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HRP20180341T1 - Derivati 6-(5-hidroksi-1h-pirazol-1-il)nikotinamida i njihova uporaba kao inhibitora phd - Google Patents

Derivati 6-(5-hidroksi-1h-pirazol-1-il)nikotinamida i njihova uporaba kao inhibitora phd Download PDF

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Publication number
HRP20180341T1
HRP20180341T1 HRP20180341TT HRP20180341T HRP20180341T1 HR P20180341 T1 HRP20180341 T1 HR P20180341T1 HR P20180341T T HRP20180341T T HR P20180341TT HR P20180341 T HRP20180341 T HR P20180341T HR P20180341 T1 HRP20180341 T1 HR P20180341T1
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Croatia
Prior art keywords
pyrazol
hydroxy
pyridin
carbonyl
methylbenzonitrile
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HRP20180341TT
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Inventor
Jason W. Brown
Melinda DAVIS
Anthony IVETAC
Benjamin Jones
Andre A. Kiryanov
Jon KUEHLER
Marion Lanier
Joanne Miura
Sean Murphy
Xiaolun Wang
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Takeda Pharmaceutical Company Limited
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Publication of HRP20180341T1 publication Critical patent/HRP20180341T1/hr

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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Claims (17)

1. Spoj prema formuli [image] ili njegova farmaceutski prihvatljiva sol, naznačen time da q je 0, 1, ili 2; s je 0, 1, ili 2; R3, svaki puta, je neovisno odabran iz skupine koju čine vodik, hidroksil, amino, C1-8 alkilamino, cijano, halo, proizvoljno supstituiran C1-6 alkil, i C1-4 alkoksi; R4 je odabran iz skupine koju čine vodik, cijano, halo, metil, etil, metoksi, i trifluorometil; R5 je odabran iz skupine koju čine [image] G je ugljik; A je odabran iz skupine koju čine N, O, S, CR6 i NR6; E je odabran iz skupine koju čine N, O, S, i CR6; pod uvjetom da samo jedan od A i E može biti O ili S; ili G je N i A i E su CR6; ili G i A su N i E je CR6; ili G, A, i E su N; R6, svaki puta, je neovisno odabran iz skupine koju čine vodik, cijano, halo, C3-8 cikloalkil, proizvoljno supstituiran C1-6 alkil, C1-4 alkoksi, i trifluorometil; R7 je odabran iz skupine koju čine cijano i cijanometil; R8, svaki puta, je neovisno odabran iz skupine koju čine vodik, cijano, halo, C1-4 alkil, C1-4 alkoksi, i trifluorometil; i R9 je odabran iz skupine koju čine vodik, C1-6 alkil proizvoljno supstituiran s 1 do 3 fluoro, i C3-8 cikloalkil.
2. Spoj ili farmaceutski prihvatljiva sol prema zahtjevu 1, naznačen time da R5 je [image] .
3. Spoj ili farmaceutski prihvatljiva sol prema bilo kojem od zahtjeva 1 ili 2, naznačen time da R9 je C1-6 alkil.
4. Spoj ili farmaceutski prihvatljiva sol prema bilo kojem od zahtjeva 1 do 3, naznačen time da s je 1 i q je 1.
5. Spoj ili farmaceutski prihvatljiva sol prema bilo kojem od zahtjeva 1 do 4, naznačen time da svaki R8 je vodik.
6. Spoj ili farmaceutski prihvatljiva sol prema bilo kojem od zahtjeva 1 do 4, naznačen time da jedan od R8 je C1-4 alkil i svaki drugi R8 je vodik.
7. Spoj ili farmaceutski prihvatljiva sol prema bilo kojem od zahtjeva 1 do 4, naznačen time da jedan od R8 je metil i svaki drugi R8 je vodik.
8. Spoj ili farmaceutski prihvatljiva sol prema bilo kojem od zahtjeva 1 do 7, naznačen time da svaki R3 je vodik i R4 je vodik.
