HRP20230737T1 - 4-metilsulfonil-supstituirani spojevi piperidin uree korisni za liječenje srčanih poremećaja kao što je dilatirana kardiomiopatija (dcm) - Google Patents

4-metilsulfonil-supstituirani spojevi piperidin uree korisni za liječenje srčanih poremećaja kao što je dilatirana kardiomiopatija (dcm) Download PDF

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HRP20230737T1
HRP20230737T1 HRP20230737TT HRP20230737T HRP20230737T1 HR P20230737 T1 HRP20230737 T1 HR P20230737T1 HR P20230737T T HRP20230737T T HR P20230737TT HR P20230737 T HRP20230737 T HR P20230737T HR P20230737 T1 HRP20230737 T1 HR P20230737T1
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pharmaceutically acceptable
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Johan Oslob
Danielle Aubele
Jae Kim
Robert Mcdowell
Yonghong Song
Arvinder Sran
Min Zhong
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MyoKardia, Inc.
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Claims (23)

1. Spoj koji ima formulu (I): [image] ili njegova farmaceutski prihvatljiva sol, pri čemu Ar1 je 5- do 6-člani heteroaril koji ima najmanje jedan atom dušika član prstena; i koji je izborno supstituiran sa od 1-3 Ra; Ar2 je 5- do 10-člani aril ili heteroaril, koji je izborno supstituiran sa 1-5 Rb; R1 i R2 su svaki neovisno član izabran iz grupe koja se sastoji od sljedećih: H, F, C1-C4 alkil, C1-C4 deuteroalkil i C1-C4 haloalkil; ili izborno R1 i R2 mogu se kombinirati da formiraju C3- do C5 karbociklični prsten, koji je izborno supstituiran sa jednim ili dva F; R3 je član izabran iz grupe koja se sastoji od sljedećih: H, F, OH i C1-C4 alkil; svaki Ra je neovisno izabran iz grupe koja se sastoji od sljedećih: halo, CN, hidroksil, C1-C4 alkil, C1-C4 haloalkil, C1-C4 hidroksialkil, C1-C4 alkoksi, C1-C4 haloalkoksi, -CORa1, -CO2Ra1, -SO2Ra1, -SO2NRa1Ra2, i -CONRa1Ra2, pri čemu svaki Ra1 i Ra2 je neovisno izabran iz grupe koja se sastoji od sljedećih: H i C1-C4 alkil, ili izborno Ra1 i Ra2 kada su vezani za atom dušika se kombiniraju i formiraju 4- do 6-člani prsten; ili izborno, dva Ra supstituenta na susjednim članovima prstena se kombiniraju da bi se formirao 5- ili 6-člani prsten koji ima 0, 1 ili 2 člana prstena izabrana od O, N i S; i svaki Rb je neovisno izabran iz grupe koja se sastoji od sljedećih: halo, CN, hidroksil, C1-C4 alkil, C1-C4 deuteroalkil, C1-C4 haloalkil, C1-C4 alkoksi, C1-C4 haloalkoksi, C3-C6 cikloalkil, -NRb1Rb2, -CORb1, -CO2Rb1, -SO2Rb1, -SO2NRb1Rb2, -CONRb1Rb2 i 5- ili 6-člani heteroaril, koji je izborno supstituiran sa C1-C4 alkil, i pri čemu svaki Rb1 i Rb2 je neovisno izabran iz grupe koja se sastoji od sljedećih: H i C1-C4 alkil ili izborno Rb1 i Rb2 kada su vezani za atom dušika se kombiniraju i formiraju 4- do 6-člani prsten; ili izborno, dva Rb supstituenta na susjednim članovima prstena se kombiniraju da bi se formirao 5- ili 6-člani prsten koji ima 0, 1 ili 2 člana prstena izabrana od O, N i S.
