HRP20110764T1 - Inhibitori mitotskog kinezina i postupci njihove upotrebe - Google Patents

Inhibitori mitotskog kinezina i postupci njihove upotrebe Download PDF

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HRP20110764T1
HRP20110764T1 HR20110764T HRP20110764T HRP20110764T1 HR P20110764 T1 HRP20110764 T1 HR P20110764T1 HR 20110764 T HR20110764 T HR 20110764T HR P20110764 T HRP20110764 T HR P20110764T HR P20110764 T1 HRP20110764 T1 HR P20110764T1
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alkyl
phenyl
nrarb
membered
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Hans Jeremy
M. Wallace Eli
Zhao Qian
P. Lyssikatos Joseph
Aicher Tom
Laird Ellen
Robinson John
Allen Shelley
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Array Biopharma
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Abstract

Spoj Formulei njegove solvati, razdvojeni enantiomeri, dijastereomeri, racemične smjese i farmaceutski prihvatljive soli, naznačen time što: R je Z-NR2R3;R1 je C1-C10 alkil, C2-C10 alkenil, C2-C12 alkinil, fenil, 5-7-eročlani heteroaril, zasićeni ili djelomično nezasićeni C3-C12 cikloalkil, zasićeni ili djelomično nezasićeni 3-8-eročlani heterocikloalkil, -OR3, -NR4OR5, CRb(=NORc), C(=O)Ra ili -NR4R5, gdje su navedeni alkil, alkenil, alkinil, fenil, heteroaril, cikloalkil i heterocikloalkil izborno supstituirani s jednom ili više skupina, koje se neovisno bira između okso (uz uvjet da supstitucija nije na navedenom fenilu ili heteroarilu), halogena, cijano, nitro, trifluormetila, difluormetila, fluormetila, fluormetoksi, difluormetoksi, trifluormetoksi, azido, -O(C=O)ORd, -NRbSO2Rd, -SO2NRaRb, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OCH2C(=O)ORa, -NRbC(=O)ORd, -NRbC(=O)Ra, -C(=O)NRaRb, -NRaRb, -NRcC(=O)NRaRb, -NRcC(NCN)NRaRb, -ORa, -OP(=O)(ORa)2, C1-C10 alkila, C2-C10 alkenila, C2-C12 alkinila, C3-C12 cikloalkila, fenila, 5-7-eročlanog heteroarila, fenil-C1-C3-alkila, 5-6-eročlanog heteroaril-C1-3-alkila, 3-8-eročlanog heterociklila i 5-6-eročlanog heterociklil-C1-3-alkila; Ar1 i Ar2 su neovisno fenil ili 5-7-eročlani heteroaril, gdje su navedeni fenil i heteroaril izborno supstituirani s jednom ili više skupina, koje se neovisno bira između F, Cl, Br, I, cijano, nitro, C1-C10 alkila, C2-C10 alkenila, C2-C12 alkinila, zasićenog ili djelomično nezasićenog C3-C12 cikloalkila, zasićenog ili djelomično nezasićenog 3-8-eročlanog heterocikloalkila, trifluormetila, difluormetila, fluormetila, fluormetoksi, difluormetoksi, trifluormetoksi, ORa, -O(C=O)ORd, -OP(=O)(ORa)(ORa), NRaRb, -NRbSO2Rd, -SO2NRaR, SR6, SOR6, SO2R6, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OCH2C(=O)ORa, -NRbC(=O)ORd, -NRbC(=O)Ra, -C(=O)NRaRb i -NRcC(=O)NRaRb;R2 i R3 se neovisno bira između vodika, C1-C10 alkila, zasićenog ili djelomično nezasićenog C3-C12 cikloalkila, aminokiseline koju se bira iz skupine koju čine Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hil, Hip, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tir, Val, fosfoserin, fosfotreonin, fosfotirozin, 4-hidroksiprolin, hidroksilizin, demozin, izodemozin, γ-karboksiglutamat, hipurna kiselina, oktahidroindol-2-karboksilna kiselina, statin, 1,2,3,4-tetrahidroizokinolin-3-karboksilna kiselina, penicilamin, ornitin, 3-metilhistidin, norvalin, ?