HRP20160725T1 - Biciklični heterociklični derivati kao inhibitori fgfr kinaze za primjenu u terapiji - Google Patents

Biciklični heterociklični derivati kao inhibitori fgfr kinaze za primjenu u terapiji Download PDF

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HRP20160725T1
HRP20160725T1 HRP20160725TT HRP20160725T HRP20160725T1 HR P20160725 T1 HRP20160725 T1 HR P20160725T1 HR P20160725T T HRP20160725T T HR P20160725TT HR P20160725 T HRP20160725 T HR P20160725T HR P20160725 T1 HRP20160725 T1 HR P20160725T1
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heterocyclyl group
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Gordon Saxty
Valerio Berdini
Eddy Jean Edgard Freyne
Alexandra Papanikos
Pascal Benderitter
Werner Constant Johan Embrechts
Berthold Wroblowski
Rhalid Akkari
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Astex Therapeutics Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Claims (17)

1. Spoj formule (I) [image] pri čemu svaki X1, X2 i X3 je neovisno izabran između ugljika ili dušika, tako da barem jedan od X1X3 predstavlja dušik; X4 predstavlja CR3, dušik, NH ili C=O; X5 predstavlja CR6, dušik, NH ili C=O; uz uvjet da više od tri X1X5 ne predstavljaju dušik; predstavlja jednostruku ili dvostruku vezu, tako da kada X5 predstavlja C=O, X4 i X5 su spojeni jednostrukom vezom i tako da je bar jedna veza u 5-članom prstenastom sustavu dvostruka veza; R3 predstavlja vodik, halogen, C1-6 alkil, C2-6 alkenil, C2-6 alkinil, C1-6 alkoksi, C3-6 cikloalkil, C3-6 cikloalkenil, cijano, haloC1-6 alkil ili haloC1-6 alkoksi, amino, ili C1-6 alkilamino; R6 predstavlja halogen, vodonik, C1-6 alkil, C1-6 alkoksi, C2-6 alkenil, C2-6 alkinil, ,-C≡N, C3-8 cikloalkil, C3-8 cikloalkenil, -NHSO2Rw, -CH=N-ORw ili 3-6 članu monocikličnu heterociklil grupu pri čemu svaka C1-6 alkil, C2-6 alkenil, C2-6 alkinil, C1-6 alkoksi i heterociklil grupa mogu opcijski biti zamjenjene s jednom ili više Ra grupa; A predstavlja aromatičnu ili nearomatičnu karbociklil ili heterociklil grupu koja može biti opcijski supstituirana s jednom ili više (npr. 1, 2 ili 3) Ra grupa; R1 predstavlja -NHCONR4R5, -NHCOOR4, -NH-CO-(CH2)n-NR4R5, -NH-(CH2)n-CONR4R5, -NH-CO-(CH2)n-COOR4, -NH-CO-(CH2)n-CSOR4, -NHSO2R4, NHSO2NR4R5, -NHCSNR4R5, -NHCOR4, -NHCSR4, -NHCSSR4, -NHC(=NR4)NR4R5, -NHC(=N-CN)NR4R5, -NHC(=NR4)R5, -NH-C(=NH)-NH-CO-R4, -NHCSOR4 ili -NHCOSR4 ili NH-heterociklil grupu pri čemu heterociklil grupa predstavlja tiadiazolil ili oksadiazolil i heterociklil grupa može biti opcijski supstituirana s jednom ili više (npr. 1, 2 ili 3) Ra grupa; R4 i R5 neovisno predstavljaju vodik, C1-6 alkil, C2-6 alkenil, C2-6 alkinil, C3-8 cikloalkil, C3-8 cikloalkenil, C1-6 alkanol, haloC1-6 alkil, -(CH2)n-NRxRy, -(CH2)s-COOR2, -(CH2)n-O-(CH2)m-OH, -(CH2)n-aril, -(CH2)n-O-aril, -(CH2)n-heterociklil