HRP20211997T1 - Novi supstituirani nukleozidni analozi 6-6 bicikličkog aromatskog prstena za upotrebu kao inhibitori prmt5 - Google Patents

Novi supstituirani nukleozidni analozi 6-6 bicikličkog aromatskog prstena za upotrebu kao inhibitori prmt5 Download PDF

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HRP20211997T1
HRP20211997T1 HRP20211997TT HRP20211997T HRP20211997T1 HR P20211997 T1 HRP20211997 T1 HR P20211997T1 HR P20211997T T HRP20211997T T HR P20211997TT HR P20211997 T HRP20211997 T HR P20211997T HR P20211997 T1 HRP20211997 T1 HR P20211997T1
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4alkyl
halo
group
hydrogen
compound
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HRP20211997TT
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Tongfei Wu
Dirk Brehmer
Lijs Beke
An Boeckx
Gaston Stanislas Marcella Diels
Ronaldus Arnodus Hendrika Joseph Gilissen
Edward Charles LAWSON
Vineet PANDE
Marcus Cornelis Bernardus Catharina Parade
Wim Bert Griet Schepens
Johannes Wilhelmus John F Thuring
Marcel Viellevoye
Weimei SUN
Lieven Meerpoel
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Janssen Pharmaceutica Nv
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Claims (34)

1. Spoj s formulom (I) [image] naznačen time što R1 predstavlja vodik ili -C(=O)-C1-4alkil; R2 predstavlja vodik ili -C(=O)-C1-4alkil; Y predstavlja -CH2- ili -CF2-; Z predstavlja -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, -C≡C-, -O-, ili -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, i R5h svaki neovisno predstavljaju vodik ili C1-4alkil; X predstavlja -O-, -S-, ili -NR11-; R11 predstavlja vodik, C1-4alkil, ili C1-4alkil supstituiran s jednim supstituentom odabranim iz skupine koja sadrži -OH, -O-C1-4alkil, R12, -NH2, -NH-C1-4alkil, i -N(C1-4alkil)2; R12 predstavlja 4-, 5-, 6- ili 7-eročlani heterociklički prsten koji sadrži jedan dušikov atom i po izboru jedan kisikov atom; navedeni 4-, 5-, 6- ili 7-eročlani heterociklički prsten je vezan za ostatak molekule preko atoma dušika u prstenu; Ar predstavlja 10-eročlani biciklički aromatični prstenasti sustav koji se sastoji od dva kondenzirana 6-eročlana prstena, [image] pri čemu je najmanje 1 atom ugljika u prstenu prstena B zamijenjen atomom dušika; pri čemu je po izboru 1 dodatni atom ugljika u prstenu prstena A ili prstena B zamijenjen atomom dušika; pod uvjetom da kada atom dušika zamjenjuje jedan od dva kondenzirana ugljikova atoma, karbonilna skupina je prisutna u navedenom bicikličkom aromatičnom prstenastom sustavu; Ar je po izboru supstituiran s jednim, dva, tri ili četiri supstituenta koji su svaki neovisno odabrani iz skupine koja sadrži halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR10d, -NR10cR10d, cijano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkil, -C(=O)-C1-4alkil, C1-4alkiloksi, -C(=O)-O-C1-4alkil, C3-6cikloalkil, -O-C3-6cikloalkil, -NH-C3-6cikloalkil, -N(C3-6cikloalkil)2, C2-6alkenil, C1-4alkil supstituiran s jednim C1-4alkiloksi, i C1-4alkil po izboru supstituiran s jednim -NR10aR10b; R10a i R10b svaki neovisno predstavljaju vodik ili C1-4alkil; R10c i R10d svaki neovisno predstavljaju C3-6cikloalkil; R13; R14; C3-6cikloalkil supstituiran s jednim, dva ili tri supstituenta koji je svaki neovisno odabran iz skupine koja sadrži halo, -OH i -O-C1-4alkil; C1-4alkil supstituiran s jednim, dva ili tri supstituenta koji je svaki neovisno odabran iz skupine koja sadrži halo, -OH i -O-C1-4alkil; ili C1-4alkil supstituiran s jednim supstituentom odabranim iz skupine koja sadrži C3-6cikloalkil, R13 i R14; R13 predstavlja 4- do 7-eročlani monociklički aromatski prsten koji sadrži jedan, dva ili tri heteroatoma svaki