-alanin, γ-aminomaslačna kiselina, citrulin, homocistein, homoserin, metilalanin, para-benzoilfenilalanin, fenilglicin, propargilglicin, sarkozin, metionin, sulfon i tert-butilglicin, te dipeptida, gdje su navedeni alkil i cikloalkil izborno supstituirani; R4 i R5 su neovisno H, trifluormetil, difluormetil, fluormetil, C1-C10 alkil, C2-C10 alkenil, C2-C12 alkinil, zasićeni ili djelomično nezasićeni C3-C12 cikloalkil, zasićeni ili djelomično nezasićeni 3-8-eročlani heterocikloalkil, fenil ili 5-7-eročlani heteroaril, gdje su navedeni alkil, alkenil, alkinil, cikloalkil, heterocikloalkil, fenil

Claims (25)

1. Spoj Formule [image] i njegove solvati, razdvojeni enantiomeri, dijastereomeri, racemične smjese i farmaceutski prihvatljive soli, naznačen time što: R je Z-NR2R3; R1 je C1-C10 alkil, C2-C10 alkenil, C2-C12 alkinil, fenil, 5-7-eročlani heteroaril, zasićeni ili djelomično nezasićeni C3-C12 cikloalkil, zasićeni ili djelomično nezasićeni 3-8-eročlani heterocikloalkil, -OR3, -NR4OR5, CRb(=NORc), C(=O)Ra ili -NR4R5, gdje su navedeni alkil, alkenil, alkinil, fenil, heteroaril, cikloalkil i heterocikloalkil izborno supstituirani s jednom ili više skupina, koje se neovisno bira između okso (uz uvjet da supstitucija nije na navedenom fenilu ili heteroarilu), halogena, cijano, nitro, trifluormetila, difluormetila, fluormetila, fluormetoksi, difluormetoksi, trifluormetoksi, azido, -O(C=O)ORd, -NRbSO2Rd, -SO2NRaRb, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OCH2C(=O)ORa, -NRbC(=O)ORd, -NRbC(=O)Ra, -C(=O)NRaRb, -NRaRb, -NRcC(=O)NRaRb, -NRcC(NCN)NRaRb, -ORa, -OP(=O)(ORa)2, C1-C10 alkila, C2-C10 alkenila, C2-C12 alkinila, C3-C12 cikloalkila, fenila, 5-7-eročlanog heteroarila, fenil-C1-C3-alkila, 5-6-eročlanog heteroaril-C1-3-alkila, 3-8-eročlanog heterociklila i 5-6-eročlanog heterociklil-C1-3-alkila; Ar1 i Ar2 su neovisno fenil ili 5-7-eročlani heteroaril, gdje su navedeni fenil i heteroaril izborno supstituirani s jednom ili više skupina, koje se neovisno bira između F, Cl, Br, I, cijano, nitro, C1-C10 alkila, C2-C10 alkenila, C2-C12 alkinila, zasićenog ili djelomično nezasićenog C3-C12 cikloalkila, zasićenog ili djelomično nezasićenog 3-8-eročlanog heterocikloalkila, trifluormetila, difluormetila, fluormetila, fluormetoksi, difluormetoksi, trifluormetoksi, ORa, -O(C=O)ORd, -OP(=O)(ORa)(ORa), NRaRb, -NRbSO2Rd, -SO2NRaR, SR6, SOR6, SO2R6, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OCH2C(=O)ORa, -NRbC(=O)ORd, -NRbC(=O)Ra, -C(=O)NRaRb i -NRcC(=O)NRaRb; R2 i R3 se neovisno bira između vodika, C1-C10 alkila, zasićenog ili djelomično nezasićenog C3-C12 cikloalkila, aminokiseline koju se bira iz skupine koju čine Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hil, Hip, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tir, Val, fosfoserin, fosfotreonin, fosfotirozin, 4-hidroksiprolin, hidroksilizin, demozin, izodemozin, γ-karboksiglutamat, hipurna kiselina, oktahidroindol-2-karboksilna kiselina, statin, 1,2,3,4-tetrahidroizokinolin-3-karboksilna