HRP20230409T1 - Fuzionirani pirolini koji djeluju kao inhibitori ubikvitin specifične proteaze 30 (usp30) - Google Patents

Fuzionirani pirolini koji djeluju kao inhibitori ubikvitin specifične proteaze 30 (usp30) Download PDF

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HRP20230409T1
HRP20230409T1 HRP20230409TT HRP20230409T HRP20230409T1 HR P20230409 T1 HRP20230409 T1 HR P20230409T1 HR P20230409T T HRP20230409T T HR P20230409TT HR P20230409 T HRP20230409 T HR P20230409T HR P20230409 T1 HRP20230409 T1 HR P20230409T1
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alkylene
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haloalkyl
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Alex J. BUCKMELTER
Justin Andrew CARAVELLA
Hongbin Li
Matthew W. Martin
Steven Mischke
David James Richard
Angela V. West
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Forma Therapeutics, Inc.
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Claims (15)

1. Spoj, naznačen time, što je predstavljen formulom (I): [image] ili njegova farmaceutski prihvatljiva sol, pri čemu Ra, Rb, Rc, Rd, Re, Rf, Rg i Rh su definirani kako slijedi: (i) Ra i Rb tvore C1-C4 alkilen skupinu između atoma s kojima su vezani, gdje je navedena C1-C4 alkilen skupina supstituirana s 0-4 supstituenta odabrana iz skupine koju čine halogen, C1-C3 alkil, i C1-C3 haloalkil; i Rc, Rd, Re, Rf, Rg i Rh su svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil; ili (ii) Ra i Re tvore C1-C2 alkilen skupinu između atoma s kojima su vezani, gdje je navedena C1-C2 alkilen skupina supstituirana s 0-4 supstituenta odabrana iz skupine koju čine halogen, C1-C3 alkil, i C1-C3 haloalkil; i Rb, Rc, Rd, Rf, Rg i Rh su svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil; ili (iii) Ra i Rg tvore C1-C3 alkilen skupinu između atoma s kojima su vezani, gdje je navedena C1-C3 alkilen skupina supstituirana s 0-4 supstituenta odabrana iz skupine koju čine halogen, C1-C3 alkil, i C1-C3 haloalkil; i Rb, Rc, Rd, Re, Rf i Rh su svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil; ili (iv) Rb i Rc tvore C1-C4 alkilen skupinu između atoma s kojima su vezani, gdje je navedena C1-C4 alkilen skupina supstituirana s 0-4 supstituenta odabrana iz skupine koju čine halogen, C1-C3 alkil, i C1-C3 haloalkil; i Ra, Rd, Re, Rf, Rg i Rh su svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil; ili (v) Rb i Re tvore C1-C3 alkilen skupinu između atoma s kojima su vezani, gdje je navedena C1-C3 alkilen skupina supstituirana s 0-4 supstituenta odabrana iz skupine koju čine halogen, C1-C3 alkil, i C1-C3 haloalkil; i Ra, Rc, Rd, Rf, Rg i Rh su svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil; ili (vi) Rb i Rg tvore C1-C4 alkilen skupinu između atoma s kojima su vezani, gdje je navedena C1-C4 alkilen skupina supstituirana s 0-4 