neovisno odabran od O, S, S(=O)p i N; ili 6- do 11-eročlani biciklički kondenzirani aromatski prsten koji sadrži jedan, dva ili tri heteroatoma koji su svaki neovisno odabrani od O, S, S(=O)p i N; navedeni 4- do 7-eročlani monociklički aromatski prsten ili 6- do 11-eročlani biciklički kondenzirani aromatski prsten je po izboru supstituiran s jednim ili dva supstituenta odabrana iz skupine koja sadrži C1-4alkil; p predstavlja 1 ili 2; R14 predstavlja fenil po izboru supstituiran s jednim, dva ili tri supstituenta koji je svaki neovisno odabran iz skupine koja sadrži halo; Het predstavlja biciklički aromatski heterociklički prstenasti sustav odabran iz skupine koju čine (a-1), (a-2), (a-3), (a-4) i (a-5): [image] R3a, R3b, R3c, R3d i R3e svaki neovisno predstavljaju vodik, halo, -NR7aR7b, C1-4alkil, C2-4alkenil, C3-6cikloalkil, -OH, ili -O-C1-4alkil; R7a predstavlja vodik; R7b predstavlja vodik, C3-6cikloalkil, ili C1-4alkil; R4a, R4b, R4c, R4d, R4e, R4f i R4g svaki neovisno predstavljaju vodik, halo, -NR8aR8b, ili C1-4alkil; R8a i R8b svaki neovisno predstavljaju vodik ili C1-4alkil; Q1 predstavlja N ili CR6a; Q2 predstavlja N ili CR6b; Q3 predstavlja N ili CR6c; Q4 predstavlja N ili CR6d; pod uvjetom da najviše jedan od Q3 i Q4 predstavlja N; Q8 predstavlja N ili CR6g; Q9 predstavlja N ili CR6h; Q10 predstavlja N ili CR6i; Q11 predstavlja N ili CR6j; Q5 predstavlja CR3d; Q6 predstavlja N; i Q7 predstavlja CR4f; ili Q5 predstavlja CR3d; Q6 predstavlja CR4e; i Q7 predstavlja N; ili Q5 predstavlja N; Q6 predstavlja CR4e; i Q7 predstavlja CR4f; ili Q5 predstavlja N; Q6 predstavlja CR4e; i Q7 predstavlja N; ili Q5 predstavlja N; Q6 predstavlja N; i Q7 predstavlja CR4f; ili Q5 predstavlja N; Q6 predstavlja N; i Q7 predstavlja N; R6a, R6b, R6c, R6d, R6e, R6f R6g, R6h, R6i i R6j svaki neovisno predstavljaju vodik, halogen, C1-4alkil, -NR9aR9b, ili C1-4alkil supstituiran s jednim, dva ili tri halo atoma; R9a i R9b svaki neovisno predstavljaju vodik ili C1-4alkil; ili njegova farmaceutski prihvatljiva adicijska sol ili solvat.
2. Spoj prema patentnom zahtjevu 1, naznačen time što Ar je po izboru supstituiran s jednim, dva, tri ili četiri supstituenta koji je svaki neovisno odabran iz skupine koja sadrži halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR10d, -NR10cR10d, cijano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkil,-C(=O)-C1-4alkil, C1-4alkiloksi, -C(=O)-O-C1-4alkil, C3-6cikloalkil, C2-6alkenil, C1-4alkil supstituiran s jednim C1-4alkiloksi, i C1-4alkil po izboru supstituiran s jednim - NR10aR10b; R10c i R10d svaki neovisno predstavljaju C3-6cikloalkil; C3-6cikloalkil supstituiran s jednim, dva ili tri supstituenta koji je svaki neovisno odabran iz skupine koja sadrži halo, -OH i -O-C1-4alkil; C1-4alkil supstituiran s jednim, dva ili tri supstituenta koji je svaki neovisno odabran iz skupine koja sadrži halo, -OH i - O-C1-4alkil; ili C1-4alkil supstituiran s jednim supstituentom odabranim iz skupine koja sadrži C3-6cikloalkil, R13 i R14; Het predstavlja biciklički aromatski heterociklički prstenasti sustav odabran iz skupine koju čine (a-1), (a-2) i (a-3): [image] R3a, R3b i R3c svaki neovisno predstavljaju vodik, halo, -NR7aR7b, C1-4alkil, ili -O-C1-4alkil; R7b predstavlja vodik ili C1-4alkil; R4a, R4b i R4c svaki neovisno predstavljaju vodik, halo, -NR8aR8b, ili C1-4alkil; Q1 predstavlja N ili CR6a; Q2 predstavlja N ili CR6b; Q3 predstavlja N ili CR6c; Q4 predstavlja N ili CR6d; pod uvjetom da najviše jedan od Q3 i Q4 predstavlja N; R6a, R6b, R6c, R6d, R6e i R6f svaki neovisno predstavljaju vodik, halogen, C1-4alkil, -NR9aR9b, ili C1-4alkil supstituiran s jednim, dva ili tri halo atoma.