kiselina, penicilamin, ornitin, 3-metilhistidin, norvalin, β-alanin, γ-aminomaslačna kiselina, citrulin, homocistein, homoserin, metilalanin, para-benzoilfenilalanin, fenilglicin, propargilglicin, sarkozin, metionin, sulfon i tert-butilglicin, te dipeptida, gdje su navedeni alkil i cikloalkil izborno supstituirani; R4 i R5 su neovisno H, trifluormetil, difluormetil, fluormetil, C1-C10 alkil, C2-C10 alkenil, C2-C12 alkinil, zasićeni ili djelomično nezasićeni C3-C12 cikloalkil, zasićeni ili djelomično nezasićeni 3-8-eročlani heterocikloalkil, fenil ili 5-7-eročlani heteroaril, gdje su navedeni alkil, alkenil, alkinil, cikloalkil, heterocikloalkil, fenil i heteroaril izborno supstituirani s jednom ili više skupina, koje se neovisno bira između okso (uz uvjet da supstitucija nije na navedenom fenilu ili heteroarilu), halogena, cijano, nitro, trifluormetila, difluormetila, fluormetila, fluormetoksi, difluormetoksi, trifluormetoksi, azido, -O(C=O)ORd, -NRbSO2Rd, -SO2NRaRb, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -NRbC(=O)ORd, -NRbC(=O)Ra, -C(=O)NRaRb, -NRaRb, -NRcC(=O)NRaRb, -NRcC(NCN)NRaRb, -ORa, C1-C10 alkila, C2-C10 alkenila, C2-C12 alkinila, C3-C12 cikloalkila, fenila, 5-7-eročlanog heteroarila, fenil-C1-C3-alkila, 5-6-eročlanog heteroaril-C1-3-alkila, 3-8-eročlanog heterocikloalkila i 5-6-eročlanog heterociklil-C1-3-alkila, ili R4 i R5, zajedno s atomima na koje su vezani, tvore zasićeni ili djelomično nezasićeni 3-8-eročlani heterociklički prsten, koji može sadržavati 1 do 3 dodatna heteroatoma, uz heteroatome na koje su vezani navedeni R4 i R5, koje se bira između N, O i S, gdje je navedeni heterociklički prsten izborno supstituiran s jednom ili više skupina, koje se neovisno bira između okso, halogena, cijano, nitro, trifluormetila, difluormetila, fluormetila, fluormetoksi, difluormetoksi, trifluormetoksi, azido, -O(C=O)ORd, -NRbSO2Ra, -SO2NRaRb, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -NRbC(=O)ORd, -NRbC(=O)Ra, -C(=O)NRaRb, -NRaRb, -NRcC(=O)NRaRb, -NRcC(NCN)NRaRb, -ORa, C1-C10 alkila, C2-C10 alkenila, C2-C12 alkinila, C3-C12 cikloalkila, fenila, 5-7-eročlanog heteroarila, fenil-C1-C3-alkila, 5-6-eročlanog heteroaril-C1-3-alkila, 3-8-eročlanog heterocikloalkila i 5-6-eročlanog heterociklil-C1-3-alkila; R6 je C1-C10 alkil, C2-C10 alkenil, C2-C12 alkinil, C1-C12 heteroalkil, C1-C12 heteroalkenil, C1-C12 heteroalkinil, zasićeni ili djelomično nezasićeni C3-C12 cikloalkil, zasićeni ili djelomično nezasićeni 3-8-eročlani heterocikloalkil, fenil ili 5-7-eročlani heteroaril, gdje su navedeni alkil, alkenil, alkinil, heteroalkil, heteroalkenil, heteroalkinil, cikloalkil, heterocikloalkil, fenil i heteroaril izborno supstituirani s jednom ili više skupina, koje se neovisno bira između okso (uz uvjet da supstitucija nije na navedenom fenilu ili heteroarilu), halogena, cijano, nitro, trifluormetila, difluormetila, fluormetila, fluormetoksi, difluormetoksi, trifluormetoksi, azido, -O(C=O)ORd, -NRbSO2Rd, -SO2NRaRb, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -NRbC(=O)ORd, -NRbC(=O)Ra, -C(=O)NRaRb, -NRaRb, -NRcC(=O)NRaRb, -NRcC(NCN)NRaRb, -ORa, C1-C10 alkila, C2-C10 