HRP20160382T1 - Pirolopirazin-spirociklični piperidin amidi kao modulatori ionskih kanala - Google Patents

Pirolopirazin-spirociklični piperidin amidi kao modulatori ionskih kanala Download PDF

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HRP20160382T1
HRP20160382T1 HRP20160382TT HRP20160382T HRP20160382T1 HR P20160382 T1 HRP20160382 T1 HR P20160382T1 HR P20160382T T HRP20160382T T HR P20160382TT HR P20160382 T HRP20160382 T HR P20160382T HR P20160382 T1 HRP20160382 T1 HR P20160382T1
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alkyl
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cycloalkyl
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HRP20160382TT
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Sara S. Hadida Ruah
Edward Adam Kallel
Mark Thomas Miller
Vijayalaksmi Arumugam
Jason Mccartney
Corey Anderson
Peter Diederik Jan Grootenhuis
Licong JIANG
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Vertex Pharmaceuticals Incorporated
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Publication of HRP20160382T8 publication Critical patent/HRP20160382T8/hr

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Claims (25)

1. Spoj formule I: [image] ili njegova farmaceutski prihvatljiva sol, u kojem, nezavisno od svakog slučaja: R1 je H, C1-C8 alkil, C3-C8 cikloalkil, halo, CN, NR8SO2R8, SO2R8, SR8, SOR8, NR8COR8, NR8CO2R8, CON(R8)2, SO2N(R8)2, CF3, heterocikloalkil ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do dvije CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR8, ili dva R1 uzeta zajedno formiraju okso grupu, ili 3 do 7-člani fuzionirani cikloalkil prsten, ili 3 do 7-člani spirocikličan prsten; R2 je H, C1-C8 alkil, halo, C1-C8 haloalkil, CN, OH, SO2R8, SR8, SOR8, COR8, CO2R8, CON(R8)2, SO2N(R8)2, CF3, CHF2 ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do dvije CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2, CF2 ili NR8; R3 je H, C1-C8 alkil, C3-C8 cikloalkil, CO2R8, COR8, COH, CON(R8)2, CF3, CH2CF3, CH2CHF2 ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do dvije CHF2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR8; R4 je H, C1-C8 alkil, halo, C3-C8 cikloalkil, gdje do dvije CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR8, ili 2 R4 uzeti zajedno formiraju fuzionirani 3 do 7-člani cikloalkil prsten; R8 je H, C1-C8 alkil, CF3, C3-C8 cikloalkil, fluoroalkil, aril, heteroaril ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do dvije CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR, ili 2 R8 uzeta zajedno sa atomima za koje su vezani formiraju prsten; R9 je H, CF3, CO2R, OH, aril, heteroaril, C3-C8 cikloalkil, heterocikloalkil, N(R)2, NRCOR, CON(R)2, CN, halo ili SO2R; R je H, C1-C8 alkil, aril, heteroaril, C3-C8 cikloalkil ili heterocikloalkil; A je izborno supstituiran aril, heteroaril ili heterociklik; m je cijeli broj od 0 do 4 uključujući 0 i 4; n je cijeli broj od 0 do 3 uključujući 0 i 3; i o je cijeli broj od 0 do 4 uključujući 0 i 4.
2. Spoj prema patentnom zahtjevu 1, naznačen time što nezavisno od svakog slučaja: R1 je H, C1-C6 alkil, C3-C8 cikloalkil, halo, CN, NR8SO2R8, SO2R8, SR8, SOR8, NR8COR8, NR8CO2R8, CON(R8)2, SO2N(R8)2, CF3, heterocikloalkil ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do dvije CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR8, ili dva R1 uzeta zajedno formiraju okso grupu, ili 3 do 7-člani fuzionirani cikloalkil prsten, ili 3 do 7-člani spirociklični prsten; R2 je H, C1-C6 alkil, C1-C6 haloalkil, CN, OH, SO2R8, SR8, SOR8, CO2R8, CON(R8)2, SO2N(R8)2, CF3, CHF2, ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do dvije CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2, CF2 ili NR8; R3 je H, C1-C6 alkil, C3-C8 cikloalkil, CO2R8, COR8, COH, CON(R8)2, CF3, CH2CF3, CH2CHF2 ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do dvije CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR8; R4 je H, C1-C6 alkil, halo, C3-C8 cikloalkil, gdje do dvije CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR8, ili 2 R4 uzeti zajedno formiraju fuzionirani 3 do 7-člani cikloalkil prsten; R8 je H, C1-C6 alkil, CF3, C3-C8 cikloalkil ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do dvije CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR, ili 2 R8 uzeta zajedno sa atomima za koje su vezani formiraju prsten; R9 je H, CF3, CO2R, OH, aril, heteroaril, C3-C8 cikloalkil, heterocikloalkil, N(R)2, NRCOR, CON(R)2, CN ili SO2R; R je H, C1-C6 alkil, aril, heteroaril, C3-C8 cikloalkil ili heterocikloalkil; A je izborno supstituiran aril, heteroaril ili heterociklik; m je cijeli broj od 0 do 4 uključujući 0 i 4; n je cijeli broj od 0 do 3 uključujući 0 i 3; i o je cijeli broj od 0 do 4 uključujući 0 i 4.