3. Spoj prema patentnom zahtjevu 1 ili 2, naznačen time što Ar je po izboru supstituiran s jednim, dva, tri ili četiri supstituenta koji je svaki neovisno odabran iz skupine koja sadrži halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, -CF3, -C(=O)-NH-C1-4alkil,-C(=O)-C1-4alkil, C1-4alkiloksi, i C1-4alkil po izboru supstituiran s jednim -NR10aR10b; Het predstavlja biciklički aromatski heterociklički prstenasti sustav odabran iz skupine koju čine (a-1), (a-2) i (a-3): [image] R3a, R3b i R3c svaki neovisno predstavljaju vodik, halo, -NR7aR7b, ili -O-C1-4alkil; R7b predstavlja vodik ili C1-4alkil; R4a, R4b i R4c svaki neovisno predstavljaju vodik, halo, -NR8aR8b, ili C1-4alkil; Q1 predstavlja N ili CR6a; Q2 predstavlja N ili CR6b; Q3 predstavlja N ili CR6c; Q4 predstavlja N ili CR6d; pod uvjetom da najviše jedan od Q3 i Q4 predstavlja N; R6a, R6b, R6c, R6d, R6e i R6f svaki neovisno predstavljaju vodik, halogen, C1-4alkil, -NR9aR9b, ili C1-4alkil supstituiran s jednim, dva ili tri halo atoma.
4. Spoj prema patentnom zahtjevu 1, naznačen time što R1 predstavlja vodik; R2 predstavlja vodik; Y predstavlja -CH2-; Z predstavlja -X-CR5aR5b-, -CR5eR5g-CR5fR5h-, ili -CR5aR5b-X-; R5a, R5b, R5e, R5f, R5g, i R5h predstavljaju vodik; X predstavlja -O-; Ar predstavlja [image] pri čemu Ar je po izboru supstituiran u položaju označenom s α sa supstituentom odabranim iz skupine koju čine -NH2, -NH-C1-4alkil, i -NHR10d; i pri čemu Ar je po izboru supstituiran u položaju označenom s β sa supstituentom odabranim iz skupine koju čine halo i CF3; međutim pod uvjetom da je Ar supstituiran u najmanje jednom od položaja označenih s α ili β; R10d predstavlja C3-6cikloalkil; C1-4alkil supstituiran s jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituiran s jednim C3-6cikloalkilnim supstituentom; Het predstavlja biciklički aromatski heterociklički prstenasti sustav odabran iz skupine koju čine (a-1) i (a-4); R3a i R3d svaki neovisno predstavljaju vodik, halo, -NR7aR7b, C1-4alkil, ili -O-C1-4alkil; R7a predstavlja vodik; R7b predstavlja vodik ili C1-4alkil; R4a, R4d i R4f svaki neovisno predstavljaju vodik ili halo; Q1 predstavlja CR6a; Q2 predstavlja CR6b; Q8 predstavlja CR6g; Q9 predstavlja CR6h; Q5 predstavlja CR3d; Q6 predstavlja N; i Q7 predstavlja CR4f; R6a, R6b, R6g, i R6h predstavljaju vodik.
5. Spoj prema bilo kojem od patentnih zahtjeva 1 do 4, naznačen time što R1 predstavlja vodik; R2 predstavlja vodik; Y predstavlja -CH2-; Z predstavlja -X-CR5aR5b- ili -CR5eR5g-CR5fR5h-; R5a, R5b, R5e, R5f, R5g, i R5h predstavljaju vodik; X predstavlja -O-; Ar predstavlja [image] pri čemu Ar je po izboru supstituiran u položaju označenom s α sa supstituentom odabranim iz skupine koju čine -NH2, -NH-C1-4alkil, i -NHR10d; te pri čemu je Ar po izboru supstituiran u položaju označenom s β sa supstituentom odabranim iz skupine koju čine halo i CF3; međutim pod uvjetom da je Ar supstituiran u najmanje jednom od položaja označenih s α ili β; R10d predstavlja C3-6cikloalkil; C1-4alkil supstituiran s jednim, dva ili tri halo supstituenta; ili C1-4alkil supstituiran s jednim C3-6cikloalkilnim supstituentom; Het predstavlja biciklički aromatski heterociklički prstenasti sustav odabran iz skupine koju čine (a-1); R3a predstavlja vodik, halo, -NR7aR7b, C1-4alkil, ili -O-C1-4alkil; R7a predstavlja vodik; R7b predstavlja vodik ili C1-4alkil; R4a predstavlja vodik ili halo; Q1 predstavlja CR6a; Q2 predstavlja CR6b; R6a i R6b predstavljaju vodik.