alkenila, C2-C12 alkinila, C3-C12 cikloalkila, fenila, 5-7-eročlanog heteroarila, fenil-C1-C3-alkila, 5-6-eročlanog heteroaril-C1-3-alkila, 3-8-eročlanog heterocikloalkila i 5-6-eročlanog heterociklil-C1-3-alkila; Ra je vodik, trifluormetil, C1-C10 alkil, C2-C10 alkenil, C2-C12 alkinil, zasićeni ili djelomično nezasićeni C3-C12 cikloalkil, cikloalkilalkil, fenil, arilalkil, 5-7-eročlani heteroaril, 5-6-eročlani heteroaril-C1-3-alkil, 3-8-eročlani heterocikloalkil ili zasićeni ili djelomično nezasićeni 5-6-eročlani heterociklil-C1-3-alkil, gdje su navedeni alkil, alkenil, alkinil, cikloalkil, cikloalkilalkil, fenil, arilalkil, heteroaril, heteroarilalkil, heterocikloalkil i heterociklilalkil izborno supstituirani s jednom ili više skupina, koje se neovisno bira između okso (uz uvjet da supstitucija nije na navedenom fenilu ili heteroarilu), halogena, cijano, nitro, trifluormetila, difluormetila, fluormetila, fluormetoksi, difluormetoksi, trifluormetoksi, azido, -O(C=O)ORh, -NRfSO2Rh, -SO2NReRf, -C(=O)Re, -C(=O)ORe, -OC(=O)Re, -NRfC(=O)ORh, -NRfC(=O)Re, -C(=O)NReRf, -NReRf, -NRgC(=O)NReRf, -NRcC(NCN)NReRf, -ORe, C1-C10 alkila, C2-C10 alkenila, C2-C12 alkinila, zasićenog ili djelomično nezasićenog C3-C12 cikloalkila, fenila, 5-7-eročlanog heteroarila, fenil-C1-C3-alkila, 5-6-eročlanog heteroaril-C1-3-alkila, zasićenog ili djelomično nezasićenog 3-8-eročlanog heterocikloalkila i 5-6-eročlanog heterociklil-C1-3-alkila; Rb, Rc, Rf i Rg su neovisno vodik ili C1-C10 alkil; ili Ra i Rb, zajedno s atomom na kojeg su vezani, tvore 4 do 10-eročlani zasićeni ili djelomično nezasićeni heterociklički prsten, koji može sadržavati 1 do 3 dodatna heteroatoma, uz atom dušika na kojeg su navedeni Ra i Rb vezani, koje se bira između N, O i S; Rd i Rh su neovisno trifluormetil, C1-C10 alkil, zasićeni ili djelomično nezasićeni C3-C12 cikloalkil, fenil, fenil-C1-C3-alkil, 5-7-eročlani heteroaril, 5-6-eročlani heteroaril-C1-3-alkil, zasićeni ili djelomično nezasićeni 3-8-eročlani heterocikloalkil ili 5-6-eročlani heterociklil-C1-3-alkil; Re je vodik, trifluormetil, C1-C10 alkil, C2-C10 alkenil, C2-C12 alkinil, zasićeni ili djelomično nezasićeni C3-C12 cikloalkil, C3-C12 cikloalkil-C1-3-alkil, fenil, fenil-C1-C3-alkil, 5-7-eročlani heteroaril, 5-6-eročlani heteroaril-C1-3-alkil, zasićeni ili djelomično nezasićeni 3-8-eročlani heterocikloalkil ili 5-6-eročlani heterociklil-C1-3-alkil; i Z je alkilen s 1 do 6 ugljika, ili alkenilen ili alkinilen, svaki s po 2 do 6 ugljika, gdje su navedeni alkilen, alkenilen i alkinilen izborno supstituirani s jednom ili više skupina, koje se neovisno bira između okso, halogena, cijano, nitro, trifluormetila, difluormetila, fluormetila, fluormetoksi, difluormetoksi, trifluormetoksi, azido, -O(C=O)ORd, -NRbSO2Rd, -SO2NRaRb, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -NRbC(=O)ORd, -NRbC(=O)Re, -C(=O)NRaRb, -NRaRb, -NRcC(=O)NRaRb, -ORa, C1-C10 alkila, C2-C10 alkenila, C2-C12 alkinila, C3-C12 cikloalkila, fenila, 5-7-eročlanog heteroarila, fenil-C1-C3-alkila, 5-6-eročlanog heteroaril-C1-3-alkila, 3-8-eročlanog heterocikloalkila i 5-6-eročlanog heterociklil-C1-3-alkila.
