-metyl-2-imidazolyl, (c) R<2>er H, metyl eller cyklopropyl og R<2>' er hydrogen.
6. Forbindelse ifølge krav 1, hvori forbindelsen har ett eller flere trekk valgt fra gruppen bestående av: (a) Rx og RY tas sammen med pyrimidingruppen for å danne en quinazolingruppe, (b)R<1>er en fenylring som kan være substituert med en eller flere substituenter valgt fra gruppen bestående av -Cl, -Br, -F, -CF3, -COOH, -COOMe, -NH2, -NHAc, -NHS02Me, - NHS02Et, NHS02(n-propyl), -NHS02(isopropyl), -NHCOEt, - NHCOCH2N(C02t-Bu) CH3. -NHCOCH2N (CH3) 2, -NHCO (cyklopropyl) , - NHCO(isopropyl), -NHCO(isobutyl), -NHCOCH2 (morfolin-4-yl) , -NHCOCH2CH2/morfolin-4-yl) , -NHCOCH2CH2CH2 (morfolin-4-yl) , - NHC02 (t-butyl) , -OMe, -0H, -CONHCH2CH2N (CH3) 2, - CONHCH2N (CH3) 2, -NHCOCH2N (CH3) 2, -NHCOCH2NHCH3, metyl og etyl; og (c) R<2>er metyl eller cyklopropyl og R<2>' er hydrogen; ellerR<2>ogR<2>' tas sammen for a danne en eventuelt substituert benzoring.
7. Forbindelse ifølge krav 6, hvori: (a) Rx og Ry tas sammen med pyrimidingruppen for å danne en quinazolingruppe; (b)R<1>er en fenylring som kan være substituert med en eller flere substituenter valgt fra gruppen bestående av -Cl, -Br, -F, -CF3, -COOH, -COOMe, -NH2, -NHAc, -NHS02Me, - NHS02Et, NHS02(n-propyl), -NHS02(isopropyl), -NHCOEt, - NHCOCH2N(C02t-Bu) CH3. -NHCOCH2N (CH3) 2, -NHCO (cyklopropyl) , - NHCO(isopropyl), -NHCO(isobutyl), -NHCOCH2 (morfolin-4-yl), -NHCOCH2CH2/morfolin-4-yl) , -NHCOCH2CH2CH2 (morfolin-4-yl) , - NHCO2 (t-butyl) , -OMe, -0H, -CONHCH2CH2N (CH3) 2, - CONHCH2N (CH3) 2, -NHCOCH2N(CH3) 2, -NHCOCH2NHCH3, metyl og etyl; og (c) R<2>er metyl eller cyklopropyl og R<2>' er hydrogen; ellerR<2>ogR<2>' tas sammen for å danne en eventuelt substituert benzoring.
8. Forbindelse ifølge ethvert av kravene 1-7 hvorR<2>er metyl.
9. Forbindelse ifølge ethvert av kravene 1-7 hvor R<2>er cyklopropyl.
10. Forbindelse valgt fra gruppen bestående av: (5-metyl-2if-pyrazol-3-yl) - (2-fenylsulfanyl-kinazolin-4-yl) - amin;
[2- (4-klorfenylsulfanyl) -kinazolin-4-yl] - (5-metyl-2if-pyra-zol-3-yl)-amin;
[2-(2,4-diklorfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin;
[2- (4-metoksyfenylsulfanyl) -kinazolin-4-yl] - (5-metyl-2if-py-razol-3-yl)-amin;
[2- (2-etylfenylsulfanyl) -kinazolin-4-yl] - (5-metyl-2i?-pyra-zol-3-yl)-amin;
{2-[2,4-bis(trifluormetyl)fenylsulfanyl]-kinazolin-4-yl'-(5-metyl-2H-pyrazol-3-yl) -amin;
[2- (2-klorfenylsulfanyl) -kinazolin-4-yl] - (5-metyl-2if-pyra-zol-3-yl)-amin;
[2- (2,3-diklorfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin;
[2- (3-klorfenylsulfanyl) -kinazolin-4-yl] - (5-metyl-2i?-pyra-zol-3-yl)-amin;
[2-(l-metylimidazol-2-ylsulfanyl)-kinazolin-4-yl]-(5-metyl-2ff-pyrazol-3-yl) -amin;
[2- (2-hydroksyf enylsulf anyl) -kinazolin-4-yl] - (5-metyl-2if-pyrazol-3-yl)-amin;