2. Spoj prema zahtjevu 1, ili njegova farmaceutski prihvatljiva sol: pri čemu Ar1 je izabran iz grupe koja se sastoji od sljedećih: piridil, piridazinil, oksazolil, izoksazolil, 1,2,3-tiadiazolil, izotiazolil i tiazolil, od kojih je svaki izborno supstituiran sa od 1 do 2 Ra; ili pri čemu Ar2 je izabran iz grupe koja se sastoji od sljedećih: fenil, piridil i pirazolil, od kojih je svaki izborno supstituiran sa od 1 do 3 Rb; ili pri čemu R1 je izabran iz grupe koja se sastoji od H, F i CH3; ili pri čemu R2 je izabran iz grupe koja se sastoji od H, F i CH3; ili pri čemu R1 i R2 uzeti zajedno sa atomom ugljika za koji je svaki vezan formiraju ciklopropan ili ciklobutan prsten; ili pri čemu R1 i R2 nisu isti i najmanje jedan od R1 i R2 je izabran iz grupe koja se sastoji od F i CH3; ili pri čemu R3 je H ili F; ili pri čemu Ar1 je 4-piridinil i Ar2 je fenil, izborno supstituiran sa od 1 do 3 Rb.
3. Spoj prema zahtjevu 2, ili njegova farmaceutski prihvatljiva sol, naznačen time što Rb je izabran iz grupe koja se sastoji od sljedećih: halo, CN, C1-C4 alkil, C1-C4 haloalkil, C1-C4 alkoksi i C1-C4 haloalkoksi.
4. Spoj prema zahtjevu 1 ili 2, ili njegova farmaceutski prihvatljiva sol, naznačen time što atom ugljika koji nosi R1 i R2 ima stereokemijsku R konfiguraciju.
5. Spoj prema zahtjevu 1, ili njegova farmaceutski prihvatljiva sol: pri čemu R3 je H i svaki od R1 i R2 je F, ili pri čemu R3 je H i svaki od R1 i R2 je CH3, ili pri čemu R3 je H, R1 je CH3 i R2 je F.
6. Spoj prema zahtjevu 5, ili njegova farmaceutski prihvatljiva sol, naznačen time što atom ugljika koji nosi R1 i R2 ima stereokemijsku R-konfiguraciju.
7. Spoj prema zahtjevu 1, ili njegova farmaceutski prihvatljiva sol, naznačen time što Ar1 je 4-piridazinil i Ar2 je fenil, izborno supstituiran sa od 1 do 3 Rb.
8. Spoj prema zahtjevu 7, ili njegova farmaceutski prihvatljiva sol: pri čemu R3 je H i svaki od R1 i R2 je F, ili pri čemu R3 je H i svaki od R1 i R2 je CH3, ili pri čemu R3 je H, R1 je CH3 i R2 je F; izborno pri čemu atom ugljika koji nosi R1 i R2 ima stereokemijsku R-konfiguraciju.
9. Spoj prema zahtjevu 1, ili njegova farmaceutski prihvatljiva sol, naznačen time što Ar1 je izabran iz grupe koja se sastoji od sljedećih: 1,2,3-tiadiazol-5-il, izotiazol-5-il i tiazol-5-il, od kojih je svaki izborno supstituiran sa jednim Ra.
10. Spoj prema zahtjevu 9, ili njegova farmaceutski prihvatljiva sol, naznačen time što R3 je H i svaki od R1 i R2 je F, ili pri čemu R3 je H i svaki od R1 i R2 je CH3, ili pri čemu R3 je H, R1 je CH3 i R2 je F.
11. Spoj prema zahtjevu 10, ili njegova farmaceutski prihvatljiva sol, naznačen time što atom ugljika koji nosi R1 i R2 ima stereokemijsku R-konfiguraciju.
12. Spoj prema zahtjevu 1, naznačen time što spoj je [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] ili [image] ili njegova farmaceutski prihvatljiva sol.
13. Spoj prema zahtjevu 1, naznačen time što spoj je [image] [image] [image] ili [image] ili njegova farmaceutski prihvatljiva sol, ili pri čemu spoj je [image] [image] [image] ili [image] ili njegova farmaceutski prihvatljiva sol.