3. Spoj prema patentnom zahtjevu 1, naznačen time što R2 je H, C1-C8 alkil, halo, CF3, CN, COR8, CON(R8)2, ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do dvije CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2, CF2 ili NR8.
4. Spoj prema patentnom zahtjevu 1, naznačen time što R2 je COCF3, COtBu, Cl, COCH3, CF2CF3, CH2CF3, CF3, CN, Br, COCH(CH3)2, COCH2CH3, CH(OH)CF3, SO2CH3, [image] COPh, [image] ili [image]
5. Spoj prema patentnom zahtjevu 1, naznačen time što R3 je H, C1-C8 alkil, CO2R8, COR8, COH, CON(R8)2 ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do dvije CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR8.
6. Spoj prema patentnom zahtjevu 1, naznačen time što R3 je H, CH3, CH2CH3, CH2CH2OCH3, CH2CH2OH, CH2CO2CH2CH3, CH2CON(CH3)2, CH2CONH2, CH2CN, benzil, ciklobutil, CH2CH(CH2)2, CH(CH2)2, CH2CF3, CH2CHF2, COCH3, COCH2CH3, CO2CH3, CO2CH2CH3, COH, CONH(CH3)2 ili CONHCH3.
7. Spoj prema patentnom zahtjevu 1, naznačen time što A je [image] u kojem: R5 je H, C1-C8 alkil, C3-C8 cikloalkil, C1-C8 alkoksi, halo, CN, OH, OR8, N(R8)2, NR8SO2R8, SO2R8, SOR8, SR8, CO2R8, NR8COR8, NR8CO2R8, CON(R8)2, SO2N(R8)2, CHF2, CF3, OCF3, OCHF2, R9, heterocikloalkil, heterocikloalkoksi, aril, heteroaril ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do tri CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR8; R6 je H, C1-C8 alkil, C3-C8 cikloalkil, C1-C8 alkoksi, C3-C8 cikloalkoksi, halo, CN, OH, OR8, N(R8)2, NR8SO2R8, SO2R8, SOR8, SR8, CO2R8, NR8COR8, NR8CO2R8, CON(R8)2, SO2N(R8)2, CF3, OCF3, OCHF2, R9, heterocikloalkil, heterocikloalkoksi, aril, heteroaril ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do tri CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR8; R7 je H, C1-C8 alkil, C3-C8 cikloalkil, C1-C8 alkoksi, halo, CN, OH, OR8, N(R8)2, NR8SO2R8, SO2R8, OSO2R8, SOR8, SR8, CO2R8, NR8COR8,NR8CO2R8, CON(R8)2, SO2N(R8)2, CF3, OCF3, OCHF2, R9, heterocikloalkil, heterocikloalkoksi, aril, heteroaril ili linearni, razgranati ili ciklični (C1-C8)-(R9)p, gdje p je 1 ili 2 i gdje do tri CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR8; ili dva slučaja R5 i R6, ili R6 i R7 su oba C1-C8 alkil i zajedno sa ugljicima za koje su vezani formiraju izborno supstituirani prsten koji sadrži do 2 heteroatoma.
8. Spoj prema patentnom zahtjevu 7, naznačen time što R5 je H, C1-C8 alkil, C1-C8 alkoksi, halo, OCF3, OCHF2, R9, ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do tri CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR7.
9. Spoj prema patentnom zahtjevu 7, naznačen time što R5 je H, CH3, OCH3, OCF3, OPh, Ph, OCHF2 ili F.
10. Spoj prema patentnom zahtjevu 7, naznačen time što R6 je H, C1-C8 alkil, C1-C8 alkoksi, halo, R9, ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do tri CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR8.
11. Spoj prema patentnom zahtjevu 7, naznačen time što R6 je H, CH3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CF3, CN, Ph, SO2CH3, OH, CH(CH3)2, OCH2CH2CH2CH3, F, Cl ili CH2OH.
12. Spoj prema patentnom zahtjevu 7, naznačen time što R7 je H, C1-C8 alkil, C1-C8 alkoksi, SO2R8, OSO2R8, SO2N(R8)2, R9, OCHF2, OCF3 ili linearni, razgranati ili ciklični (C1-C8)-(R9)p, gdje p je 1 ili 2 i gdje do tri CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR8.
