HRP20160476T1 - Inhibitori replikacije virusa hepatitisa c - Google Patents

Inhibitori replikacije virusa hepatitisa c Download PDF

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Publication number
HRP20160476T1
HRP20160476T1 HRP20160476TT HRP20160476T HRP20160476T1 HR P20160476 T1 HRP20160476 T1 HR P20160476T1 HR P20160476T T HRP20160476T T HR P20160476TT HR P20160476 T HRP20160476 T HR P20160476T HR P20160476 T1 HRP20160476 T1 HR P20160476T1
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Croatia
Prior art keywords
group
independently selected
6alkyl
hydrogen
methyl
Prior art date
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HRP20160476TT
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English (en)
Inventor
Craig A. Coburn
John A. Mccauley
Steven W. Ludmerer
Kun Liu
Joseph P. Vacca
Hao Wu
Bin Hu
Richard Soll
Fei Sun
Xinghai Wang
Man YAN
Chengren Zhang
Mingwei Zheng
Bin Zhong
Jian Zhu
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Merck Sharp & Dohme Corp.
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=42781502&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=HRP20160476(T1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Merck Sharp & Dohme Corp. filed Critical Merck Sharp & Dohme Corp.
Publication of HRP20160476T1 publication Critical patent/HRP20160476T1/hr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Claims (18)

1. Spoj koji ima strukturnu formulu (I): [image] i/ili njegova farmaceutski prihvatljiva sol, u kojem: svaki R1 je nezavisno izabran iz grupe koja se sastoji od vodika, halogena, -OR3a, -CN, -(CH2)0-6C(O)R3; -CO2R3a, -C(O)N(R3a)2, -SR3a, -S(O)R3a, -S(O2)R3a, -(CH2)0-6(R3a)2, -N(R3a)SO2R3a, -N(R3a)CO2R3a, -N(R3a)C(O)3, -N(R3a)COR3a, -N(R3a)C(O)N(R3a), C1-6alkil, C3-8karbociklusa koji sadrži od 0 do 3 heteroatoma izabrana od N, O i S, i fenil, i C1-6alkil, C3-8karbociklus i fenil su supstituirani sa od 0 do 3 supstituenta nezavisno izabrana iz grupe koja se sastoji od vodika, halogena, -OR3a, -CN, -CO2R3a, -C(O)N(R3a)2, -N(R3a)2, -N(R3a)CO2R3a, -SR3a, -S(O)R3a, -S(O2)R3a, -N(R3a)SO2R3a, N(R3a)CO2R3a, -N(R3a)C(O)N(R3a), C1-6alkil, -O-C1-6alkil, -S-C1-6alkil i C3-8cikloalkil; u je od 0 do 4, svaki R3 je nezavisno izabran iz grupe koja se sastoji od vodika, C1-6alkil, -OH, -O-C1-6alkil i C3-8cikloalkil, i svaki R3a je nezavisno izabran iz grupe koja se sastoji od vodika, C1-6alkil i C3-8cikloalkil; svaki R2 je nezavisno izabran iz grupe koja se sastoji od vodika, halogena, -OR4a, -CN, -CO2R4a, -C(O)R4a, -C(O)N(R4a)2, -N(R4a)2, -N(R4a)COR4, -N(R4a)CO2R4a, -N(R4a)C(O)N(R4a), -N(R4a)SO2R4a, -SR4a, -S(O)R4a, -S(O2)R4a, C1-6alkil supstituiranog sa od 0 do 4 R4 i C3-8cikloalkil supstituiranog sa od 0 do 4 R4, ν je od 0 do 4, svaki R4 je nezavisno izabran iz grupe koja se sastoji od vodika, -OH, C1-6alkil i C3-8cikloalkil; svaki R4a je nezavisno izabran iz grupe koja se sastoji od vodika, C1-6alkil i C3-8cikloalkil; gdje navedeni [image] i navedeni [image] su uzeti zajedno sa jednim navedenim supstituentom R1 i jednim navedenim supstituentom R2 da bi