supstituenta odabrana iz skupine koju čine halogen, C1-C3 alkil, i C1-C3 haloalkil; i Ra, Rc, Rd, Re, Rf i Rh su svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil; ili (vii) Rc i Rd zajedno s atomom s kojim su vezani, tvore 3-6-člani cikloalkil ili heterocikloalkil, pri čemu je navedeni 3-6-člani cikloalkil ili heterocikloalkil supstituiran s 0-4 supstituenta odabrana iz skupine koju čine halogen, C1-C3 alkil, i C1-C3 haloalkil; i Ra, Rb, Re, Rf, Rg i Rh su svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil; ili (viii) Rc i Rd zajedno tvore =O; i Ra, Rb, Re, Rf, Rg i Rh su svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil; ili (ix) Rc i Re tvore C1-C4 alkilen skupinu između atoma s kojima su vezani, pri čemu je navedena C1-C4 alkilen skupina supstituirana s 0-4 supstituenta odabrana iz skupine koju čine halogen, C1-C3 alkil, i C1-C3 haloalkil; i Ra, Rb, Rd, Rf, Rg i Rh su svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil; ili (x) Rc i Rg tvore C1-C3 alkilen skupinu između atoma s kojima su vezani, pri čemu je navedena C1-C3 alkilen skupina supstituirana s 0-4 supstituenta odabrana iz skupine koju čine halogen, C1-C3 alkil, i C1-C3 haloalkil; i Ra, Rb, Rd, Re, Rf i Rh su svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil; ili (xi) Re i Rf zajedno s atomom s kojim su vezani, tvore 3-6-člani cikloalkil ili heterocikloalkil, pri čemu je navedeni 3-6-člani cikloalkil ili heterocikloalkil supstituiran s 0-4 supstituenta odabrana iz skupine koju čine halogen, C1-C3 alkil, i C1-C3 haloalkil; i Ra, Rb, Rc, Rd, Rg i Rh su svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil; ili (xii) Re i Rf zajedno tvore =O; i Ra, Rb, Rc, Rd, Rg i Rh su svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil; ili (xiii) Re i Rg tvore C1-C3 alkilen skupinu između atoma s kojima su vezani, pri čemu je navedena C1-C3 alkilen skupina supstituirana s 0-4 supstituenta odabrana iz skupine koju čine halogen, C1-C3 alkil, i C1-C3 haloalkil; i Ra, Rb, Rc, Rd, Rf i Rh su svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil; ili (xiv) Rg i Rh zajedno s atomom s kojim su vezani, tvore 3-6-člani cikloalkil ili heterocikloalkil, pri čemu je navedeni 3-6-člani cikloalkil ili heterocikloalkil supstituiran s 0-4 supstituenta odabrana iz skupine koju čine halogen, C1-C3 alkil, i C1-C3 haloalkil; i Ra, Rb, Rc, Rd, Re i Rf su svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil; ili (xv) Rg i Rh zajedno tvore =O; i Ra, Rb, Rc, Rd, Re i Rf su svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil; i Ar1 je fenilen ili 5-6-člani heteroarilen, gdje je navedeni fenilen ili heteroarilen supstituiran s m R1 skupina; i Ar2 je fenilen ili 5-10-člani heteroarilen, gdje je navedeni fenilen ili heteroarilen supstituiran s n R2 skupina; L je -O-, -S-, -NR3-, -C(R4)2-, -S(O)2-, ili -S(O)-; M je 3-6-člani cikloalkil, fenil, ili 5-6-člani heteroaril, gdje je navedeni cikloalkil, fenil ili heteroaril supstituiran s p R5 skupina; svako pojavljivanje R1, R2 i R5 je neovisno halogen, cijano, NO2, okso, hidroksil, -R6, -OR6, C1-C6 alkil, C1-C6 haloalkil, C1-C6 hidroksialkil, -C1-C6 alkilen-R6, C1-C6 alkoksi, C1-C6 haloalkoksi, -C0-C3 alkilen-NR6R7, -C0-C3 alkilen-NR7R8, -C0-C3 alkilen-C(O)NR6R7, -C0-C3 alkilen-C(O)NR7R8, -C0-C3 alkilen-NR7C(O)R6, -C0-C3 alkilen-NR7C(O)R8, -C0-C3 alkilen-NR7S(O)2R6, -C0-C3 alkilen-C(O)R6, -C0-C3 alkilen-C(O)R7, -C0-C3 alkilen-SR6, -C0-C3 alkilen-S(O)R6, -C0-C3 alkilen-S(O)2R6, -C0-C3 alkilen-S(O)2R7, -C0-C3 alkilen-S(O)2NR6R7, -C0-C3 alkilen-S(O)2NR7R8, -C0-C3 alkilen-NR7C(O)NR8R9, -C0-C3 alkilen-NR7S(O)2NR8R9, -C0-C3 alkilen-C(O)OR7, -C0-C3 alkilen-C(O)OR6, -C0-C3 alkilen-OC(O)R7, -C0-C3 alkilen-OC(O)R6, -C0-C3 alkilen-NR7C(O)OR8, ili -C0-C3 alkilen-NR7S(O)2R8; R3 je H, C1-C6 alkil, ili C1-C6 haloalkil; svaki R4 je neovisno H, C1-C6 alkil, ili C1-C6 haloalkil, ili dvije R4 skupine zajedno s ugljikovim atomom s kojim su vezane, tvore 3-6-člani cikloalkil ili heterocikloalkil; svaki R6 je 5-10-člani heteroaril, 4-10-člani heterocikloalkil, 6-10-člani aril, ili 3-8-člani cikloalkil, gdje navedeni heteroaril, heterocikloalkil, aril, ili cikloalkil je opcionalno supstituiran s 1-5 supstituenata neovisno odabranih iz skupine koju čine halogen, okso, C1-C6 alkil, C1-C6 haloalkil, C1-C6 hidroksialkil, C1-C6 alkoksi, C1-C6 haloalkoksi, C2-C6 alkenil, C2-C6 alkinil, 5-10-člani heteroaril, 4-10-člani heterocikloalkil, 6-10-člani aril, 3-8-člani cikloalkil, -NR10C(O)NR11R12, -NR10R11, -C(O)R10, -NR10C(O)R11, -NR10C(O)OR11, -S(O)2R10, -C(O)NR10R11, -C(O)OR10, -S(O)2NR10R11, -NR10S(O)2R11, -OR10, -OC(O)R10, -OS(O)2R10, -OC(O)NR10R11, -OC(O)OR10, -OS(O)2NR10R11, -C(O)NR10C(O)NR11R12, -C(O)C(O)R10, -C(O)NR10C(O)R11, -C(O)NR10C(O)OR11, -C(O)S(O)2R10, -C(O)C(O)NR10R11, -C(O)C(O)OR10, -C(O)S(O)2NR10R11, -C(O)NR10S(O)2R11, -C1-C6 alkilen-R10, -C1-C6 alkilen-NR10C(O)NR11, -C1-C6 alkilen-NR10R11, -C1-C6 alkilen-C(O)R10, -C1-C6 alkilen-NR10C(O)R11, -C1-C6 alkilen-NR10C(O)OR11, -C1-C6 alkilen-S(O)2R10, -C1-C6 alkilen-C(O)NR10R11, -C1-C6 alkilen-C(O)OR10, -C1-C6 alkilen- S(O)2NR10R11, -C1-C6 alkilen- NR10S(O)2R11, -C1-C6 alkenilen-R10, -C1-C6 alkenilen-NR10C(O)NR10R11, -C1-C6 alkenilen-NR10R11, -C1-C6 alkenilen-C(O)R10, -C1-C6 alkenilen-NR10C(O)R11, -C1-C6 alkenilen-NR10C(O)OR11, -C1-C6 alkenilen-S(O)2R10, -C1-C6 alkenilen-C(O)NR10R11, -C1-C6 alkenilen-C(O)OR10, -C1-C6 alkenilen-S(O)2NR10R11, i -C1-C6 alkenilen-NR10S(O)2R11; svaki R7, R8 i R9 je neovisno vodik ili C1-C6 alkil; svaki R10, R11 i R12 je neovisno vodik, C1-C6 alkil, 5-10-člani heteroaril, 4-10-člani heterocikloalkil, 6-10-člani aril, ili 3-8-člani cikloalkil; m je 0-4; n je 0-4; i p je 0-4.