[2-(2,4-difluorfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin;
[2-(3,4-dimetoksyfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2if-pyrazol-3-yl) -amin;
[2- (3-metylf enylsulf anyl) -kinazolin-4-yl] - (5-metyl-2H'-pyra-zol-3-yl)-amin;
[2- (2-metoksyfenylsulfanyl) -kinazolin-4-yl] - (5-metyl-2if-py-razol-3-yl)-amin;
[2- (2-naf talenylsulfanyl) -kinazolin-4-yl] - (5-metyl-2if-pyra-zol-3-yl)-amin;
[2-(2,6-diklorfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin;
[2-(3,4-diklorfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin;
[2- (benzimidazol-2-ylsulfanyl) -kinazolin-4-yl] - (5-metyl-2if-pyrazol-3-yl)-amin;
[2- (2-aminof enylsulf anyl) -kinazolin-4-yl] - (5-metyl-2if-pyra-zol-3-yl)-amin;
(5-cyklopropyl-2if-pyrazol-3-yl) - (2-fenylsulfanyl-kinazolin-4-yl)-amin;
(5-cyklopropyl-2i?-pyrazol-3-yl) - [2- (3-metoksykarbonylfenyl-sulfanyl)-kinazolin-4-yl]-amin;
(5-cyklopropyl-2if-pyrazol-3-yl) - [2- (3-metylf enylsulf anyl) - kinazolin-4-yl]-amin;
(5-cyklopropyl-2if-pyrazol-3-yl) - [2- (3-metoksyfenylsulfanyl)-kinazolin-4-yl]-amin;
(5-cyklopropyl-2if-pyrazol-3-yl) - [2- (3, 4-dimetoksyfenylsul-fanyl) -kinazolin-4-yl]-amin;
[2-(3-karboksyfenylsulfanyl)-kinazolin-4-yl]-(5-cyklopropyl-2if-pyrazol-3-yl) -amin;
(5-cyklopropyl-2i?-pyrazol-3-yl) - [2- (naphtalen-2-ylsulfanyl)-kinazolin-4-yl]-amin;
(5-cyklopropyl-2if-pyrazol-3-yl) - [2- (2, 4-difluorfenylsulfa-nyl)-kinazolin-4-yl]-amin;
(5-cyklopropyl-2if-pyrazol-3-yl) - [2- (naftalen-2-ylsulfanyl) - 5,6,7,8-tetrahydrokinazolin-4-yl]-amin;
(5-cyklopropyl-2if-pyrazol-3-yl) - [2- (2, 3-diklorfenylsulf a-nyl)-kinazolin-4-yl]-amin;
[2-(3-klorfenylsulfanyl)-kinazolin-4-yl]-(5-cyklopropyl-2ff-pyrazol-3-yl)-amin;
[2- (2-klorfenylsulfanyl) -kinazolin-4-yl] - (5-cyklopropyl-2if-pyrazol-3-yl)-amin;
(5-cyklopropyl-2if-pyrazol-3-yl) - [2- (3, 4-dimetylfenylsulfa-nyl)-kinazolin-4-yl]-amin;
[2-(benzimidazol-2-ylsulfanyl)-kinazolin-4-yl]-(5-cyklopropyl-2if-pyrazol-3-yl) -amin;
(5-cyklopropyl-2i?-pyrazol-3-yl) - [2- (4-metoksykarbonylfenyl-sulfanyl)-kinazolin-4-yl]-amin;
[2-(4-acetamido-fenylsulfanyl)-kinazolin-4-yl]-(5-cyklopropyl-2i?-pyrazol-3-yl) -amin;
(5-cyklopropyl-2if-pyrazol-3-yl) - [2- (naftalen-l-ylsulfanyl) - kinazolin-4-yl]-amin;
[2- (4-acetamidof enylsulf anyl) -kinazolin-4-yl ] - (5-metyl-2if-pyrazol-3-yl)-amin;
[2-(4-metansulfonylamino-fenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2if-pyrazol-3-yl) -amin;
[2-(4-acetamidofenylsulfanyl)-7-metoksy-kinazolin-4-yl] -(5-metyl-2if-pyrazol-3-yl) -amin;
[2-(4-acetamidofenylsulfanyl)-8-(3-morfolin-4-yl-propoksy)-kinazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin;
[2-(4-metoksykarbonylfenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2if-pyrazol-3-yl) -amin;
[2- (4-karboksyf enylsulf anyl) -kinazolin-4-yl] - (5-metyl-2if-pyrazol-3-yl)-amin;