2. Spoj u skladu s patentnim zahtjevom 1, naznačen time što R1 je -NR4OR5.
3. Spoj u skladu s patentnim zahtjevom 2, naznačen time što se R4 i R5 neovisno bira između H, C1-C10 alkila, zasićenog ili djelomično nezasićenog C3-C12 cikloalkila i 5-7-eročlanog heteroarila.
4. Spoj u skladu s patentnim zahtjevom 1, naznačen time što R1 je C1-C10 alkil, C3-C12 cikloalkil, 3-8-eročlani heterocikloalkil, O-C1-C10 alkil, ORa, fenil, 5-7-eročlani heteroaril, CRb(=NORc) ili C(=O)Ra, gdje su navedeni alkil, cikloalkil, heterocikloalkil, fenil i heteroaril izborno supstituirani s jednom ili više skupina, koje se neovisno bira između ORa, NRaRb, halogena, C3-C12 cikloalkila, C1-C10 alkila, fenila i CF3.
5. Spoj u skladu s patentnim zahtjevom 1, naznačen time što Ar1 je supstituirani ili nesupstituirani fenil, tienil, imidazolil, piridil ili pirazolil.
6. Spoj u skladu s patentnim zahtjevom 5, naznačen time što Ar1 je izborno supstituiran s jednom ili više skupina, koje se neovisno bira između F, Cl, Br, I, ORa, NRaRb, NO2, CN, C(=O)ORa, C1-C10 alkila i CF3.
7. Spoj u skladu s patentnim zahtjevom 6, naznačen time što Ar2 je supstituirani ili nesupstituirani fenil, tienil, imidazolil, piridil ili pirazolil.
8. Spoj u skladu s patentnim zahtjevom 7, naznačen time što su Ar1 i Ar2 izborno supstituirani s jednom ili više skupina, koje se neovisno bira između F, Cl, Br, I, ORa, NRaRb, NO2, CN, C(=O)ORa, C1-C10 alkila i CF3.
9. Spoj u skladu s patentnim zahtjevom 1, formule [image] naznačen time što: Rx i Ry su neovisno H, C1-C10 alkil, zasićeni ili djelomično nezasićeni C3-C12 cikloalkil ili fenil, gdje su navedeni alkil, cikloalkil i fenil izborno supstituirani s jednom ili više skupina, koje se neovisno bira između okso (uz uvjet da supstitucija nije on navedeni fenil), halogena, cijano, nitro, trifluormetila, difluormetila, fluormetila, fluormetoksi, difluormetoksi, trifluormetoksi, azido, -O(C=O)ORd, -NRbSO2Rd, -SO2NRaRb, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OCH2C(=O)ORa, -NRbC(=O)ORd, -NRbC(=O)Ra, -C(=O)NRaRb, -NRaRb, -NRcC(=O)NRaRb, -NRcC(NCN)NRaRb, -ORa, C1-C10 alkila, C2-C10 alkenila, C2-C12 alkinila, C3-C12 cikloalkila, fenila, 5-7-eročlanog heteroarila, fenil-C1-C3-alkila, 5-6-eročlanog heteroaril-C1-3-alkila, 3-8-eročlanog heterociklila i 5-6-eročlanog heterociklil-C1-3-alkila, ili Rx i Ry, zajedno s atomom na kojeg su vezani, tvore zasićeni ili djelomično nezasićeni C3-C12 karbociklički prsten ili 3-8-eročlani heterociklički prsten koji sadrži jedan ili više heteroatoma, koje se neovisno bira između N, O i S, gdje su navedeni karbociklički i heterociklički prsteni izborno supstituirani s jednom ili više skupina, koje se neovisno bira između okso, halogena, cijano, nitro, trifluormetila, difluormetila, fluormetila, fluormetoksi, difluormetoksi, trifluormetoksi, azido, -O(C=O)ORd, -NRbSO2Rd, -SO2NRaRb, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -NRbC(=O)ORd, -NRbC(=O)Ra, -C(=O)NRaRb, -NRaRb, -NRcC(=O)NRaRb, -NRcC(NCN)NRaRb, -ORa, C1-C10 alkila, C2-C10 alkenila, C2-C12 alkinila, C3-C12 cikloalkila, fenila, 5-7-eročlanog heteroarila, fenil-C1-C3-alkila, 5-6-eročlanog heteroaril-C1-3-alkila, 3-8-eročlanog heterocikloalkila i 5-6-eročlanog