HRP20191821T1 - Antiproliferativni spojevi i načini njihove uporabe - Google Patents

Antiproliferativni spojevi i načini njihove uporabe Download PDF

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HRP20191821T1
HRP20191821T1 HRP20191821TT HRP20191821T HRP20191821T1 HR P20191821 T1 HRP20191821 T1 HR P20191821T1 HR P20191821T T HRP20191821T T HR P20191821TT HR P20191821 T HRP20191821 T HR P20191821T HR P20191821 T1 HRP20191821 T1 HR P20191821T1
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methyl
dioxopiperidin
oxoisoindolin
difluoro
acetamide
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Joshua Hansen
Matthew Daniel Correa
Raj Raheja
Antonia Lopez-Girona
Hon-Wah Man
George W. Muller
Ehab M. Khalil
Kyle Macbeth
Brian E. Cathers
Michael POURDEHNAD
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Celgene Corporation
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Claims (25)

1. Spoj formule I: ili njegov enantiomer ili smjesa enantiomera ili njegova farmaceutski prihvatljiva sol, solvat, hidrat, kokristal, klatrat ili polimorf, naznačen time, da: R1 opcijski supstituirani monociklički cikloalkil, proizvoljno supstituirani monociklički aril, proizvoljno supstituirani monociklički heteroaril ili opcionalno supstituirani monociklički heterociklil; R2 i R3 su svaki halo; pri čemu su supstituenti na R1, kad su prisutni, jedna do tri skupine Q, gdje je svaki Q neovisno alkil, halo, haloalkil, okso, opcijski supstituirani monociklički cikloalkil, opcionalno supstituirani monociklički cikloalkilalkil, opcionalno supstituirani monociklički heterociklil, opcionalno supstituirani monociklički heterociklilalkil, opcijski supstituirani monociklički aril, opcijski supstituirani monociklički heteroaril, -R4OR5, -R4O-R4OR5, -R4N(R6)(R7), -R4SR5, -R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), -C(J)R9 or R4S(O)tR8; pri čemu su supstituenti na Q, kada su prisutni u jednoj do 3 skupine Qa, pri čemu je svaki Qa je nezavisno alkil, halo, haloalkil, alkoksialkil, okso, hidroksil ili alkoksi; svaki R4 je nezavisno alkilen, alkenilen ili izravna veza; svaki R5 je nezavisno vodik, alkil, haloalkil, hidroksialkil, alkoksialkil, monociklički cikloalkil, monociklički aril, monociklički heteroaril, monociklički heterociklil ili monociklički heterociklilalkil, gdje su alkil, haloalkil, hidroksialkil, alkoksialkil, cikloalkil, aril, heteroaril, heterociklil ili heterociklilalkil skupine u R5 svaka od njih je neovisno opcijski supstituirana jednom do tri grupe Q1, gdje je svaki Q1 neovisno alkil, haloalkil ili halo; R6 i R7 su odabrani kako slijedi: i) R6 i R7 su svaki nezavisno vodik ili alkil; ili ii) R6 i R7 zajedno s dušikovim atomom na kojem su supstituirani tvore 5 ili 6-člani heterociklilni ili heteroarilni prsten, opcijski supstituiran s jednim ili dva halo, alkila ili haloalkila; R8 je alkil, haloalkil, or hidroksialkil; R9 je alkil ili aril; J je O ili S; i t je 1 ili 2.
2. Spoj sukladno zahtjevu 1, pri čemu je R1 opcionalno supstituirani monociklički aril.
3. Spoj sukladno zahtjevu 1 s formulom II: ili njegov enantiomer ili smjesa enantiomera ili njegova farmaceutski prihvatljiva sol, solvat, hidrat, kokristal, klatrat ili polimorf, naznačen time, da: R1 opcijski supstituirani monociklički cikloalkil, proizvoljno supstituirani monociklički aril, proizvoljno supstituirani monociklički heteroaril ili opcijski supstituirani monociklički heterociklil; gdje supstituenti na R1, kada su prisutni, predstavljaju jednu do tri grupe Q, pri čemu je svaki Q neovisno alkil, halo, haloalkil, opcijski supstituirani monociklički cikloalkil, opcionalno supstituirani monociklički cikloalkilalkil, opcijski supstituirani monociklički aril, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) ili R4OR4C(J)N(R6)(R7); J je O ili S; svaki R4 je nezavisno alkilen, alkenilen ili izravna veza; svaki R5 je nezavisno vodik, alkil, haloalkil ili hidroksialkil; i R6 i R7 su odabrane kako slijedi: i) R6 i R7 svaki od njih nezavisno vodik ili alkil; ili ii) R6 i R7 zajedno s dušikovim atomom na kojem su supstituirani tvore 5 ili 6-člani heterociklilni ili heteroarilni prsten, opcijski supstituiran s jednim ili dva halo, alkila ili haloalkila.