2. Spoj prema patentnom zahtjevu 1, naznačen time, što spoj je: (a) predstavljen formulom (I-B): [image] ili njegova farmaceutski prihvatljiva sol, pri čemu: X1 je C ili N; X2 je CH, CR1, O, S, N, NH, ili NR1, ukoliko valencija dopušta; X3 je CH, CR1, O, S, N, NH, ili NR1, ukoliko valencija dopušta; X4 je C ili N; X6 je CH, CR1, O, S, N, NH, ili NR1, ukoliko valencija dopušta; X3 je CH, CR2, ili N; X4 je CH, CR2, ili N; X5 je CH, CR2, ili N; X6 je CH, CR2, ili N; i/ili (b) predstavljen formulom (I-C): [image] ili njegova farmaceutski prihvatljiva sol; i/ili (c) predstavljen formulom (I-E): [image] ili njegova farmaceutski prihvatljiva sol.
3. Spoj prema patentnom zahtjevu 1 ili zahtjevu 2, naznačen time, što Rb i Rc tvore C1-C4 alkilen skupinu između atoma s kojima su vezani, i svaki od Ra, Rd, Re, Rf, Rg i Rh je vodik.
4. Spoj prema bilo kojem od patentnih zahtjeva 1 do 3, naznačen time, što spoj je: (a) predstavljen formulom (I-1): [image] ili njegova farmaceutski prihvatljiva sol, pri čemu su Rj, Rk, Rm i Rn svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil, gdje opcionalno: (i) spoj je predstavljen formulom (I-B-1): [image] ili njegova farmaceutski prihvatljiva sol; i/ili (ii) spoj je predstavljen formulom (I-C-1): [image] ili njegova farmaceutski prihvatljiva sol; i/ili (iii) svaki od Ra, Rd, Re, Rf, Rg, Rh, Rj, Rk, Rm i Rn je vodik; ili (b) predstavljen fomulom (I-2): [image] ili njegova farmaceutski prihvatljiva sol, pri čemu su Rj, i Rk svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil, gdje opcionalno: (i) spoj je predstavljen formulom (I-B-2): [image] ili njegova farmaceutski prihvatljiva sol; i/ili (ii) spoj je predstavljen formulom (I-C-2): [image] ili njegova farmaceutski prihvatljiva sol; i/ili (iii) svaki od Ra, Rd, Re, Rf, Rg, Rh, Rj i Rk je vodik; ili (c) predstavljen formulom (I-3): [image] ili njegova farmaceutski prihvatljiva sol, pri čemu su Rj, Rk, Rm, Rn, Ro i Rp svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil, gdje opcionalno: (i) spoj je predstavljen formulom (I-B-3): [image] ili njegova farmaceutski prihvatljiva sol; i/ili (ii) spoj je predstavljen formulom (I-C-3): [image] ili njegova farmaceutski prihvatljiva sol; i/ili (iii) svaki od Ra, Rd, Re, Rf, Rg, Rh, Rj, Rk, Rm, Rn, Ro i Rp je vodik.
5. Spoj prema patentnom zahtjevu 1 ili zahtjevu 2, naznačen time, što: (a) Rc i Re tvore C1-C4 alkilen skupinu između atoma s kojima su vezani; i svaki Ra, Rb, Rd, Rf, Rg i Rh je vodik; i/ili (b) spoj je predstavljen formulom (I-4): [image] ili njegova farmaceutski prihvatljiva sol, pri čemu su Rq i Rr svaki neovisno vodik, halogen, C1-C3 alkil, ili C1-C3 haloalkil, gdje opcionalno: (i) spoj je predstavljen formulom (I-B-4): [image] ili njegova farmaceutski prihvatljiva sol; i/ili (ii) spoj je predstavljen formulom (I-C-4): [image] ili njegova farmaceutski prihvatljiva sol; i/ili (iii) svaki Ra, Rb, Rd, Rf, Rg, Rh, Rq i Rr je vodik.