6. Spoj prema patentnom zahtjevu 1 ili 2, naznačen time što R1 predstavlja vodik; R2 predstavlja vodik; Y predstavlja -CH2-; Z predstavlja -CR5eR5g-CR5fR5h-; R5e, R5f, R5g, i R5h predstavljaju vodik; Ar predstavlja bilo koji od sljedećih 10-eročlanih bicikličkih aromatskih prstenastih sustava: [image] [image] Ar je po izboru supstituiran s jednim, dva, tri ili četiri supstituenta svaki neovisno odabran iz skupine koja sadrži halo, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, - NHR10d, -NR10cR10d; R10c i R10d svaki neovisno predstavljaju C3-6cikloalkil; C3-6cikloalkil supstituiran s jednim, dva ili tri supstituenta svaki neovisno odabran iz skupine koja sadrži halo, -OH i -O-C1-4alkil; C1-4alkil supstituiran s jednim, dva ili tri supstituenta svaki neovisno odabran iz skupine koja sadrži halo, -OH i - O-C1-4alkil; ili C1-4alkil supstituiran s jednim C3-6cikloalkilnim supstituentom; Het predstavlja biciklički aromatski heterociklički prstenasti sustav odabran iz skupine koju čine (a-1); R3a predstavlja vodik, -NR7aR7b, ili -O-C1-4alkil; R7a predstavlja vodik; R7b predstavlja vodik ili C1-4alkil; R4a predstavlja vodik; Q1 predstavlja CR6a; Q2 predstavlja CR6b; R6a i R6b predstavljaju vodik.
7. Spoj prema patentnom zahtjevu 1, 2 ili 6, naznačen time što Ar je odabran iz skupine koju čine: [image] pri čemu je svaki Ar je po izboru supstituiran u položaju α sa supstituentom odabranim iz skupine koju čine -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, -NHR10d, i -NR10cR10d; i pri čemu Ar po izboru supstituiran u drugom položaju s halo supstituentom.
8. Spoj prema patentnom zahtjevu 1, naznačen time što Y predstavlja -CH2-; Z predstavlja -X-CR5aR5b- ili -CH2CH2-; R5a i R5b predstavljaju vodik; X predstavlja -O-; R11 predstavlja vodik; Ar predstavlja [image] Ar je po izboru supstituiran s jednim ili dva supstituenta svaki neovisno odabran iz skupine koja sadrži halo, -OH, -NH2, -NH-C1-4alkil, -N(C1-4alkil)2, cijano, i -CF3; Het predstavlja biciklički aromatski heterociklički prstenasti sustav odabran iz skupine koju čine (a-1); R3a predstavlja -NR7aR7b; R7a predstavlja vodik; R7b predstavlja vodik; R4a predstavlja vodik; Q1 predstavlja CR6a; Q2 predstavlja CR6b; R6a i R6b predstavljaju vodik.
9. Spoj prema patentnom zahtjevu 1, 2, 3 ili 6, naznačen time što Ar predstavlja [image]
10. Spoj prema patentnom zahtjevu 1, 2, 3, 7, 8 ili 9, naznačen time što R1 i R2 predstavljaju vodik.
11. Spoj prema bilo kojem od patentnih zahtjeva 1 do 3, zahtjevu 7, i zahtjevima 9 do 10, naznačen time što Y predstavlja -CH2-.
12. Spoj prema patentnom zahtjevu 11 naznačen time što Z predstavlja -CH2CH2-.
13. Spoj prema bilo kojem od patentnih zahtjeva 1 do 4, zahtjevu 7, i zahtjevima 9 do 12, naznačen time što Het predstavlja biciklički aromatski sustav heterocikličkog prstena s formulom (a-1).