9. Spoj prema zahtjevu 1, naznačen time da je odabran iz skupine koju čine: 4-(1-(5-(4-etilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; 4-(5-hidroksi-1-(5-(4-propilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; 4-(5-hidroksi-1-(5-(4-metil-1,4-diazepane-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; 4-(5-hidroksi-1-(5-(4-metilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; 4-(1-(5-(4-(tert-butil)piperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; 4-(1-(5-(6,6-difluoro-4-metil-1,4-diazepane-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; 4-(1-(5-(4-etilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-3-metilbenzonitril; 4-(1-(5-(4-etilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-5-metilbenzonitril; 4-(1-(5-(4-ciklopropilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-3-metilbenzonitril; 4-(1-(5-(4-ciklopropilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-5-metilbenzonitril; 4-(1-(5-(4-etilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2,3-dimetilbenzonitril; 4-(1-(5-(4-ciklopropilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2,3-dimetilbenzonitril; 4-(1-(5-(4-(2,2-difluoroetil)piperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; 4-(5-hidroksi-1-(5-(4-(2,2,2-trifluoroetil)piperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; 2-fluoro-4-(5-hidroksi-1-(5-(4-metilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; 4-(1-(5-(4-ciklopropil-1,4-diazepane-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-3-metilbenzonitril; (S)-4-(1-(5-(4-etil-3-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-3-metilbenzonitril; 4-(1-(5-(4-etil-3-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-3-metilbenzonitril; (S)-4-(1-(5-(3,4-dimetilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-3-metilbenzonitril; 4-(1-(5-(3,4-dimetilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-3-metilbenzonitril; (R)-4-(1-(5-(4-etil-2-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-3-metilbenzonitril; 4-(1-(5-(4-etil-2-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-3-metilbenzonitril; (R)-2-fluoro-4-(5-hidroksi-1-(5-(4-izopropil-3-metilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; 2-fluoro-4-(5-hidroksi-1-(5-(4-izopropil-3-metilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; (R)-4-(1-(5-(4-etil-3-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-3-metilbenzonitril; (S)-2-fluoro-4-(5-hidroksi-1-(5-(4-izopropil-3-metilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; (R)-4-(1-(5-(3,4-dimetilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-3-metilbenzonitril; (S)-4-(1-(5-(4-etil-2-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-3-metilbenzonitril; 4-(5-hidroksi-1-(5-(4-(pentan-3-il)piperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; (S)-4-(1-(5-(4-etil-3-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; 4-(1-(5-(4-etil-3-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; (S)-4-(1-(5-(3,4-dimetilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; 4-(1-(5-(3,4-dimetilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; 4-(1-(5-(4-ciklobutilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; (S)-4-(5-hidroksi-1-(5-(3-metil-4-propilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; (R)-4-(5-hidroksi-1-(5-(3-metil-4-propilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; 4-(5-hidroksi-1-(5-(3-metil-4-propilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; (R)-4-(1-(5-(4-ciklopropil-3-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1 H-pirazol-4-il)-3-metilbenzonitril; 4-(1-(5-(4-ciklopropil-3-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; 4-(5-hidroksi-1-(5-(3,3,4-trimetilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; 4-(1-(5-(4-etil-3,3-dimetilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; (R)-4-(5-hidroksi-1-(5-(4-izopropil-3-metilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; 4-(5-hidroksi-1-(5-(4-izopropil-3-metilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; (R)-4-(1-(5-(2,4-dimetilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; 4-(1-(5-(2,4-dimetilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; (R)-4-(1-(5-(4-etil-3-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; (S)-4-(1-(5-(4-ciklopropil-3-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; (S)-4-(1-(5-(2,4-dimetilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; (R)-4-(1-(5-(3,4-dimetilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; (S)-4-(5-hidroksi-1-(5-(4-izopropil-3-metilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; (R)-4-(1-(5-(4-etil-3-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-5-metilbenzonitril; 