6. Spoj prema patentnom zahtjevu 1 ili zahtjevu 2, naznačen time, što: (a) Ra i Re tvore C1-C2 alkilen skupinu između atoma s kojima su vezani; i svaki Rb, Rc, Rd, Rf, Rg i Rh je vodik; ili (b) Rc i Rd zajedno s atomom s kojim su vezani, tvore 3-6-člani cikloalkil ili heterocikloalkil, i svaki Ra, Rb, Re, Rf, Rg i Rh je vodik; ili (c) Rc i Rg tvore C1-C3 alkilen skupinu između atoma s kojima su vezani; i svaki Ra, Rb, Rd, Re, Rf i Rh je vodik; ili (d) Re i Rf zajedno s atomom s kojim su vezani, tvore 3-6-člani cikloalkil ili heterocikloalkil, i svaki Ra, Rb, Rc, Rd, Rg i Rh je vodik; ili (e) Re i Rg tvore C1-C3 alkilen skupinu između atoma s kojima su vezani; i svaki Ra, Rb, Rc, Rd, Rf i Rh je vodik.
7. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, što Ar1 je: (a) 5-6-člani heteroarilen, gdje opcionalno Ar1 je 5-člani heteroarilen; ili (b) fenilen.
8. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, što Ar2 je: (a) 5-10-člani heteroarilen; ili (b) fenilen; ili (c) fenilen ili 5-6-člani heteroarilen.
9. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, što L je: (a) -O-, -S-, ili -NH-; ili (b) -O-.
10. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, što: (a) M je fenil supstituiran s p R5 skupina, opcionalno gdje M je fenil; i/ili (b) svako pojavljivanje R1, R2 i R5 je neovisno odabrano od sljedećih: halogen, cijano, hidroksil, C1-C6 alkil, C1-C6 alkoksi, C1-C6 haloalkil, i C1-C6 hidroksialkil; i/ili (c) m je 0; i/ili (d) n je 0; i/ili (e) p je 0 ili 1, opcionalno gdje p je 0.
11. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, što: [image] se bira od: [image] [image]
12. Spoj prema bilo patentnom zahtjevu 1 ili njegova farmaceutski prihvatljiva sol, naznačen time, što se spoj bira od: [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] ili time, da se spoj bira od: [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image] (nastavak) [image]
13. Farmaceutski pripravak, naznačen time, što sadrži spoj prema bilo kojem od patentnih zahtjeva 1 do 12, ili njegovu farmaceutski prihvatljivu sol, i farmaceutski prihvatljiv nosač.
14. Spoj prema bilo kojem od patentnih zahtjeva 1 do 12, ili njegova farmaceutski prihvatljiva sol, ili farmaceutski pripravak prema patentnom zahtjevu 13, naznačen time, što je za uporabu u postupku inhibiranja USP30 kod pacijenta kojemu je to potrebno, koji obuhvaća davanje pacijentu terapijski učinkovite količine spoja prema bilo kojem od patentnih zahtjeva 1 do 12, ili njegove farmaceutski prihvatljive soli, ili farmaceutskog pripravka prema patentnom zahtjevu 13.
15. Spoj prema bilo kojem od patentnih zahtjeva 1 do 12, ili njegova farmaceutski prihvatljiva sol, ili farmaceutski pripravak prema patentnom zahtjevu 13, naznačen time, što je za uporabu u postupku liječenja neurodegenerativnog poremećaja kod pacijenta kojemu je to potrebno, koji obuhvaća davanje pacijentu terapijski učinkovite količine spoja prema bilo kojem od patentnih zahtjeva 1 do 12, ili njegove farmaceutski prihvatljive soli, ili farmaceutskog pripravka prema patentnom zahtjevu 13, opcionalno pritom se kod neurodegenerativnog poremećaja radi o Parkinsonovoj bolesti.
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