14. Spoj prema patentnom zahtjevu 13, naznačen time što R3a predstavlja -NR7aR7b; i R7a i R7b predstavljaju vodik.
15. Spoj prema bilo kojem od patentnih zahtjeva 1 do 5, naznačen time što R5b, R5g i R5h predstavljaju vodik; Y predstavlja -CH2-; Het predstavlja (a-1); Q1 predstavlja CH; i Q2 predstavlja CH.
16. Spoj prema patentnom zahtjevu 1, naznačen time što je spoj [image] ili njegova farmaceutski prihvatljiva adicijska sol ili solvat.
17. Spoj prema patentnom zahtjevu 16, naznačen time što je spoj [image]
18. Farmaceutski pripravak naznačen time što sadrži farmaceutski prihvatljiv nosač i, kao aktivni sastojak, terapeutski učinkovitu količinu spoja prema bilo kojem od zahtjeva 1 do 17.
19. Spoj kako je definiran u bilo kojem od patentnih zahtjeva 1 do 18 naznačen time što je za upotrebu kao lijek.
20. Spoj kako je definiran u bilo kojem od patentnih zahtjeva 1 do 18 naznačen time što je za upotrebu u liječenju ili prevenciji bolesti ili stanja odabranog od poremećaja krvi, metaboličkih poremećaja, autoimunih poremećaja, raka, upalnih bolesti, kardiovaskularnih bolesti, neurodegenerativnih bolesti, pankreatitisa, zatajenja više organa, bolesti bubrega, agregacije trombocita, pokretljivosti spermija, odbacivanja transplantacije, odbacivanja transplantata, i ozljeda pluća.
21. Spoj za upotrebu prema patentnom zahtjevu 20 naznačen time što je za upotrebu u liječenju bolesti ili stanja odabranog od poremećaja krvi, metaboličkih poremećaja, autoimunih poremećaja, raka, upalnih bolesti, kardiovaskularnih bolesti, neurodegenerativnih bolesti, pankreatitisa, zatajenja više organa, bolesti bubrega, agregacije trombocita, pokretljivosti spermija, odbacivanja transplantacije, odbacivanja transplantata, i ozljede pluća.
22. Spoj za upotrebu prema patentnom zahtjevu 20 ili 21 naznačen time što je bolest ili stanje autoimuni poremećaj, rak, upalna bolest ili neurodegenerativna bolest.
23. Spoj za upotrebu prema patentnom zahtjevu 22 naznačen time što je bolest ili stanje rak.
24. Spoj za upotrebu prema patentnom zahtjevu 23 naznačen time što je rak ne-Hodgkinov limfom.
25. Spoj za upotrebu prema patentnom zahtjevu 24 naznačen time što je ne-Hodgkinov limfom B-stanični ne-Hodgkinov limfom.
26. Spoj za upotrebu prema patentnom zahtjevu 23 naznačen time što je rak, rak pluća.
27. Spoj za upotrebu prema patentnom zahtjevu 26 naznačen time što je rak pluća karcinom pluća nemalih stanica ili karcinom pluća malih stanica.
28. Spoj za upotrebu prema patentnom zahtjevu 23 naznačen time što je rak hematopoetski karcinom.
29. Spoj za upotrebu prema patentnom zahtjevu 28 naznačen time što je hematopoetski karcinom leukemija.
30. Spoj za upotrebu prema patentnom zahtjevu 29 naznačen time što je leukemija akutna mijelocitna leukemija, kronična limfocitna leukemija ili akutna limfocitna leukemija.
31. Spoj za upotrebu prema patentnom zahtjevu 23 naznačen time što je rak melanom ili adenoidni cistični karcinom.
32. Spoj za upotrebu prema patentnom zahtjevu 23 naznačen time što je rak, rak gušterače, rak prostate, rak debelog crijeva, rak rektuma, kolangiokarcinom, rak glave i vrata, rak nadbubrežne žlijezde, rak dojke, intraokularni melanom, rak jajnika, mijelodisplastični sindrom (MDS), ili rak žlijezda slinovnica.
33. Spoj za upotrebu prema patentnom zahtjevu 23 naznačen time što je rak, rak gušterače.
34. Spoj kako je definiran u patentnom zahtjevu 16 ili 17 naznačen time što je za upotrebu u liječenju proliferativnog poremećaja.
HRP20211997TT 2015-08-26 2016-08-25 Novi supstituirani nukleozidni analozi 6-6 bicikličkog aromatskog prstena za upotrebu kao inhibitori prmt5 HRP20211997T1 (hr)

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