ili - (CH2)n-O-heterociklil, pri čemu spomenute C1-6 alkil, C2-6 alkenil, C2-6 alkinil, C3-8 cikloalkil, C3-8 cikloalkenil, aril i heterociklil grupe mogu biti opcijski supstituiran s jednom ili više (npr. 1, 2 ili 3) Ra grupa; Rx, Ry i Rz neovisno predstavljaju vodik, C1-6 alkil, C2-6 alkenil, C2-6 alkinil, C1-6 alkanol, -COOC1-6 alkil, hidroksi, C1-6 alkoksi, haloC1-6 alkil, -(CH2)n-OH, -(CH2)n-O-C1-6alkil, -CO-(CH2)n-C1-6alkoksi, -(CH2)s-CN, -C1-6alkilamino, -C1-6 alkil-N(C1-6 alkil)2, -C1-6 alkil-NH(C1-6 alkil), -(CH2)s-C3-8 cikloalkil, amino, -aminoC1-6alkil,-amino(C1-6 alkil)2, -(CH2)s-NH-SO2-N(C1-6alkil)q, -(CH2)s-N(C1-4alkil)-SO2-N(C1-6alkil)q, -(CH2)s-O-C(=O)-C1-4alkil-N(C1-6alkil)q, -(CH2)s-C3-8cikloalkenil, ili kada je vezan za atom azota ili ugljenika Rx i Ry mogu obrazovati prsten; R2 predstavlja -CRv=N-ORw grupu; Rv predstavlja vodonik ili Rbi Rw predstavljaju –O-Ra, pri čemu Q predstavlja izravnu vezu i Ra predstavlja -(CH2)n-O-Rx, -(CH2)s-NRxRy ili-(CH2)s-NRx-(CH2)s-SO2Ry; ili Rv predstavlja -Y-karbociklil ili -Z-heterociklil grupu a Rw predstavlja vodik ili Rb , ili Rw predstavlja vodik ili Rbi Rw predstavlja -Y-karbociklil ili-Z-heterociklil grupu; pri čemu su spomenute karbociklil i heterociklil grupe opcijski supstituirane jednom ili više (npr. 1, 2 ili 3) Ra grupa; Ra predstavlja halogen, C1-6alkil, C2-6alkenil, C2-6alkinil, C3-8cikloalkil, C3-8cikloalkenil, -ORx, -(CH2)n-O-Rx,-O-(CH2)n-ORx, haloC1-6alkil, haloC1-6alkoksi, C1-6alkanol, =O, =S, nitro, -Si(Rx)4, -(CH2)s-CN, -S-Rx, -SO-Rx, -SO2-Rx, -CORx, aril, heterociklil grupu, -(CRxRy)s-COORz, -(CRxRy)s-CONRxRy, -(CH2)s-NRxRy, -(CH2)s-NRxCORy, -(CH2)s-NRx-(CH2)s-SO2-Ry, -NRx-(CH2)s-Rz, -(CH2)s-O-C(=O)-C1-4alkil-NRxRy, -(CH2)s-NRx-(CH2)n-O-C(=O)-Rz, -(CRxRy)-O-C(=O)-Rz, -(CH2)s-NH-SO2-NRxRy, -OCONRxRy, -(CH2)s-NRxCO2Ry, -O-(CH2)s-CRxRy-(CH2)t-ORz, -(CH2)s-SO2NRxRy ili-NH-C(=NH)-NH2 grupe; pri čemu pomenuti C1-6alkil, C2-6 alkenil, C2-6alkinil, C3-8cikloalkil, C3-8 cikloalkenil, aril i heterociklil grupe mogu opcijski biti supstituirane s jednom ili više Rx grupa; Rbpredstavlja -Q-Ra grupu ili -Y-karbociklil ili -Z-heterociklil grupu pri čemu spomenute karbociklil i heterociklil grupe mogu opcijski biti supstituirane s jednom ili više (npr. 1, 2 ili 3) Ra grupa; Y i Z neovisno predstavljaju izravnu vezu, -CO-(CRxRy)s-, -(CRxRy)s-CO-, -COO-, -(CRxRy)n-, -NRx-(CRxRy)s-, -(CRxRy)s-NRx-, -CONRx-, -NRxCO-, -SO2NRx-, -NRxSO2-,-NRxCONRy-, -NRxCSNRy-, -O-(CRxRy)s-, -(CRxRy)s-O-, S-, -SO- ili -(CRxRy)s-SO2-; Q predstavlja NRx, S(O)q ili izravnu vezu; m i n neovisno predstavljaju cijeli broj od 1-4; s i t neovisno predstavljaju cijeli broj od 0-4; q predstavlja cijeli broj od 0-2; ili njegovu farmaceutski prihvatljivu sol, tautomer, N-oksid ili solvat.