se formirao 5- do 9-člani karbociklični prsten koji sadrži 1 ili 2 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N, O i S, predstavljenim grupom izabranom iz grupe koja se sastoji od: [image] [image] i [image] gdje W je izabran iz grupe koja se sastoji od -(CH2)1-3-, -(CH2)0-2NH(CH2)0-2, -(CH2)0-2N(C1-6alkil)(CH2)0-2-, -(CH2)0-2O(CH2)0-2- i -(CH2)0-2C(O)(CH2)0-2-, gdje je W supstituiran sa od 0 do 4 Rw, gdje je svaki Rw nezavisno izabran od C1-6alkil i C3-8cikloalkil; V je izabran iz grupe koja se sastoji od -C(O)- i -CH2-, i gdje V je -CH2-, V je supstituiran sa od 0 do 2 Rv, gdje je svaki Rv nezavisno izabran iz grupe koja se sastoji od C1-6alkil i C3-8cikloalkil; svako D je grupa nezavisno izabrana od [image] i [image] svako E je grupa nezavisno izabrana iz grupe koja se sastoji od: (a) jednogube veze, (b) -(C(R7)2)0-2NR7C(O)O0-1- i (c) pirolidinil derivata izabranog iz grupe koja se sastoji od: [image] i [image] I je bivalentna grupa izabrana od -C(O)-, -CO2- i -C(O)N(R7)-, J je fuzionirani sustav prstena izabran iz grupe koja se sastoji od 3- do 7-članih karbociklusa i 5- ili 6-članih aril prstenova koji sadrže od 0 do 4 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N, O i S, i supstituiranih na C ili N atomima sa supstituentima R9, svaki R8a je nezavisno izabran iz grupe koja se sastoji od vodika, halogena, -OH, -OC1-6alkil o C1-6alkil, ili dva R8a mogu biti uzeta zajedno tako da formiraju okso, svaki R8b je nezavisno izabran iz grupe koja se sastoji od vodika, halogena, -OH, -OC1-6alkil i C1-6alkil, ili dva R8b mogu biti uzeta zajedno tako da formiraju okso, svaki R8c je nezavisno izabran iz grupe koja se sastoji od vodika i C1-6alkil, ili bilo koje dvije grupe izabrane od R8a, R8b i R8c mogu biti uzete zajedno tako da formiraju spiro-biciklični ili premošćen biciklični prsten; svaki R9 je nezavisno izabran iz grupe koja se sastoji od vodika, halogena, C1-6alkil, -O-C1-6alkil, -S-C1-6alkil, -NH-C1-6alkil i -NHC(O)-C1-6alkil, svaki R7 je nezavisno izabran iz grupe koja se sastoji od vodika, C1-6alkil i fenil, i C1-6alkil i fenil su susptituirani sa od 0 do 3 supstituenta izabrana nezavisno iz grupe koja se sastoji od vodika, halogena, C1-6alkil, -O-C1-6alkil i -S-C1-6alkil; i svaki G je nezavisno izabran iz grupe koja se sastoji od: (a) vodika, (b) -OR10a, (c) -CN, (d) -CO2R10a, (e) -C(O)N(R10)2, (f) -SR10a, (g) -S(O)R10a, (h) -S(O2)R10a, (i) -N(R10)2, (j) -N(R10)SO2R10a, (k) -NCO2R10a, (l) =NC(O)N(R10)2, (m) C1-6alkil koji ima 0 do 4 supstituenta R11, svaki R11 je nezavisno izabran iz grupe koja se sastoji od: (i) -OH, (ii) -N(R10)2, (iii) =NR10, (iv) -O-C1-6alkil, (v) -C(O)R10, (vi) -S-C1-6alkil, (vii) -SO2-C1-6alkil, (viii) 3- do 8-članih karbociklusa koji sadrže od 0 do 3 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N, O i S, i koja ima od 0 do 3 supstituenta R12 na N ili C atomima, i svaki R12 je nezavisno izabran iz grupe koja se sastoji od vodika, halogena, C1-6alkil koji ima od 0 do 3 supstituenta izabrana od