[2-(4-acetamidofenylsulfanyl)-8-metoksy-kinazolin-4-yl] -(5-metyl-2if-pyrazol-3-yl) -amin;
[2-(4-acetamidofenylsulfanyl)-7-(3-morfolin-4-yl-propoksy)-kinazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin;
[2- (4-bromfenylsulfanyl) -kinazolin-4-yl] - (5-metyl-2if-pyra-zol-3-yl)-amin;
[2- (3-bromfenylsulfanyl) -kinazolin-4-yl] - (5-metyl-2if-pyra-zol-3-yl)-amin;
[2-(4-isopropansulfonylamino-fenylsulfanyl)-kinazolin-4-yl] - (5-metyl-2ir-pyrazol-3-yl) -amin;
[2-(4-isobutyrylamino-fenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2i?-pyrazol-3-yl) -amin;
(5-metyl-2if-pyrazol-3-yl) - [2- (4-propionylamino-fenylsulfanyl) -kinazolin-4-yl]-amin;
[2-(4-cyklopropankarbonylamino-fenylsulfanyl)-kinazolin-4-yl] - (5-metyl-2ir-pyrazol-3-yl) -amin;
[2-(4-acetamido-fenylsulfanyl)-8-hydroksykinazolin-4-yl]-(5-metyl-2if-pyrazol-3-yl) -amin;
[2-(4-acetamido-fenylsulfanyl)-7-nitrokinazolin-4-yl]-(5-metyl-2if-pyrazol-3-yl) -amin;
(5-metyl-2if-pyrazol-3-yl) - {2 - [4 - (propan-1-sul f onylamino) - fenylsulfanyl]-kinazolin-4-yl'-amin;
[2-(4-etylsulfonylamino-fenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2if-pyrazol-3-yl) -amin;
[2-(4-acetamido-fenylsulfanyl)-7-hydroksyaminokinazolin-4-yl] - (5-metyl-2if-pyrazol-3-yl) -amin;
[2-(4-isobutankarbonylamino-fenylsulfanyl)-kinazolin-4-yl]-(5-metyl-2if-pyrazol-3-yl) -amin;
[2-(4-tert-butoksykarbonylamino-fenylsulfanyl)-kinazolin-4-yl] - (5-metyl-2i?-pyrazol-3-yl) -amin;
[2-(4-acetamido-fenylsulfanyl)-7-aminokinazolin-4-yl]-(5-metyl-2ir-pyrazol-3-yl) -amin;
(5-metyl-2#-pyrazol-3-yl) -{2- [4- (2-morfolin-4-yl-acetyla-mino)-fenylsulfanyl]-kinazolin-4-yl'-amin;
(5-cykloprpyl-2i?-pyrazol-3-yl) - [2- (4-metylsulfonylamino-fenylsulfanyl)-kinazolin-4-yl]-amin;
[2- (4-amino-fenylsulfanyl) -kinazolin-4-yl] - (5-metyl-2if-py-razol-3-yl)-amin;
[2- (4-acetamido-fenylsulfanyl) -kinazolin-4-yl] - (2ff-pyrazol-3-yl)-amin;
(5-metyl-2Jf-pyrazol-3-yl) -{2- [4- (4-morfolin-4-yl-butyryla-mino)-fenylsulfanyl]-kinazolin-4-yl'-amin;
(5-metyl-2Jf-pyrazol-3-yl) -{2- [4- (2-morfolin-4-yl-etylkarba-moyl)-fenylsulfanyl]-kinazolin-4-yl'-amin;
[8-metoksy-2-(4-metylsulfonylamino-fenylsulfanyl)-kinazo-lin-4-yl] - (5-metyl-2if-pyrazol-3-yl) -amin;
{2-[4-(2-dimetylamino-etylkarbamoyl)-fenylsulfanyl]-kinazo-lin-4-yl'-(5-metyl-2H-pyrazol-3-yl)-amin;
{2-[4-(2-dimetylamino-acetylamino)-fenylsulfanyl]-kinazo-lin-4-yl' - (5-metyl-2if-pyrazol-3-yl) -amin;
[8-hydroksy-2-(4-metylsulfonylamino-fenylsulfanyl)-kinazo-lin-4-yl] - (5-metyl-2if-pyrazol-3-yl) -amin;
{2-[4-(3-dimetylamino-propylkarbamoyl)-fenylsulfanyl]-kina-zolin-4-yl'- (5-metyl-2if-pyrazol-3-yl) -amin;
{2-[4-(3-dimetylamino-propionylamino)-fenylsulfanyl]-kina-zolin-4-yl'- (5-metyl-2H-pyrazol-3-yl) -amin;
[2-(4-acetamido-fenylsulfanyl)-8-metoksy-kinazolin-4-yl]-(5-cyklopropyl-2if-pyrazol-3-yl) -amin;