heterociklil-C1-3-alkila; ili Ra i Rx, zajedno s atomima na koje su vezani, tvore zasićeni ili djelomično nezasićeni 3-8-eročlani heterociklički prsten, koji može sadržavati 1 do 3 dodatna heteroatoma, uz tom kisika na kojeg je navedeni Ra vezan, koje se bira između N, O i S, gdje je navedeni heterociklički prsten izborno supstituiran s jednom ili više skupina, koje se neovisno bira između okso, halogena, cijano, nitro, trifluormetila, difluormetila, fluormetila, fluormetoksi, difluormetoksi, trifluormetoksi, azido, -O(C=O)ORh, -NRfSO2Rh, -SO2NReRf, -C(=O)Re, -C(=O)ORe, -OC(=O)Re, -NRfC(=O)ORh, -NRfC(=O)Re, -C(=O)NReRf, -NReRf, -NRgC(=O)NReRf, -NRcC(NCN)NReRf, -ORe, C1-C10 alkila, C2-C10 alkenila, C2-C12 alkinila, C3-C12 cikloalkila, fenila, 5-7-eročlanog heteroarila, fenil-C1-C3-alkila, 5-6-eročlanog heteroaril-C1-3-alkila, 3-8-eročlanog heterocikloalkila i 5-6-eročlanog heterociklil-C1-3-alkila.
10. Spoj u skladu s patentnim zahtjevom 9, naznačen time što najmanje jedan od Rx i Ry nije H.
11. Spoj of any of patentni zahtjevi 9 ili 10, naznačen time što Ra je H ili C1-C10 alkil.
12. Spoj u skladu s patentnim zahtjevom 11, naznačen time što Rx je C1-C10 alkil.
13. Spoj u skladu s patentnim zahtjevom 1, naznačen time što ga se bira između: [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] i njihovih razdvojenih enantiomera i dijastereomera.
14. Spoj u skladu s patentnin zahtjevom 13, naznačen time što ima strukturu: [image] i njegove farmaceutski prihvatljive soli.
15. Spoj u skladu s patentnin zahtjevom 13, naznačen time što ima strukturu: [image] i njegove farmaceutski prihvatljive soli.
16. Spoj u skladu s patentnin zahtjevom 13, naznačen time što ima strukturu: [image] i njegove farmaceutski prihvatljive soli.
17. Spoj u skladu s patentnin zahtjevom 13, naznačen time što ima strukturu: [image] i njegove farmaceutski prihvatljive soli.
18. Spoj u skladu s patentnin zahtjevom 13, naznačen time što ima strukturu: [image] i njegove farmaceutski prihvatljive soli.
19. Spoj u skladu s patentnin zahtjevom 13, naznačen time što ima strukturu: [image] i njegove farmaceutski prihvatljive soli.
20. Farmaceutski pripravak, naznačen time što sadrži spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 19 i farmaceutski prihvatljivu podlogu.
21. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 20, naznačen time što je namijenjen upotrebi kao medikament.
22. Upotreba spoja u skladu s bilo kojim od patentnih zahtjeva 1 do 20, naznačena time što je navedeni spoj namijenjen proizvodnji medikamenta za liječenje bolesti ili poremećaja kod čovjeka ili životinje koje se može liječiti inhibiranjem mitoze.
23. Upotreba u skladu s patentnim zahtjevom 21, naznačena time što je navedena bolest ili poremećaj hiperproliferativni poremećaj.
24. Upotreba u skladu s patentnim zahtjevom 22, naznačena time što je navedeno stanje s abnormalnim rastom stanica rak, autoimuna bolest, artritis, odbacivanje presatka, upalna bolest crijeva, ili proliferacija do koje je došlo nakon medicinskih zahvata.
25. Upotreba u skladu s patentnim zahtjevom 21, naznačena time što je navedena bolest ili poremećaj gljivična ili koja druga eukariotska infekcija.
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