R10, -O-C1-6alkil, -S-C1-6alkil, -OR10a, -CN, -C(O)R10, -CO2R10a, -C(O)N(R10)2, -SR10a, -S(O)R10a, -S(O2)R10a, -N(R10)SO2R10a, -NCO2R10a, -NC(O)N(R10)2 i -N(R10)2, ili dva R12 su uzeti zajedno tako da formiraju okso, i (ix) 5- ili 6-članog arila koji sadrži od 0 do 3 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N, O i S, i koja ima od 0 do 3 supstituenta R13 na N ili C atomima, i svaki R13 je nezavisno izabran iz grupe koja se sastoji od vodika, halogena, C1-6alkil, -O-C1-6alkil i 3- do 8-članih karbociklusa koji sadrže od 0 do 3 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N, O i S, (n) 3- do 8-članih karbociklusa koji sadrže od 0 do 3 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N, O i S, i koja ima od 0 do 3 supstituenta R10 na N ili C atomima; i (o) aril sustava prstenova G’ izabranih iz grupe koja se sastoji od: (i) 5- do 7-članih monocikličnih sustava prstenova i (ii) 8- do 10-članih bicikličnih sustava prstenova, i aril sustava prstenova G’ koji sadrži od 0 do 4 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N, O i S, i supstituiran na C ili N atomima sa 0 do 3 supstituenta R10; svaki R10 je nezavisno izabran iz grupe koja se sastoji od (i) vodika, (ii) -CN, (iii) C1-6alkil, (iv) -O-C1-6alkil, (v) -S-C0-6alkil, (vi) C1-6alkil-O-R14, (vii) -C(O)R14, (viii) -CO2R14, (ix) -SO2R14, (x) -N(R14)2, (xi) -N(R14)SO2R14, (xii) -NCO2R14, (xiii) -NC(O)N(R14)2 i (xiv) 3- do 8-članih karbociklusa koji sadrže od 0 do 3 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N, O i S, ili dva R10 mogu biti uzeti zajedno tako da formiraju okso; svaki R10a je nezavisno izabran iz grupe koja se sastoji od (i) vodika, (ii) -CN, (iii) C1-6alkil, (iv) C1-6alkil-O-R14, (v) -C(O)R14, (vi) -CO2R14, (vii) -SO2R14, (x) -N(R14)2, (xi) -N(R14)SO2R14, (xii) -NCO2R14, (xiii) -NC(O)N(R14)2 i (xiv) 3- do 8-članih karbociklusa koji sadrži od 0 do 3 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N, O i S, i dvije R10 ili R10a grupe mogu biti uzete zajedno sa N za koji su vezani tako da formiraju prsten, koji može biti supstituiran sa od 0 do 3 supstituenta R14, i svaki R14 je nezavisno izabran iz grupe koja se sastoji od vodika, C1-6alkil, C3-8cikloalkil, -(CH2)0-3C3-8cikloalkil i fenil; ili spoj je metil [(2S)-1-{(2S)-2-[5-(10-{2-[(2S)-1-{(2S)-2-[(metoksikarbonil)amino]-3-metilbutanoil}pirolidin-2-il]-1H-imidazol-5-il}-6-fenilindolo[1,2-c][1,3]benzoksazin-3-il)-1H-imidazol-2-il]pirolidin-1-il}-3-metil-1-oksobutan-2-il]karbamat.
2. Spoj prema patentnom zahtjevu 1, naznačen time što navedeni [image] i navedeni [image] 2. , uzeti zajedno sa jednim navedenim supstituentom R1 i jednim navedenim supstituentom R2, su predstavljeni grupom izabranom iz grupe koja se sastoji od: [image] i [image]
3. Spoj prema patentnom zahtjevu 2, naznačen time što W je izabran iz grupe koja se sastoji od -CH2-, -NH-, -N(C1-6alkil)-, -C(O)-, -CH2NH-, -CH2N(C1-6alkil)-, -CH2CH2-, -C(O)CH2-, -CH2C(O)-, -CH2O-, -CH2CH2CH2-, -C(O)CH2CH2-,-CH2C(O)CH2-, -CH2OCH2-, -CH2CH2C(O)-, -CH2CH2O-, -CH2CH2NH-, -CH2CH2N(C1-6alkil)-, -CH2NHCH2-, -CH2N(C1-6alkil)CH2-, -NHCH2CH2- i -N(C1-6alkil)CH2CH2-.