13. Spoj prema patentnom zahtjevu 7, naznačen time što R7 je H, CH3, CH2CH3, tBu, Cl, F, OH, C(=CH2)CH3, OC(=CH2)CH3, OCH3, OCH2CH2CH2CH3, CH2OH, OCH2CH2OH, OCH2CH2CH2OH, OtBu, OCH(CH3)(CH2CH3), OCH2C(CH3)2OH, C(CH3)2OH, CH2C(CH3)2OH, CH(OH)CH(CH3)2, C(CH3)2CH2OH, OCH2CH2CH(CH3)2, OCH2CH2CH3, OCH(CH3)2, OCH2CH2OCH3, [image] SO2CH3, SO2tBu, SO2CH2CH3, SO2CH2CH(CH3)2, SO2CH(CH3)2, [image] , SO2NH(CH3), SO2NH(CH(CH2)2), SO2NH(CH2CH3), SO2NH(CH(CH3)2), SO2N(CH3)2, [image] , OPh, Ph, [image] , OCH2CH2OCH3, CH(CH3)2, SO2N(CH2CH3)2, CH2CH2CH2CH3, CH2CH2CH3, OCH2CH2CH2CH3, CH2OPh, [image] , OCH2Ph, CH2CH2CH2CH2CH3, OCH2CH3, OCH2CH(CH3)2, CH2CH3, CH2Ph, [image] , CCCH2OCH3, SO2CHF2, OCF3, [image] , OCHF2, [image] , CH2CH(CH3)2, OCH2tBu, [image] , OCH2CF3, [image] , [image] , CH2OCH2CH2CF3, CH2OCH2CF3, SO2CF3, C(CH3)2CH2CH3, C(CH2CH3)3, CH(OCH2CF3)2, [image] , CF3, OCH2C(CH3)2F, [image] , [image] , [image] , [image] , [image] , [image] , [image] , [image] , [image] , [image] , [image] , [image] , [image] , CH(OH)CH2OCH2CF3, CH(OCH2CF3)CH2OH, OSO2CF3, [image] ili OCH2CH2OCF3.
14. Spoj prema patentnom zahtjevu 7, naznačen time što [image] je: [image] [image] [image] [image] [image] [image] [image] [image] [image] ili [image]
15. Spoj prema patentnom zahtjevu 1, naznačen time što spoj ima formulu IA: [image] u kojem: R2 je C1-C8 alkil, halo, C1-C8 haloalkil, CN, OH, SO2R8, SR8, SOR8, COR8, CO2R8, CON(R8)2, SO2N(R8)2, CF3, CHF2 ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do dvije CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 CF2 ili NR8; R3 je H, C1-C8 alkil, CO2R8, COR8, COH, CON(R8)2, CF3 ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do dvije CH2 jedinice mogu biti zamijenjene sa CF2, O, CO, S, SO, SO2 ili NR8; R6 je H, C1-C8 alkil, C3-C8 cikloalkil, C1-C8 alkoksi, C3-C8 cikloalkoksi, halo, CN, OH, OR8, N(R8)2, NR8SO2R8, SO2R8, SOR8, SR8, CO2R8, NR8COR8, NR8CO2R8, CON(R8)2, SO2N(R8)2, CF3, OCF3, OCHF2, R9, heterocikloalkil, heterocikloalkoksi, aril, heteroaril ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do tri CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR8; R7 je H, C1-C8 alkil, C3-C8 cikloalkil, C1-C8 alkoksi, halo, CN, OH, OR8, N(R8)2, NR8SO2R8, SO2R8, SOR8, SR8, CO2R8, NR8COR8, NR8CO2R8, CON(R8)2, SO2N(R8)2, CF3, OCF3, OCHF2, R9, heterocikloalkil, heterocikloalkoksi, aril, heteroaril ili linearni, razgranati ili ciklični (C1-C8)-R9 gdje do tri CH2 jedinice mogu biti zamijenjene sa O, CO, S, SO, SO2 ili NR8.
16. Spoj prema patentnom zahtjevu 15, naznačen time što R2 je H, COCF3, COtBu, Cl, COCH3, CF2CF3, CH2CF3, CF3, CN, Br, COCH(CH3)2, COCH2CH3, CH(OH)CF3, SO2CH3, [image] COPh, [image] ili [image]
17. Spoj prema patentnom zahtjevu 15, naznačen time što R3 je H, CH3, CH2CH3, CH2CH2OCH3, CH2CH2OH, CH2CO2CH2CH3, CH2CON(CH3)2, CH2CONH2, CH2CN, benzil, ciklobutil, CH2CH(CH2)2, CH(CH2)2, CH2CF3, CH2CHF2, COCH3, COCH2CH3, CO2CH3, CO2CH2CH3, COH, CONH(CH3)2 ili CONHCH3.