2. Spoj kao što je definirano u zahtjevu 1, pri čemu A predstavlja fenil grupu opcionalno supstituiranu s jednom ili više Ra grupa, na primer, opciono supstituisanu na poziciji 3.
3. Spoj kao što je definirano u zahtjevu 2, pri čemu A predstavlja nesupstituirani fenil.
4. Spoj kao što je definirano u bilo kojem od prethodnih zahtjeva, pri čemu R1 predstavlja -NHCONR4R5, na primjer, -NHCONHCH2CF3
5. Spoj kao što je definirano u bilo kojem od prethodnih zahtjeva, pri čemu Rv i/ili Rw predstavlja Rb i Rb predstavlja -Y-karbociklil ili -Z-heterociklil grupu pri čemu je spomenuta karbociklil i heterociklil grupa supstituirana s jednom ili više (npr. 1, 2 ili 3) Ra grupa i Ra predstavlja halogen, C1-6alkil, C2-6alkenil, C2-6alkinil, C3-8cikloalkil, C3-8cikloalkenil, -ORx, -(CH2)n-O-Rx, -O-(CH2)n-ORx, haloC1-6alkil, haloC1-6alkoksi, C1-6alkanol, =O, =S, nitro, -Si(Rx)4, -(CH2)s-CN, -S-Rx, -SO-Rx, -SO2-Rx, aril, heterociklil grupu, -(CRxRy)s-CONRxRy, -(CH2)s-NRxRy, -(CH2)s-NRxCORy,-(CH2)s-NRx-(CH2)s-SO2-Ry, -NRx-(CH2)s-Rz, -(CH2)s-O-C(=O)-C1-4alkil-NRxRy, -(CH2)s-NRx-(CH2)n-O-C(=O)-Rz, -(CRxRy)-O-C(=O)-Rz, -(CH2)s-NH-SO2-NRxRy,-OCONRxRy, -(CH2)s-NRxCO2Ry, -O-(CH2)s-CRxRy-(CH2)t-ORz, -(CH2)s-SO2NRxRyili -NH-C(=NH)-NH2; pri čemu spomenuti C1-6alkil, C2-6alkenil, C2-6alkinil, C3-8cikloalkil, C3-8cikloalkenil, aril i heterociklil grupe mogu opcijski biti supstituirane s jednom ili više Rxgrupa.
6. Spoj kao što je definirano u bilo kojem od zahtjeva 1 do 4, pri čemu Rv predstavlja -Y-karbociklil ili -Z-heterociklil grupu i Rw predstavlja vodik ili Rb , ili Rv predstavlja vodik ili Rb i Rw predstavlja -Y-karbociklil ili -Z-heterociklil grupu.
7. Spoj kao što je definirano u bilo kojem od zahtjeva 1 do 4, pri čemu (i) Rv predstavlja vodik i Rw predstavlja -O-Ra i Q predstavlja izravnu vezu i Ra predstavlja : -(CH2)n-O-Rx; -(CH2)s-NRxRy; ili -(CH2)s-NRx-(CH2)s-SO2Ry, ili (ii) Rv predstavlja -Q-Ra pri čemu Q predstavlja izravnu vezu i Ra predstavlja C1-6alkil i Rw predstavlja -Z-heterociklil grupu pri čemu spomenuta heterociklil grupa može biti opcijski supstituirana s jednom ili više (npr. 1, 2 ili 3) Ra grupa, ili (ii) Rv predstavlja -Y-karbociklil grupu i Rw predstavlja vodik; ili (iii) Rv predstavlja -Y-karbociklil grupu i Rw predstavlja -Q-Ra i Q predstavlja izravnu vezu i Ra predstavlja C1-6alkil ili -(CH2)n-O-Rx.