4. Spoj prema patentnom zahtjevu 1, 2 ili 3, naznačen time što svako E je nezavisno izabrano iz grupe koja se sastoji od jednogube veze, -CH2NHC(O)-, -CH2N(CH3)C(O)-, -C(CH3)HNHC(O)-, -C(CH3)HN(CH3)C(O)-, -C(CH3)2NHC(O)-, -C(CH3)2N(CH3)C(O)-, -CH2NHC(O)O-, -CH2N(CH3)C(O)O-, -C(CH3)HNHC(O)O-, -C(CH3)HN(CH3)C(O)O-, -C(CH3)2NHC(O)O-, -C(CH3)2N(CH3)C(O)O-, [image] [image] i [image] gdje, jedan od R8a i R8b je -OH ili fluor.
5. Spoj prema patentnom zahtjevu 7, naznačen time što svako E je nezavisno izabrano iz grupe koja se sastoji od jednogube veze, [image] i [image] gdje jedan od R8a i R8b je -OH ili fluor.
6. Spoj prema bilo kojem od patentnih zahtjeva 1-5, naznačen time što svako G je nezavisno izabrano iz grupe koja se sastoji od: (a) C1-6alkil koji ima 0 do 4 supstituenta R11, (b) 3- do 8-članih karbociklusa koji sadrže od 0 do 3 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N, O i S, i koja ima od 0 do 3 supstituenta R10 na N ili C atomima; i (c) aril sustava prstenova G’ izabranih iz grupe koja se sastoji od: (i) 5- do 7-članih monocikličnih sustava prstenova i (ii) 8- do 10-članih bicikličnih sustava prstenova, i aril sustava prstenova G’ koji sadrže od 0 do 4 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N, O i S, i supstituiranih na C ili N atomima sa 0 do 3 supstituenta R10.
7. Spoj prema bilo kojem od patentnih zahtjeva 1-6, naznačen time što svako G je nezavisno izabran iz grupe koja se sastoji od (a) vodika, (b) -CN, (c) C1-5alkil koji ima 1 do 3 supstituenta R11, svaki R11 je nezavisno izabran iz grupe koja se sastoji od -OH, -NH2, -NCH3H, -N(CH3)2, -N(CH2CH3)2, =NH, =NCH3, -C(O)H, -C(O)OH, -C(O)CH3, -C(O)OCH3, -NHC(O)H, -NHC(O)OH, -NHC(O)CH3, -NHC(O)OCH3, ciklopropil, ciklobutil, ciklopentil, cikloheksil, piranil, pirolidinil, piperidinil, oksaciklopentil i oksacikloheksil, fenil, piridinil, pirimidinil i pirolil, gdje su ciklopropil, ciklobutil, ciklopentil, cikloheksil, piranil, pirolidinil, piperidinil, oksaciklopentil i oksacikloheksil supstituirani sa od 0 do 2 supstituenta R12 na N ili C atomima, i svaki R12 je nezavisno izabran iz grupe koja se sastoji od vodika, halogena, karboksi, C1-6alkil, -O-C1-6alkil i -S-C1-6alkil; i fenil, piridinil, pirimidinil i pirolil su supstituirani sa od 0 do 3 supstituenta R13 na N ili C atomima, i svaki R13 je nezavisno izabran iz grupe koja se sastoji od vodika, halogena, C1-6alkil i 3- do 8-članog cikloalkil koji sadrži od 0 do 3 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N, O i S, (d) ciklopropil, ciklobutil, ciklopentil, cikloheksil, piranil, pirolidinil, piperidinil, oksaciklopentil i oksacikloheksil koji imaju od 0 do 3 supstituenta R10 na N ili C atomima, pri čemu je navedeni R10 nezavisno izabran iz grupe koja se sastoji od vodika, halogena, karboksi, C1-6alkil, -O-C1-6alkil, -S-C1-6alkil, fenil i benzil, i (e) aril sustava prstenova G’ izabranih iz grupe koja se sastoji od: fenil, piridinil i 9-članih bicikličnih sustava prstenova koji sadrže od 0 do 2 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N i O.
