ME02463B - Biciklični heterociklični derivati kao inhibitori fgfr kinaze za primjenu u terapiji - Google Patents

Biciklični heterociklični derivati kao inhibitori fgfr kinaze za primjenu u terapiji

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Publication number
ME02463B
ME02463B MEP-2016-133A MEP13316A ME02463B ME 02463 B ME02463 B ME 02463B ME P13316 A MEP13316 A ME P13316A ME 02463 B ME02463 B ME 02463B
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compound
crxry
alkyl
heterocyclyl group
group
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MEP-2016-133A
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German (de)
English (en)
French (fr)
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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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Publication of ME02463B publication Critical patent/ME02463B/me

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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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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Claims (17)

1.Jedinjenje formule (I)pri čemusvaki X1, X2 i X3 je nezavisno izabran između ugljenika ili azota, tako da najmanje jedan od X1X3 predstavlja azot;X4 predstavlja CR3, azot, NH ili C=O;X5 predstavlja CR6, azot, NH ili C=O;uz uslov da više od tri X1X5 ne predstavljaju azot;·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 sistemu dvostruka veza;R3 predstavlja vodonik, 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 opcioni biti zamenjene sa jednom ili više Ra grupa;A predstavlja aromatičnu ili nearomatičnu karbociklil ili heterociklil grupu koja može biti opciono supstituisana sa 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 opciono supstituisana sa jednom ili više (npr. 1, 2 ili 3) Ra grupa;R4 i R5 nezavisno predstavljaju vodonik, 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 pomenute C1-6 alkil, C2-6 alkenil, C2-6 alkinil, C3-8 cikloalkil, C3-8 cikloalkenil, aril i heterociklil grupe mogu biti opciono supstituisane sa jednom ili više (npr. 1, 2 ili 3) Ra grupa;Rx, Ry i Rz nezavisno predstavljaju vodonik, 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 Rb i Rw predstavljaju –O-Ra, pri čemu Q predstavlja direktnu vezu i Ra predstavlja -(CH2)n-O-Rx, -(CH2)s-NRxRy ili-(CH2)s-NRx-(CH2)s-SO2Ry; iliRv predstavlja -Y-karbociklil ili -Z-heterociklil grupu a Rw predstavlja vodonik ili Rb , ili Rw predstavlja vodonik ili Rb i Rw predstavlja -Y-karbociklil ili-Z-heterociklil grupu; pri čemu su pomenute karbociklil i heterociklil grupe opciono supstituisane 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 opciono biti supstituisane sa jednom ili više Rx grupa;Rb predstavlja -Q-Ra grupu ili -Y-karbociklil ili -Z-heterociklil grupu pri čemu pomenute karbociklil i heterociklil grupe mogu opciono biti supstituisane sa jednom ili više (npr. 1, 2 ili 3) Ra grupa;Y i Z nezavisno predstavljaju direktnu 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 direktnu vezu;m i n nezavisno predstavljaju ceo broj od 1-4;s i t nezavisno predstavljaju ceo broj od 0-4;q predstavlja ceo broj od 0-2;ili njegovu farmaceutski prihvatljivu so, tautomer, N-oksid ili solvat.
2.Jedinjenje kao što je definisano u zahtjevu 1, pri čemu A predstavlja fenil grupu opciono supstituisanu sa jednom ili više Ra grupa, na primer, opciono supstituisanu na poziciji 3.
3.Jedinjenje kao što je definisano u zahtjevu 2, pri čemu A predstavlja nesupstituisani fenil.
4.Jedinjenje kao što je definisano u bilo kom od prethodnih zahtjeva, pri čemu R1 predstavlja -NHCONR4R5, na primer, -NHCONHCH2CF3
5.Jedinjenje kao što je definisano u bilo kom od prethodnih zahtjeva, pri čemu Rv i/ili Rw predstavlja Rb i Rb predstavlja -Y-karbociklil ili -Z-heterociklil grupu pri čemu je pomenutea karbociklil i heterociklil grupa supstituisana sa 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-SO2NRxRy ili -NH-C(=NH)-NH2; pri čemu pomenuti C1-6alkil, C2-6alkenil, C2-6 alkinil, C3-8cikloalkil, C3-8cikloalkenil, aril i heterociklil grupe mogu opciono biti supstituisane sa jednom ili više Rx grupa.
6.Jedinjenje kao što je definisano u bilo kom od zahtjeva 1 do 4, pri čemu Rv predstavlja -Y-karbociklil ili -Z-heterociklil grupu i Rw predstavlja vodonik ili Rb , ili Rv predstavlja vodonik ili Rb i Rw predstavlja -Y-karbociklil ili -Z-heterociklil grupu.