8. Spoj kao što je definirano u zahtjevu 1, pri čemu Rv predstavlja vodik i Rw predstavlja -Z-heterociklil grupu pri čemu spomenuta heterociklil grupa može biti opcijski supstituirana s jednom ili više (npr. 1, 2 ili 3) Ra grupa, na primjer supstituirana s jednom ili više C1-6alkil, -O-Rx, -(CH2)n-O-Rx, -(CH2)s-SO2-NRxRy,-(CH2)sNRxRyili -NH-C(=NH)-NH2 grupom.
9. Spoj kao što je definirano u zahtjevu 8, pri čemu Z predstavlja izravnu vezu,-(CRxRy)n, -(CRxRy)s-NRxili -(CRxRy)s-CO-.
10. Spoj kao što je definirano u zahtjevu 8, pri čemu Rw je -(CRxRy)n-heterociklil, pri čemu je heterociklil grupa heterociklil grupa koja sadrži dušik.
11. Spoj kao što je definirano u zahtjevu 7, pri čemu (i) Rv predstavlja -Q-Rapri čemu Q predstavlja izravnu vezu i Rapredstavlja C1-6alkil, Rw predstavlja –Z-heterociklil grupu pri čemu spomenuta heterociklil grupa može biti opcijski supstituirana s jednom ili više (npr. 1, 2 ili 3) Ragrupa i Z predstavlja -(CRxRy)n-, ili (ii) Rvpredstavlja -Y-karbociklil grupu, Rwpredstavlja vodonik i Y je izravna veza ili -(CRxRy)n-, ili (iii) Rvpredstavlja a-Y-karbociklil grupu, Rwpredstavlja -Q-Ra, Q predstavlja izravnu vezu, Rapredstavlja C1-6alkil ili -(CH2)n-O-Rx, i Y je izravna veza ili -(CRxRy)n-.
12. Spoj kao što je definirano u zahtjevu 1 pri čemu su X1-X5 onakvi kao što je definirano slijedećim prstenastim sistemom: [image]
13. Spoj kao što je definirano u bilo kojem od prethodnih zahtjeva, pri čemu je spoj izabran između: [image] [image] [image] [image] [image] [image] [image]
14. Spoj kao što je definirano u bilo kojem od zahtjeva 1 do 13 ili njegova farmaceutski prihvatljiva sol ili solvat.
15. Farmaceutska kompozicija koja sadrži spoj formule (I) kao što je definirano u bilo kojem od zahtjeva 1 do 14.
16. Spoj kao što je definirano u bilo kojem od zahtjeva 1 do 14: (i) za primjenu u terapiji, ili (ii) za primjenu u profilaksi ili liječenju bolesti ili stanja izabranih između multiplog mijeloma, mijeloproliferativnih poremećaja, raka endometrija, raka prostate, raka mokraćnog mjehura, raka pluća, raka jajnika, raka dojke, raka želuca, kolorektalnog raka, i oralnog raka skvamoznih stanica, ili (iii) za primjenu u profilaksi ili liječenju raka.
17. Primjena spoja kao što je definirano u bilo kojem od zahtjeva 1 do 14 za proizvodnju lijeka za profilaksu ili liječenje raka.
HRP20160725TT 2009-04-15 2016-06-24 Biciklični heterociklični derivati kao inhibitori fgfr kinaze za primjenu u terapiji HRP20160725T1 (hr)

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US16948709P 2009-04-15 2009-04-15
GBGB0906472.6A GB0906472D0 (en) 2009-04-15 2009-04-15 New compounds
EP10718659.5A EP2419427B1 (en) 2009-04-15 2010-04-15 Bicyclic heterocyclyl derivatives as fgfr kinase inhibitors for therapeutic use
PCT/GB2010/050617 WO2010119284A1 (en) 2009-04-15 2010-04-15 Bicyclic heterocyclyl derivatives as fgfr kinase inhibitors for therapeutic use

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