8. Spoj prema patentnom zahtjevu 7, naznačen time što svako G je nezavisno izabran iz grupe koja se sastoji od C1-4alkil koji ima 1 do 2 supstituenta R11, gdje je svaki R11 nezavisno izabran iz grupe koja se sastoji od -OH, -NH2, -NCH3H, -N(CH3)2, - N(CH2CH3)2, -C(O)OCH3, ciklopropil, ciklobutil, ciklopentil, cikloheksil, piranil, pirolidinil, piperidinil, oksaciklopentil, oksacikloheksil, fenil, piridinil, pirimidinil i pirolil.
9. Spoj prema patentnom zahtjevu 1, naznačen time što spoj koji ima strukturnu formulu (I) je spoj koji ima strukturnu formulu (Ib): [image] ili njegova farmaceutski prihvatljiva sol, pri čemu navedeni [image] i navedeni [image] uzeti zajedno sa jednim navedenim supstituentom R1 i jednim navedenim supstituentom R2, su predstavljeni sa [image] gdje V je -CH2-, W je -(CH2)0-2O(CH2)0-2-, R1 je fluor, i oba slučaja G su [image]
10. Spoj prema patentnom zahtjevu 1, naznačen time što navedeni [image] i navedeni [image] uzeti zajedno sa jednim navedenim supstituentom R1 i jednim navedenim supstituentom R2, predstavljeni su grupom koja je izabrana iz grupe koja se sastoji od: [image] [image] i [image] gdje W je izabran iz grupe koja se sastoji od -(CH2)1-3-, -(CH2)0-2NH(CH2)0-2-, -(CH2)0-2N(C1-6alkil)(CH2)0-2-, -(CH2)0-2O(CH2)0-2- i -(CH2)0-2C(O)(CH2)0-2-, gdje je W supstituiran sa od 0 do 4 Rw, gdje je svako Rw nezavisno izabrano od C1-6alkil i C3-8cikloalkil; i V je izabran iz grupe koja se sastoji od -C(O)- i -CH2-, i gdje V je -CH2-, V je supstituiran sa od 0 do 2 Rv, gdje je svaki Rw nezavisno izabran iz grupe koja se sastoji od C1-6alkil i C3-8cikloalkil; svaki R1 je nezavisno izabran iz grupe koja se sastoji od vodika, halogena, -OR3, -CN, -C(O)R3, -CO2R3, -C(O)N(R3a)2, -SR3, -S(O)R3, -S(O2)R3, -N(R3a)2, -(CH2)0-2N(R3a)2, -N(R3a)SO2R3, -N(R3a)CO2R3, -N(R3a)COR3, -N(R3a)C(O)N(R3a), C1-6alkil, C3-8karbociklus koji sadrži od 0 do 3 heteroatoma izabrana od N, O i S, i fenil, i C1-6alkil, C3-8karbociklus i fenil su supstituirani sa od 0 do 3 supstituenta nezavisno izabrana iz grupe koja se sastoji od vodika, halogena, -OR3a, -CN, -CO2R3a, -C(O)N(R3a)2, -N(R3a)2, -N(R3a)CO2R3a, -SR3a, -S(O)R3a, -S(O2)R3a, -N(R3a)SO2R3a, -N(R3a)CO2R3a, -N(R3a)C(O)N(R3a), C1-6alkil, -O-C1-6alkil i -S-C1-6alkil, svaki R3 je nezavisno izabran iz grupe koja se sastoji od vodika, C1-6alkil, -OH, -O-C1-6alkil i C3-8cikloalkil, i svaki R3a je nezavisno izabran iz grupe koja se sastoji od vodika, C1-6alkil