4. Spoj sukladno zahtjevu 1, pri čemu je R1 opcionalno supstituirani monociklički aril; gdje su supstitienti na R1, kada su prisutni, jedna do tri skupine Q, gdje je svaki Q neovisno alkil, halo, haloalkil, proizvoljno supstituirani monociklički cikloalkil, proizvoljno supstituirani monociklički cikloalkilalkil, proizvoljno supstituirani monociklički aril, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) ili R4OR4C(J)N(R6)(R7); J je O ili S; svaki R4 je nezavisno alkilen, alkenilen ili izravna veza; svaki R5 je nezavisno vodik, alkil, haloalkil ili hidroksialkil; i R6 i R7 su odabrani kako slijedi: i) R6 i R7 svaki od njih nezavisno vodik ili alkil; ili ii) R6 i R7 zajedno s dušikovim atomom na kojem su supstituirani tvore 5 ili 6-člani heterociklilni ili heteroarilni prsten, opcijski supstituiran s jednim ili dva halo, alkila ili haloalkila.
5. Spoj sukladno zahtjevu 1, pri čemu je R1 je opcijski supstituirani fenil, opcionalno supstituirani cikloheksil, opcijski supstituirani piperidinil ili opcijski supstituirani piridil, gdje su supstituenti R1, kada su prisutni, jedna od tri skupine Q, gdje je svaki Q neovisno halo, alkil, -R4OR5 ili -R4N(R6)(R7); svaki R4 je neovisno izravna veza ili alkilen; svaki R5 je neovisno hidrogen, alkil, ili haloalkil; a R6 i R7 su odabrani kako slijedi: i) R6 i R7 je svaki nezavisno vodik ili alkil; ili ii) R6 i R7 zajedno s dušikovim atomom na kojem su supstituirani tvore 5 ili 6-člani heterociklil prsten.
6. Spoj sukladno zahtjevu 1, pri čemu je R1 je opcijski supstituiran fenil, gdje su supstituenti na R1, kada su prisutni, jedna do tri skupine Q, gdje je svaki Q je neovisno fluor, kloro, metil, tert butil, -R4OR5, -R4SR5 ili R4OR4C(J)N(R6)(R7); svaki R4 je neovisno izravna veza ili metilen; svaki R5 je nezavisno vodik, metil, etil ili trifluorometil; i R6 i R7 svaki od njih nezavisno vodik ili metil.
7. Spoj sukladno zahtjevu 1, pri čemu spoj ima formulu III ili njegov enantiomer ili smjesa enantiomera ili njegova farmaceutski prihvatljiva sol, solvat, hidrat, kokristal, klatrat ili polimorf, naznačen time, da: svaki Q1 je nezavisno alkil, halo, haloalkil, opcijski supstituirani monociklički cikloalkil, opcionalno supstituirani monociklički cikloalkilalkil, opcijski supstituirani monociklički aril, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J je O ili S; svaki R4 je nezavisno alkilen, alkenilen ili izravna veza; svaki R5 je nezavisno vodik, alkil, haloalkil ili hidroksialkil; R6 i R7 su odabrane kako slijedi: i) R6 i R7 svaki od njih nezavisno vodik ili alkil; ili ii) R6 i R7 zajedno s dušikovim atomom na kojem su supstituirani tvore 5 ili 6-člani heterociklilni ili heteroarilni prsten, opcijski supstituiran s jednim ili dva halo, alkila ili haloalkila; i n je 0-3.
8. Spoj sukladno zahtjevu 1, pri čemu spoj ima formulu IV ili njegov ili njegov enantiomer ili smjesa enantiomera ili njegova farmaceutski prihvatljiva sol, solvat, hidrat, kokristal, klatrat ili polimorf, naznačena time, da: enantiomer ili smjesa enantiomera ili njegova farmaceutski prihvatljiva sol, solvat, hidrat, kokristal, klatrat ili polimorf, naznačena time, da: Q2 je vodik, alkil, halo, haloalkil, opcionalno supstituirani monociklički cikloalkil, opcionalno supstituirani monociklički cikloalkilalkil, opcijski supstituirani monociklički aril, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) ili R4OR4C(J)N(R6)(R7); J je O ili S; svaki R4 je nezavisno alkilen, alkenilen ili izravna veza; svaki R5 je nezavisno vodik, alkil, haloalkil ili hidroksialkil; i R6 i R7 je svaki nezavisno vodik ili alkil.