4-(1-(5-(4-etil-3-metilpiperazin-1 -karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-5-metilbenzonitril; 2-fluoro-4-(5-hidroksi-1-(5-(4-metilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-5-metilbenzonitril; (S)-4-(1-(5-(4-etil-3-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-5-metilbenzonitril; (S)-4-(1-(5-(3,4-dimetilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-5-metilbenzonitril; (R)-4-(1-(5-(3,4-dimetilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-5-metilbenzonitril; 4-(1-(5-(3,4-dimetilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-5-metilbenzonitril; 4-(1-(5-(4-ciklopropilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; 4-(5-hidroksi-1-(5-(4-propilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; 4-(5-hidroksi-1-(5-(4-propil-1,4-diazepane-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril; 4-(5-hidroksi-1-(4-metil-5-(4-metilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)benzonitril; (S)-4-(1-(5-(4-etil-2-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-5-metilbenzonitril; (R)-4-(1-(5-(4-etil-2-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-5-metilbenzonitril; 4-(1-(5-(4-etil-2-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-2-fluoro-5-metilbenzonitril; (R)-4-(1-(5-(4-etil-2-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; (S)-4-(1-(5-(4-etil-2-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; i 4-(1-(5-(4-etil-2-metilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril; i farmaceutski prihvatljiva sol bilo kojeg od gore navedenih spojeva.
10. Spoj prema zahtjevu 1, naznačen time da je 4-(1-(5-(4-etilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril ili njegova farmaceutski prihvatljiva sol.
11. Spoj prema zahtjevu 1, naznačen time da je 4-(5-hidroksi-1-(5-(4-metilpiperazin-1-karbonil)piridin-2-il)-1H-pirazol-4-il)-3-metilbenzonitril ili njegova farmaceutski prihvatljiva sol.
12. Spoj prema zahtjevu 1, naznačen time da je 4-(1-(5-(4-(2,2-difluoroetil)piperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril ili njegova farmaceutski prihvatljiva sol.
13. Spoj prema zahtjevu 1, naznačen time da je (S)-4-(1-(5-(3,4-dimetilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril ili njegova farmaceutski prihvatljiva sol.
14. Spoj prema zahtjevu 1, naznačen time da je (R)-4-(1-(5-(2,4-dimetilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril ili njegova farmaceutski prihvatljiva sol.
15. Spoj prema zahtjevu 1, naznačen time da je (R)-4-(1-(5-(3,4-dimetilpiperazin-1-karbonil)piridin-2-il)-5-hidroksi-1H-pirazol-4-il)-3-metilbenzonitril ili njegova farmaceutski prihvatljiva sol.
16. Farmaceutski pripravak naznačen time da sadrži spoj ili farmaceutski prihvatljivu sol kako je definirano u bilo kojem od zahtjeva 1 do 15, i farmaceutski prihvatljivo pomoćno sredstvo.
17. Spoj ili farmaceutski prihvatljiva sol prema bilo kojem od zahtjeva 1 do 15 naznačen time da je za uporabu kao lijek.
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ZA201506484B (en) 2017-11-29
JO3722B1 (ar) 2021-01-31
EA201591889A1 (ru) 2016-01-29
CA2903875A1 (en) 2014-10-02
CA2903875C (en) 2021-07-20
ES2660914T3 (es) 2018-03-26
AU2014241183B2 (en) 2018-08-09
LT2978752T (lt) 2018-03-26
US10407409B2 (en) 2019-09-10
CR20150517A (es) 2016-01-12
SI2978752T1 (en) 2018-04-30
EA031647B1 (ru) 2019-02-28
JP2020073538A (ja) 2020-05-14
JP6874114B2 (ja) 2021-05-19
US9708296B2 (en) 2017-07-18
MX370388B (es) 2019-12-11
PL2978752T3 (pl) 2018-06-29
WO2014160810A1 (en) 2014-10-02
EP3336084B1 (en) 2021-03-17
US9040522B2 (en) 2015-05-26
CL2015002473A1 (es) 2016-08-26
KR102376354B1 (ko) 2022-04-04

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