i C3-8cikloalkil; svaki R2 je nezavisno izabran iz grupe koja se sastoji od vodika, halogena, -OR4a, -CN, -CO2R4a, -C(O)N(R4a)2, -N(R4a)2, -N(R4a)CO2R4a, -SR4a, -S(O)R4a, -S(O2)R4a, -N(R4a)SO2R4a, -N(R4a)CO2R4a, -N(R4a)C(O)N(R4a), C3-6alkil supstituiran sa od 0 do 4 R4 i C3-8cikloalkil supstituiran sa od 0 do 4 R4, svaki R4 je nezavisno izabran iz grupe koja se sastoji od vodika, -OH, C1-6alkil i C3-8cikloalkil, i gdje je svaki E nezavisno izabran iz grupe koja se sastoji od jednogube veze, -CH2NHC(O)-, -CH2N(CH3)C(O)-, -C(CH3)HNHC(O)-, -C(CH3)HN(CH3)C(O)-, -C(CH3)2NHC(O)-, -C(CH3)2N(CH3)C(O)-, -CH2NHC(O)O-, -CH2N(CH3)C(O)O-, -C(CH3)HNHC(O)O-, -C(CH3)HN(CH3)C(O)O-, -C(CH3)2NHC(O)O-, -C(CH3)2N(CH3)C(O)O-, [image] i [image] gdje, jedan od R8a i R8b je -OH ili fluor; gdje je svaki G nezavisno izabran iz grupe koja se sastoji od (a) vodika, (b) -CN, (c) C1-5alkil koji ima 1 do 3 supstituenta R11, svaki R11 je nezavisno izabran iz grupe koja se sastoji od -OH, -NH2, -NCH3H, -N(CH3)2, -N(CH2CH3)2, =NH, =NCH3, -C(O)H, -C(O)OH, -C(O)CH3, -C(O)OCH3, -NHC(O)H, -NHC(O)OH, -NHC(O)CH3, -NHC(O)OCH3, ciklopropil, ciklobutil, ciklopentil, cikloheksil, piranil, pirolidinil, piperidinil, oksaciklopentil i oksacikloheksil, fenil, piridinil, pirimidinil i pirolil, gdje su ciklopropil, ciklobutil, ciklopentil, cikloheksil, piranil, pirolidinil, piperidinil, oksaciklopentil i oksacikloheksil supstituirani sa od 0 do 2 supstituenta R12 na N ili C atomima, i svaki R12 je nezavisno izabran iz grupe koja se sastoji od vodika, halogena, karboksi, C1-6alkil, -O-C1-6alkil i -S-C1-6alkil; i fenil, piridinil, pirimidinil i pirolil su supstituirani sa od 0 do 3 supstituenta R13 na N ili C atomima, i svaki R13 je nezavisno izabran iz grupe koja se sastoji od vodika, halogena, C1-6alky i 3- do 8-članog cikloalkil koji sadrži od 0 do 3 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N, O i S, (d) ciklopropil, ciklobutil, ciklopentil, cikloheksil, piranil, pirolidinil, piperidinil, oksaciklopentil i oksacikloheksil koji ima od 0 do 3 supstituenta R10 na N ili C atomima, pri čemu je navedeni R10 nezavisno izabran iz grupe koja se sastoji od vodika, halogena, karboksi, C1-6alkil, -O-C1-6alkil, -S-C1-6alkil, fenil i benzil, i (e) aril sustava prstenova G’ izabranih iz grupe koja se sastoji od: fenil, piridinil i 9-članih bicikličnih sustava prstenova koji sadrže od 0 do 2 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N i O.