9. Spoj sukladno zahtjevu 1, pri čemu je spoj formule V ili njegov enantiomer ili smjesa enantiomera ili njegova farmaceutski prihvatljiva sol, solvat, hidrat, kokristal, klatrat ili polimorf, naznačena time, da: Q3 i Q4 svaki od njih nezavisno vodik, alkil, halo, haloalkil, opcijski supstituirani monociklički cikloalkil, opcijski supstituirani monociklički cikloalkilalkil, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) ili R4OR4C(J)N(R6)(R7); J je O ili S; svaki R4 je nezavisno alkilen, alkenilen ili izravna veza; svaki R5 je nezavisno vodik, alkil, haloalkil, hidroksialkil ili alkoksialkil; i R6 i R7 je svaki nezavisno vodik ili alkil.
10. Spoj sukladno zahtjevu 1, pri čemu spoj ima formulu VI ili njegov enantiomer ili smjesa enantiomera ili njegova farmaceutski prihvatljiva sol, solvat, hidrat, kokristal, klatrat ili polimorf, naznačena time, da: Q4 i Q5 svaki od njih nezavisno vodik, alkil, halo, haloalkil, opcijski supstituirani monociklički cikloalkil, opcijski supstituirani monociklički cikloalkilalkil, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) ili R4OR4C(J)N(R6)(R7); J je O ili S; svaki R4 je nezavisno alkilen, alkenilen ili izravna veza; svaki R5 je nezavisno vodik, alkil, haloalkil, alkoksialkil ili hidroksialkil; i R6 i R7 su odabrani kako slijedi: i) R6 i R7 svaki od njih nezavisno vodik ili alkil; ili ii) R6 i R7 zajedno s dušikovim atomom na kojem su supstituirani tvore 5 ili 6-člani heterociklilni ili heteroarilni prsten, opcijski supstituiran s jednim ili dva halo, alkila ili haloalkila.
11. Spoj sukladno zahtjevu 10, pri čemu Q4 i Q5 je svaki nezavisno vodik, halo, alkil, -R4N(R6)(R7), ili -R4OR5; R4 je izravna veza ili alkilen; R5 je vodik, alkil ili haloalkil; i R6 i R7 zajedno s dušikovim atomom na kojem su supstituirani tvore 6-člani heterociklil.
12. Spoj sukladno zahtjevu 1, pri čemu spoj ima formulu VII ili njegov enantiomer ili smjesa enantiomera ili njegova farmaceutski prihvatljiva sol, solvat, hidrat, kokristal, klatrat ili polimorf, naznačena time, da: Q5 je vodik, alkil, halo, haloalkil, opcionalno supstituirani monociklički cikloalkil, opcionalno supstituirani monociklički cikloalkilalkil,-R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) ili R4OR4C(J)N(R6)(R7); J je O ili S; svaki R4 je nezavisno alkilen, alkenilen ili izravna veza; svaki R5 je nezavisno vodik, alkil, haloalkil, alkoksialkil ili hidroksialkil; i R6 i R7 su odabrani kako slijedi: i) R6 i R7 svaki od njih nezavisno vodik ili alkil; ili ii) R6 i R7 zajedno s dušikovim atomom na kojem su supstituirani tvore 5 ili 6-člani heterociklilni ili heteroarilni prsten, opcijski supstituiran s jednim ili dva halo, alkila ili haloalkila.
13. Spoj sukladno zahtjevu 12, pri čemu je Q5 je vodik, halo, alkil, -R4N(R6)(R7) ili -R4OR5; R4 predstavlja izravnu vezu ili alkilen; i R5 je vodik, alkil ili haloalkil; i R6 i R7 zajedno s dušikovim atomom na kojem su supstituirani tvore 6-člani heterociklil.
14. Spoj sukladno zahtjevu 1, pri čemu spoj ima formulu VIII ili njegov enantiomer ili smjesa enantiomera ili njegova farmaceutski prihvatljiva sol, solvat, hidrat, kokristal, klatrat ili polimorf, naznačen time, da: Q2 i Q5 svaki od njih nezavisno vodik, alkil, halo, haloalkil, opcijski supstituirani monociklički cikloalkil, opcijski supstituirani monociklički cikloalkilalkil, opcijski supstituirani monociklički aril, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) ili R4OR4C(J)N(R6)(R7); J je O ili S; svaki R4 je nezavisno alkilen, alkenilen ili izravna veza; svaki R5 je nezavisno vodik, alkil, haloalkil ili hidroksialkil; i R6 i R7 je svaki neovisno vodik ili alkil, ili R6 i R7 zajedno s dušikovim atomom na kojem su supstituirani tvore 6-člani heterociklil.