7.Jedinjenje kao što je definisano u bilo kom od zahtjeva 1 do 4, pri čemu (i)Rv predstavlja vodonik i Rw predstavlja -O-Ra and Q predstavlja direktnu 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 direktnu vezu i Ra predstavlja C1-6 alkil i Rw predstavlja -Z-heterociklil grupu pri čemu pomenuta heterociklil grupa može biti opciono supstituisana sa jednom ili više (npr. 1, 2 ili 3) Ra grupa, ili (ii)Rv predstavlja -Y-karbociklil grupu i Rw predstavlja vodonik; ili (iii)Rv predstavlja -Y-karbociklil grupu i Rw predstavlja -Q-Ra i Q predstavlja direktnu vezu i Ra predstavlja C1-6alkil ili -(CH2)n-O-Rx.
8.Jedinjenje kao što je definisano u zahtjevu 1, pri čemu Rv predstavlja vodonik i Rw predstavlja -Z-heterociklil grupu pri čemu pomenuta heterociklil grupa može biti opciono supstituisana sa jednom ili više (npr. 1, 2 ili 3) Ra grupa, na primer supstituisana sa jednom ili više C1-6alkil, -O-Rx, -(CH2)n-O-Rx, -(CH2)s-SO2-NRxRy,-(CH2)sNRxRy ili -NH-C(=NH)-NH2 grupom.
9.Jedinjenje kao što je definisano u zahtjevu 8, pri čemu Z predstavlja direktnu vezu,-(CRxRy)n, -(CRxRy)s-NRx ili -(CRxRy)s-CO-.
10.Jedinjenje kao što je definisano u zahtjevu 8, pri čemu Rw je -(CRxRy)n-heterociklil, pri čemu je heterociklil grupa heterociklil group koja sadrži azot.
11.Jedinjenje kao što je definisano u zahtjevu 7, pri čemu (i) Rv predstavlja -Q-Ra pri čemu Q predstavlja direktnu vezu i Ra predstavlja C1-6 alkil, Rw predstavlja –Z-heterociklil grupu pri čemu pomenuta heterociklil grupa može biti opciono supstituisana sa jednom ili više (npr. 1, 2 ili 3) Ra grupa i Z predstavlja -(CRxRy)n-, ili (ii) Rv predstavlja -Y-karbociklil grupu, Rw predstavlja vodonik i Y je direktna veza ili -(CRxRy)n-, ili (iii) Rv predstavlja -Y-karbociklil grupu, Rwpredstavlja -Q-Ra, Q predstavlja direktnu vezu, Ra predstavlja C1-6alkil ili -(CH2)n-O-Rx, i Y je direktna veza ili -(CRxRy)n-.
12.Jedinjenje kao što je definisano u zahtjevu 1 pri čemu su X1-X5 onakvi kao što je definisano sledećim prstenastim sistemom:
13.Jedinjenje kao što je definisano u bilo kom od prethodnih zahtjeva, pri čemu je jedinjenje izabrano između: jedinjenje 1-1 jedinjenje 1-2 jedinjenje 1-3 jedinjenje 1-4 jedinjenje 1-5 jedinjenje 1-6 jedinjenje 1-7 jedinjenje 1-8 jedinjenje 1-9 jedinjenje 1-10 jedinjenje 1-11 jedinjenje 1-12 jedinjenje 1-13 jedinjenje 1-14 jedinjenje 1-15 jedinjenje 1-16 jedinjenje 1-17 jedinjenje 1-18, (E) jedinjenje 1-19 jedinjenje 1-20, (E) jedinjenje 1-24 jedinjenje 1-27 jedinjenje 1-28 jedinjenje 1-29 jedinjenje 1-30 jedinjenje 1-31, 90:10 E:Z smeša jedinjenje 1-32, (E) jedinjenje 1-33, (Z) jedinjenje 1-34 jedinjenje 1-35 jedinjenje 1-36 jedinjenje 1-37 jedinjenje 1-38 jedinjenje 1-39 jedinjenje 1-40 jedinjenje 1-42 jedinjenje 1-43 jedinjenje 1-44, (E) jedinjenje 1-45, (E) jedinjenje 1-46, (E) jedinjenje 1-47, (E) jedinjenje 1-48 jedinjenje 1-49 jedinjenje 1-50 jedinjenje 1-51 jedinjenje 1-52 jedinjenje 1-53 jedinjenje 1-54 jedinjenje 1-55 jedinjenje 1-56 jedinjenje 1-57 jedinjenje 1-58 jedinjenje 1-59 jedinjenje 1-60 jedinjenje 1-61 jedinjenje 1-62 jedinjenje 1-63 jedinjenje 1-64, (Z) jedinjenje 1-65, (E) jedinjenje 1-66, (E) jedinjenje 1-67, (E/Z)
14.Jedinjenje kao što je definisano u bilo kom od zahtjeva 1 do 13 ili njegova farmaceutski prihvatljiva so ili solvat.
15.Farmaceutska kompozicija koja sadrži jedinjenje formule (I) kao što je definisano u bilo kom od zahtjeva 1 do 14.
16.Jedinjenje kao što je definisano u bilo kom od zahtjeva 1 do 14: (i) za primenu u terapiji, ili (ii) za primenu u profilaksi ili lečenju bolesti ili stanja izabranih između multiplog mijeloma, mijeloproliferativnih poremećaja, kancera endometrijuma, kancera prostate, kancera mokraćne bešike, kancera pluća, kancera jajnika, kancera dojke, kancera želuca, kolorektalnog kancera, i oralnog karcinoma skvamoznih ćelija, ili (iii) za primenu u profilaksi ili lečenju kancera.
17. Primena jedinjenja kao što je definisano u bilo kom od zahtjeva 1 do 14 za proizvodnju leka za profilaksu ili lečenje kancera. 1
MEP-2016-133A 2009-04-15 2010-04-15 Biciklični heterociklični derivati kao inhibitori fgfr kinaze za primjenu u terapiji ME02463B (me)

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

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