18. Spoj prema patentnom zahtjevu 15, naznačen time što R6 je H, CH3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CF3, CN, Ph, SO2CH3, OH, CH(CH3)2, OCH2CH2CH2CH3, F, Cl ili CH2OH.
19. Spoj prema patentnom zahtjevu 15, naznačen time što R7 je H, CH3, CH2CH3, tBu, Cl, F, OH, C(=CH2)CH3, OC(=CH2)CH3, OCH3, OCH2CH2CH2CH3, CH2OH, OCH2CH2OH, OCH2CH2CH2OH, OtBu, OCH(CH3)(CH2CH3), OCH2C(CH3)2OH, C(CH3)2OH, CH2C(CH3)2OH, CH(OH)CH(CH3)2, C(CH3)2CH2OH, OCH2CH2CH(CH3)2, OCH2CH2CH3, OCH(CH3)2, OCH2CH2OCH3, [image] SO2CH3, SO2tBu, SO2CH2CH3, SO2CH2CH(CH3)2, SO2CH(CH3)2, [image] , SO2NH(CH3), SO2NH(CH(CH2)2), SO2NH(CH2CH3), SO2NH(CH(CH3)2), SO2N(CH3)2, [image] , OPh, Ph, [image] , OCH2CH2OCH3, CH(CH3)2, SO2N(CH2CH3)2, CH2CH2CH2CH3, CH2CH2CH3, OCH2CH2CH2CH3, CH2OPh, [image] , OCH2Ph, CH2CH2CH2CH2CH3, OCH2CH3, OCH2CH(CH3)2, CH2CH3, CH2Ph, [image] , CCCH2OCH3, SO2CHF2, OCF3, [image] , OCHF2, [image] , CH2CH(CH3)2, OCH2tBu, [image] , OCH2CF3, [image] , [image] , CH2OCH2CH2CF3, CH2OCH2CF3, SO2CF3, C(CH3)2CH2CH3, C(CH2CH3)3, CH(OCH2CF3)2, [image] , CF3, OCH2C(CH3)2F, [image] , [image] , [image] , [image] , [image] , [image] , [image] , [image] , [image] , [image] , [image] , [image] , [image] , CH(OH)CH2OCH2CF3, CH(OCH2CF3)CH2OH, OSO2CF3, [image] ili OCH2CH2OCF3.
20. Spoj prema patentnom zahtjevu 15, naznačen time što [image] grupa je: [image] [image] [image] [image] [image] [image] [image] ili [image]
21. Spoj prema patentnom zahtjevu 1, naznačen time što je spoj izabran iz slijedeće tabele: [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] [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] [image] [image] [image] [image] [image] [image] .
22. Farmaceutska kompozicija koja sadrži spoj prema patentnom zahtjevu 1 i farmaceutski prihvatljiv nosač.
23. Spoj prema patentnom zahtjevu 1 za uporabu u postupku inhibicije od napona zavisnog natrijeva ionskog kanala u: pacijentu; ili biološkom uzorku; koji sadrži primjenu na pacijenta, ili dovođenje u kontakt biološkog uzorka, sa spojem prema patentnom zahtjevu 1.
24. Spoj za uporabu prema patentnom zahtjevu 23, naznačen time što od napona ovisan natrijev ionski kanal je NaV 1.7.
25. Spoj prema patentnom zahtjevu 1 za uporabu u postupku liječenja ili redukcije težine kod subjekta akutne, kronične, neuropatske ili inflamatorne boli, artritisa, migrene, klaster glavobolja, trigeminalne neuralgije, herpatične neuralgije, općih neuralgija, epilepsije ili epileptičnih stanja, neurodegenerativnih bolesti, psihijatrijskih poremećaja, anksioznosti, depresije, bipolarnog poremećaja, miotonije, aritmije, poremećaja kretanja, neuroendokrinih poremećaja, ataksije, multiple skleroze, sindroma iritabilnog crijeva, inkontinencije, viscerale boli, osteoartritične boli, postherpetične neuralgije, dijabetičke neuropatije, radikularne boli, išijasa, boli u leđima, boli u glavi ili vratu, teške ili uporne boli, nociceptivne boli, probadajuće boli, post-kirurške boli, kancerske boli, moždanog udara, cerebralne ishemije, traumatske povrede mozga, amiotrofne lateralne skleroze, angine incirane stresom ili tjelesnim vježbama, palpitacija, hipertenzije, migrene ili abormalne gastro-intestinalne pokretljivosti, koji sadrži primjenu efikasne količine spoja prema patentnom zahtjevu 1.
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