15. Spoj sukladno zahtjevu 14, pri čemu su Q2 i Q5 svaki od njih nezavisno vodik, halo, alkil, opcijski supstituirani monociklički aril, ili -R4OR5; R4 predstavlja izravnu vezu ili alkilen; i R5 je vodik, alkil ili haloalkil.
16. Spoj sukladno zahtjevu 1, naznačen time što ima formulu IX: ili njegov enantiomer ili smjesa enantiomera ili njegova farmaceutski prihvatljiva sol, solvat, hidrat, kokristal, klatrat ili polimorf, naznačen time, da: svaki Q1 je nezavisno alkil, halo, haloalkil, opcijski supstituirani monociklički cikloalkil; opcijski supstituirani monociklički cikloalkilalkil, opcijski supstituirani monociklički heterociklil, -R4OR5, -R4O-R4OR5, -R4N(R6)(R7), -R4SR5, -R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), -C(J)R9 ili R4S(O)tR8; svaki R4 je nezavisno alkilen, alkenilen ili izravna veza; svaki R5 je nezavisno vodik, okso, alkil, haloalkil, hidroksialkil, alkoksialkil, monociklični cikloalkil, monociklični aril, monociklični heteroaril, monociklični heterociklil ili monociklički heterociklilalkil, gdje su alkil, haloalkil, hidroksialkil, alkoksialkil, cikloalkil, aril, heteroaril, heteroaril, heteroaril, heteroaril R5 svaki od njih je neovisno opcijski supstituiran sa jednom do tri grupe Q1 odabran između alkila, haloalkila ili halo; R6 i R7 je svaki nezavisno vodik ili alkil; R8 je alkil, haloalkil ili hidroksialkil; R9 je alkil ili aril; J je O ili S; t je 1 ili 2; i n je 0-3.
17. Spoj sukladno zahtjevu 1, pri čemu je spoj odabran iz skupine 2-(3-kloro-4-metilfenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; 2-(4-klorofenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-etoksifenilmetoksifenil)acetamid; 2-(3-klorofenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-fluorofenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-p-tolilacetamid; 2-(3,4-diklorofenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; 2-(2-klorofenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(2-(trifluorometil)fenil)acetamid; 2-(4-tert-butilfenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-phenylacetamid; 2-(3-kloro-4-fluorofenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-(trifluoromethiltio)fenil)acetamid; 2-(2,6-difluorofenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-o-tolilacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(2-fluorofenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2-(2-etoksifenil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(2-(trifluorometoksi)fenil)acetamid; 2-(3-bromo-4-(trifluorometoksi)fenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; 2-(3-kloro-4-etoksifenilmetoksifenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-m-tolilacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-isopropoksifenil)acetamid; 2-(3,4-difluorofenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-fluorofenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-(trifluorometil)piridin-2-il)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-isopropilfenil)acetamid; 2-(2,4-diklorofenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(2-etoksifenilmetoksifenil)acetamid; 2-(4-ciklopropilfenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; 2-(4-kloro-2-fluorofenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; 2-(4-kloro-3-fluorofenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-fluoro-2-metilfenil)acetamid; 2-(3-kloro-2-metilfenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-fluoro-2-(trifluorometil)fenil)acetamid; 2-(4-kloro-2-metilfenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-fluoro-2-metilfenil)acetamid; 2-(4-kloro-2-(trifluorometil)fenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; 2-cikloheksil-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; 2-(4-kloro-2-(trifluorometoksi)fenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-(2-metoksietoksi)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-(2-hidroksietoksi)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-(2-metoksietoksi)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-(2-hidroksihidroksietil)fenil)acetamid; 2-(3-(dimetilamino)fenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-(piperidin-1-il)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-morfolinofenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-fluoro-2-isopropoksifenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(2-(2,2,2-trifluoroetoksi)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2-(2-etoksi-4-fluorofenil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(2-isopropoksifenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(2-fluoro-4-isopropoksifenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-(morfolinometil)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-fluoro-2-(2,2,2-trifluoroetoksi)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-isopropoksi-2-metilfenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-isopropoksi-3-metilfenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-fluoro-4-isopropoksifenil)acetamid; 2-(3-kloro-4-isopropoksifenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(2-metil-4-(trifluorometoksi)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(2-fluoro-4-(trifluorometoksi)fenil)acetamid; 2-(5-kloropiridin-2-il)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(5-fluoropiridin-2-il)acetamid; 2-(2,4-difluorofenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; 