14. Spoj prema zahtjevu 1, naznačen time što spoj je formule: [image] ili njegova farmaceutski prihvatljiva sol.
15. Spoj prema zahtjevu 1, naznačen time što spoj je formule: [image]
16. Farmaceutski pripravak koji sadrži spoj prema bilo kojem od zahtjeva 1-13, ili njegovu farmaceutski prihvatljivu sol, i farmaceutski prihvatljiv ekscipijens.
17. Farmaceutski pripravak koji sadrži spoj ili njegovu farmaceutski prihvatljivu sol prema zahtjevu 14 ili spoj prema zahtjevu 15, i farmaceutski prihvatljiv ekscipijens.
18. Spoj ili njegova farmaceutski prihvatljiva sol prema bilo kom od zahtjeva 1-14 ili spoj prema zahtjevu 15: za uporabu za liječenje dilatirane kardiomiopatije (DCM) ili srčanog poremećaja koji ima patofiziološku karakteristiku DCM, kao što su poremećaji sa sistolnom disfunkcijom ili smanjenjem sistolne rezerve, ili za uporabu za liječenje bolesti ili poremećaja izabranog iz grupe koja se sastoji od sistolne disfunkcije, dijastolne disfunkcije, HFrEF, HFpEF, kronične srčane insuficijencije i akutne srčane insuficijencije.
19. Spoj ili njegova farmaceutski prihvatljiva sol prema bilo kojem od zahtjeva 1-14 ili spoj prema zahtjevu 15, za uporabu za liječenje bolesti ili poremećaja naznačeno sistolnom disfunkcijom lijeve komore ili smanjenim kapacitetom vježbanja zbog sistolne disfunkcije; u kombinaciji sa terapijama koje imaju za cilj liječenje srčane insuficijencije.
20. Spoj ili njegova farmaceutski prihvatljiva sol prema bilo kojem od zahtjeva 1-14 ili spoj prema zahtjevu 15, za uporabu za liječenje dilatirane kardiomiopatije (DCM) ili srčanog poremećaja koji ima patofiziološku karakteristiku povezanu sa DCM, u kombinaciji sa terapijama koje usporavaju progresiju srčane insuficijencije nishodnom regulacijom neurohormonske stimulacije srca i pokušavaju spriječiti remodeliranje srca (npr. ACE inhibitori, blokatori angiotenzinskih receptora (ARB), β-blokatori, antagonisti receptora aldosterona ili inhibitori neuronske endopeptidaze); terapije koje poboljšavaju srčanu funkciju stimulacijom srčane kontraktilnosti (npr. pozitivna inotropna sredstva, kao što je β-adrenergički agonist dobutamin ili inhibitor fosfodiesteraze milrinon); i/ili terapije koje smanjuju preopterećenje srca (npr. diuretici, kao što je furosemid) ili naknadno opterećenje (vazodilatatori bilo koje klase, uključujući, ali ne ograničavajući se na blokatore kalcijevih kanala, inhibitore fosfodiesteraze, antagoniste endotelinskih receptora, inhibitore renina ili modulatore miozina glatkih mišića).
21. Spoj, ili njegova farmaceutski prihvatljiva sol, za uporabu prema zahtjevu 20, naznačen time što se navedeni spoj, ili njegova farmaceutski prihvatljiva sol, primjenjuje u kombinaciji sa beta-blokatorom.
22. Spoj ili njegova farmaceutski prihvatljiva sol prema zahtjevu 14 ili spoj prema zahtjevu 15 za uporabu za liječenje dilatirane kardiomiopatije (DCM), ili srčanog poremećaja koji ima patofiziološku karakteristiku DCM, kao što su poremećaji sa sistolnom disfunkcijom ili smanjenjem sistolne rezerve.
23. Spoj ili njegova farmaceutski prihvatljiva sol prema zahtjevu 14 ili spoj prema zahtjevu 15 za uporabu za liječenje sistolne disfunkcije ili HFrEF.
HRP20230737TT 2015-01-22 2016-01-21 4-metilsulfonil-supstituirani spojevi piperidin uree korisni za liječenje srčanih poremećaja kao što je dilatirana kardiomiopatija (dcm) HRP20230737T1 (hr)

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