[2-(4-acetamidofenylsulfanyl)-8-(3-dimetylamino-propoksy)-kinazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin;
[2-(4-acetamidofenylsulfanyl)-7-hydroksy-kinazolin-4-yl]-(5-metyl-2H-pyrazol-3-yl)-amin;
[2-(4-acetamidofenylsulfanyl)-7-(3-dimetylamino-propoksy)-kinazolin-4-yl] - (5-metyl-2H'-pyrazol-3-yl) -amin;
(2-{4-[2-(tert-butoksykarbonyl-metyl-amino)-acetylamino]-fenylsulfanyl'-kinazolin-4-yl) - (5-metyl-2ff-pyrazol-3-yl) - amin;
{2-[4-(2-metylamino-acetylamino)-fenylsulfanyl]-kinazolin-4-yl' - (5-metyl-2ff-pyrazol-3-yl) -amin;
[2-(4-acetamidofenylsulfanyl)-8-fluor-kinazolin-4-yl]-(5-metyl-2ir-pyrazol-3-yl) -amin; og (lH-indazol-3-yl)-(2-fenylsulfanyl-kinazolin-4-yl)-amin.
11. Sammensetning omfattende en forbindelse ifølge et hvilket som helst av kravene 1-8, og en farmasøytisk akseptabel bærer.
12. Sammensetning ifølge krav 11, hvori sammensetningen er formulert for administrasjon til et menneske.
13. Fremgangsmåte for å hemme Aurora-2-, GSK-3-, CDK-2-eller Src-aktivitet i en biologisk prøve omfattende trinnet å kontakte den biologiske prøve med en forbindelse ifølge et hvilket som helst av kravene 1-8.
14. Anvendelse av forbindelse ifølge ethvert av kravene 1-8 for fremstilling av et medikament til behandling av kreft så som tarm-, bryst-, mage- eller ovariekreft.
15. Anvendelse av sammensetning ifølge krav 11 eller 12 for fremstiling av et medikament til behandling av en sykdom valgt fra gruppen bestående av diabetes, Alzheimers sykdom, Huntingtons Sykdom, Parkinsons Sykdom, AIDS-assosiert demens, amyotrofisk lateralsklerose (AML), multippel sklerose (MS), schizofreni, kardiomycett hypertrofi, reper-fusjon/iskemi eller skallethet.
16. Anvendelse ifølge krav 15, hvori sykdommen er diabetes .
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US25788700P | 2000-12-21 | 2000-12-21 | |
US28694901P | 2001-04-27 | 2001-04-27 | |
PCT/US2001/051120 WO2002059111A2 (en) | 2000-12-21 | 2001-12-19 | Pyrazole compounds useful as protein kinase inhibitors |
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NO20032703A NO328501B1 (no) | 2000-12-21 | 2003-06-13 | Pyrazolforbindelser samt anvendelse derav for fremstilling av medikamenter til behandling av lidelser assosiert med Aurora-2-, GSK-3- eller Src-aktivitet |
NO20032736A NO20032736L (no) | 2000-12-21 | 2003-06-16 | Pyrazolforbindelser nyttige som proteinkinaseinhibitorer |
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NO20032703A NO328501B1 (no) | 2000-12-21 | 2003-06-13 | Pyrazolforbindelser samt anvendelse derav for fremstilling av medikamenter til behandling av lidelser assosiert med Aurora-2-, GSK-3- eller Src-aktivitet |
NO20032736A NO20032736L (no) | 2000-12-21 | 2003-06-16 | Pyrazolforbindelser nyttige som proteinkinaseinhibitorer |
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