2-(4-bromofenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(2-(2-metoksietoksi)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(1-hidroksicikloheksil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(1-hidroksiciklopentil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-methyl-4-(trifluorometoksi)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2-(3-etoksipiridin-2-il)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-metilpiridin-2-il)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(5-metilpiridin-2-il)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2-(2-etoksi-6-fluorofenil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4'-fluorobifenil-4-il)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2-(2-etoksi-5-fluorofenil)-2,2-difluoroacetamid; 2-ciklopentil-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; 2-(3-kloro-4-(trifluorometoksi)fenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-metoksi-2-(trifluorometil)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(2-(2-hidroksietoksi)fenil)acetamid; 2-(4-kloro-2-etoksifenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(2-hidroksifenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(2-(metilamino)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-isopropoksi-2-(trifluorometil)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-metilcikloheksil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-(2-isopropoksietoksi)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-hidroksifenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-((4-metilpiperazin-1-il)metil)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-metil-2-(trifluorometil)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-(2-(2-metoksietoksi)etoksi)fenil)acetamid; 2-(3-(2-(dimetilamino)etoksi)fenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(5-isopropilpiridin-2-il)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-(2-(metilsulfonil)etoksi)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-(3-(metilsulfoil)propil)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-(2-fluoropropan-2-il)fenil)acetamid; 2-(1-benzil-6-okso-1,6-dihidropiridin-3-il)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(5-metoksipiridin-2-il)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(1-metil-6-okso-1,6-dihidropiridin-3-il)acetamid; 2-(5-tert-butilpiridin-2-il)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; 2-(5-ciklopropilpiridin-2-il)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(5-isopropoksipiridin-2-il)acetamid; 2-(5-bromopiridin-2-il)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-fluoro-2-(trifluorometoksi)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-fluorocikloheksil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(4-(metilsulfonil)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-(metilsulfonil)fenil)acetamid; 2-(2-aminopirimidin-5-il)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(5-(trifluoromethiltio)piridin-2-il)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-(2-(metilamino)etoksi)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(1-metil-6-okso-1,6-dihidropiridazin-3-il)acetamid; 2-(2-aminopirimidin-4-il)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(pirimidin-4-il)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-(2-(piperidin-1-il)etoksi)fenil)acetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-(2-morfolinoetoksi)fenil)acetamid; 2-(3-(2-(4,4-difluoropiperidin-1-il)etoksi)fenil)-N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoroacetamid; N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(1-metil-6-okso-1,6-dihidropiridazin-4-il)acetamid; i N-((2-(2,6-dioksopiperidin-3-il)-1-oksoizoindolin-5-il)metil)-2,2-difluoro-2-(3-(4-metilpiperazin-1-il)fenil)acetamid; ili njegov enantiomer ili smjesa enantiomera ili njegova farmaceutski prihvatljiva sol, solvat, hidrat, kokristal, klatrat ili polimorf.
18. Spoj sukladno bilo kojem od zahtjeva 1 do 17, naznačen time, da se upotrebljava kao lijek.
19. Spoj sukladno bilo kojem od zahtjeva 1 do 17, naznačen time, da se upotrebljava u postupku liječenja raka, postupak se sastoji u primjeni na sisavcu koji ima rak terapeutski učinkovite količine spoja.
20. Spoj za uporabu u skladu s patentnim zahtjevom 19, naznačen time što je rak leukemija.
21. Spoj za uporabu u skladu s patentnim zahtjevom 20, naznačen time što je leukemija kronična limfocitna leukemija, kronična mijelocitna leukemija, akutna limfoblastična leukemija ili akutna mijeloična leukemija.
22. Spoj za uporabu u skladu s patentnim zahtjevom 20 ili 21, naznačen time što je leukemija akutna mijeloidna leukemija.
23. Spoj za uporabu sukladno bilo kojem od zahtjeva 20 do 22, naznačen time da je leukemija relapsana, refraktorna ili rezistentna na konvencionalnu terapiju.
24. Spoj za uporabu sukladno bilo kojem od zahtjeva 19 do 23, naznačen time, da postupak nadalje uključuje primjenu terapeutski učinkovite količine drugog drugog aktivnog sredstva ili potpornu terapiju.
25. Spoj za uporabu u skladu s patentnim zahtjevom 24, naznačen time što je sljedeće drugo aktivno sredstvo terapeutsko antitijelo koje se specifično veže na antigen raka, hematopoetski faktor rasta, citokin, sredstvo protiv raka, antibiotik, inhibitor cox-2, imunomodulacijsko sredstvo, imunosupresivno sredstvo , kortikosteroid ili njegov farmakološki aktivni mutant ili derivat.
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