11. Spoj prema patentnom zahtjevu 1 izabran od: (2S,2’S)-N,N’-6,11-dihidro-5H-benzo[a]karbazol-3,8-diilbis[1-(fenilacetil)pirolidin-2-karboksamid]; dibenzil (2S,2’S)2,2’-(6,-dihidro-5H-benzo[a]karbazol-3,8-diildikarbamoil) dipirolidin-1-karboksilat; di-terc-butil(6,11-dihidro-5H-benzo[a]karbazol-3,8-diilbis{karbamoil(2S)pirolidin-2,1-diil[(1S)-2-okso-1-feniletan-2,1-diil]})biskarbamat; (2S,2’S)-N,N’,6,11-dihidro-5H-behzo[a]karbazol-3,8-diilbis{1-[(2R)-2-(dimetilamino)-2-fenilacetil]pirolidin-2-karboksamid}; (2S;2’S)-N,N’-5,6,7,12-tetrahidrobenzo[6,7]ciklohepta[1,2-b]indol-3,9-diilbis{1-[(2R)-2-(dimetilamino)-2-fenilacetil]pirolidin-2-karboksamid}; N-(6,11-dihidro-5H-benzo[a]karbazol-3-il)-1-{(2S)-2-[(3,3-dimetilbutanoil)amino]-2-fenilacetil}-L-prolinamid; terc-butil {(1R)-2-[(2S)-2-(6,11-dihidro-5H-benzo[a]karbazol-3-ilkarbamoil)pirolidin-1-il]-2-okso-1-feniletil}karbamat; di-terc-butil (5,6,7,12-tetrahidrobenzo[6,7]ciklohepta[1,2-b]indol-3,9-diilbis {karbamoil(2S)pirolidin-2,1-diil[(1R)-2-okso-1-feniletan-2,1-diil]})biskarbamat; metil[(2S)-1-{(2S)-2-[5-(10-{2-[(2S)-1-{(2S)-2-[(metoksikarbonil)amino]-3-metilbutanoil}pirolidin-2-il]-1H-imidazol-5-il}indolo[1,2-c][1,3]benzoksazin-3-il)-1H-imidazol-2-il]pirolidin-1-il}-3-metil-1-oksobutan-2-il]karbamat; dimetil (indolo[1,2-c][1,3]benzoksazin-3,10-diilbis{1H-imidazol-5,2-diil(2S)pirolidin-2,1-diil[(1R)-2-okso-1-feniletan-2,1-diil]})biskarbamat; metil[(2S)-1-{(2S)-2-[5-(11-{2-[(2S)-1-{(2S)-2-[(metoksikarbonil)amino]-3-metilbutanoil}pirolidin-2-il]-1H-imidazol-5-il}-6,7-dihidroindolo[1,2-d][1,4]benzoksazepin-3-il)-1H-imidazol-2-il]pirolidin-1-il}-3-metil-1-oksobutan-2-il]karbamat; metil[(2S)-1-{(2S)-2-[5-(3-{2-[(2S)-1-{(2S)-2-[(metoksikarbonil)amino]-3-metilbutanoil}pirolidin-2-il]-1H-imidazol-5-il}-6,6-dimetilindolo[1,2-c][1,3]benzoksazin-10-il)-1H-imidazol-2-il]pirolidin-1-il}-3-metil-1-oksobutan-2-il]karbamat; metil [(2S)-1-{(2S)-2-[5-(12-fiuoro-10-{2-[(2S)-1-{(2S)-2-[(metoksikarbonil)amino]-3-metilbutanoil}pirolidin-2-il]-1H-imidazol-5-il}-6-metilindolo[1,2-c][1,3]benzoksazin-3-il)-1H-imidazol-2-il]pirolidin-1-il}-3-metil-1-oksobutan-2-il]karbamat; metil [(2S)-1-{(2S)-2-[5-(3-{2-[(2S)-1-{(2S)-2-[(metoksikarbonil)amino]-3-metilbutanoil}pirolidin-2-il]-1H-imidazol-5-il}indolo[1,2-c]hinazolin-10-il)-1H-imidazol-2-il]pirolidin-1-il}-3-metil-1-oksobutan-2-il]karbamat; metil[(2S)-1-{(2S)-2-(5-(12-{2-[(2S)-1-{(2S)-2-[(metoksikarbonil)amino]-3-metilbutanoil}pirolidin-2-il]-1H-imidazol-5-il}-7,8-dihidro-6H-indolo[1,2-e][1,5]benzoksazocin-3-il)-1H-imidazol-2-il]pirolidin-1-il}-3-metil-1-oksobutan-2-il]karbamat; metil[(2S)-1-{(2S)-2-[5-(3-{2-[(2S)-1-{(2S)-2-[(metoksikarbonil)amino]-3-metilbutanoil}pirolidin-2-il]-1H-imidazo1-5-il}-6-okso-5,6-dihidroindolo[1,2-c]hinazolin-10-il)-1H-imidazol-2-il]pirolidin-1-il}-3-metil-1-oksobutan-2-il]karbamat; metil [(2S)-1-{(2S)-2-[5-(10-{2-[(2S)-1-{(2S)-2-[(metoksikarbonil)amino]-3-metilbutanoil}pirolidin-2-il]-1H-imidazol-5-il}-6-fenilindolo[1,2-c][1,3]benzoksazin-3-il)-1H-imidazol-2-il]pirolidin-1-il}-3-metil-1-oksobutan-2-il]karbamat; metil [(2S)-1-{(2S)-2-[5-(3-{2-[(2S)-1-{(2S)-2-[(metoksikarbonil)amino]-3-metilbutanoil}pirolidin-2-il]-1H-imidazo1-5-il}-6-metilindolo[1,2-c]hinazolin-10-il)-1H-imidazol-2-il]pirolidin-1-il}-3-metil-1-oksobutan-2-il]karbamat; metil[(2S)-1-{(2S)-2-[5-(10’-{2-[(2S)-1-{(2S)-2-[(metoksikarbonil)amino]-3-metilbutanoil}pirolidin-2-il]-1H-imidazol-5-il}spiro[cikloheksan-1,6’-indolo[1,2-c][1,3]benzoksazin]-3’-il)-1H-imidazol-2-il]pirolidin-1-il}-3-metil-1-oksobutan-2-il]karbamat; metil [(2S)-1-{(2S)-2-[5-(1,12-difluoro-10-{2-[(2S)-1-{(2S)-2-[(metoksikarbonil)amino]-3-metilbutanoil}pirolidin-2-il]-1H-imidazol-5-il}indolo[1,2-c][1,3]benzoksazin-3-il)-1H-imidazol-2-il]pirolidin-1-il}-3-metil-1-oksobutan-2-il]karbamat; metil [(2S)-1-{(2S)-2-[5-(12-cijano-10-{2-[(2S)-1-{(2S)-2-[(metoksikarbonil)amino]-3-metilbutanoil}pirolidin-2-il]-1H-imidazol-5-il}indolo[1,2-c][1,3]benzoksazin-3-il)-1H- imidazol-2-il]pirolidin-1-il}-3-metil-1-oksobutan-2-il]karbamat; i njihove farmaceutski prihvatljive soli.
12. Spoj prema patentnom zahtjevu 11 koji je metil [(2S)-1-{(2S)-2-[5-(3-{2-[(2S)-1-{(2S)-2-[(metoksikarbonil)amino]-3-metilbutanoil}pirolidin-2-il]-1H-imidazol-5-il}-6-okso-5,6-dihidroindolo[1,2-c]hinazolin-10-il)-1H-imidazol-2-il]pirolidin-1-il}-3-metil-1-oksobutan-2-il]karbamat i njegove farmaceutski prihvatljive soli.
13. Spoj prema patentnom zahtjevu 11 koji je metil [(2S)-1-{(2S)-2-[5-(10-{2-[(2S)-1-{(2S)-2-[(metoksikarbonil)amino]-3-metilbutanoil}pirolidin-2-il]-1H-imidazol-5-il}-6-fenilindolo[1,2-c][1,3]benzoksazin-3-il)-1H-imidazol-2-il]pirolidin-1-il}-3-metil-1-oksobutan-2-il]karbamat i njegove farmaceutski prihvatljive soli.
14. Spoj prema patentnom zahtjevu 11 koji je metil [(2S)-1-{(2S)-2-[5-(3-{2-[(2S)-1-{(2S)-2-[(metoksikarbonil)amino]-3-metilbutanoil}pirolidin-2-il]-1H-imidazol-5-il}-6-metilindolo[1,2-c]hinazolin-10-il)-1H-imidazol-2-il]pirolidin-1-il}-3-metil-1-oksobutan-2-il]karbamat i njegove farmaceutski prihvatljive soli.
15. Farmaceutska kompozicija koja sadrži efikasnu količinu spoja prema bilo kojem od patentnih zahtjeva 1-14 ili njegove farmaceutski prihvatljive soli, i farmaceutski prihvatljiv nosač.
16. Spoj prema bilo kojem od patentnih zahtjeva 1 do 14, ili njegova farmaceutski prihvatljiva sol, za uporabu u postupku za liječenje ljudskog tijela putem terapije.
17. Spoj za uporabu prema patentnom zahtjevu 16 naznačen time što, terapija je liječenje HCV.
18. Uporaba spoja prema bilo kojem od patentnih zahtjeva 1 do 15, ili njegove farmaceutski prihvatljive soli, za proizvodnju lijeka za liječenje HCV.
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