ME02418B - Inhibitori replikacije virusa hepatitisa c - Google Patents

Inhibitori replikacije virusa hepatitisa c

Info

Publication number
ME02418B
ME02418B MEP-2016-84A MEP8416A ME02418B ME 02418 B ME02418 B ME 02418B ME P8416 A MEP8416 A ME P8416A ME 02418 B ME02418 B ME 02418B
Authority
ME
Montenegro
Prior art keywords
group
6alkyl
independently selected
hydrogen
imidazol
Prior art date
Application number
MEP-2016-84A
Other languages
German (de)
English (en)
French (fr)
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
Original Assignee
Merck Sharp & Dohme
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
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=ME02418(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Merck Sharp & Dohme filed Critical Merck Sharp & Dohme
Publication of ME02418B publication Critical patent/ME02418B/me

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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
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Claims (18)

1. Jedinjenje koje ima strukturnu formulu (I):i/ili njegova farmaceutski prihvatljiva so, u kome:svaki R1 je nezavisno izabran iz grupe koja se sastoji od vodonika, 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 supstituisani sa od 0 do 3 supstituenta nezavisno izabrana iz grupe koja se sastoji od vodonika, 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 vodonika, C1-6alkil, -OH, -O-C1-6alkil i C3-8cikloalkil, isvaki R3a je nezavisno izabran iz grupe koja se sastoji od vodonika, C1-6alkil i C3-8cikloalkil;svaki R2 je nezavisno izabran iz grupe koja se sastoji od vodonika, 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 supstituisanog sa od 0 do 4 R4 i C3-8cikloalkil supstituisanog sa od 0 do 4 R4,ν je od 0 do 4,svaki R4 je nezavisno izabran iz grupe koja se sastoji od vodonika, -OH, C1-6alkil i C3-8cikloalkil;svaki R4a je nezavisno izabran iz grupe koja se sastoji od vodonika, C1-6alkil i C3-8cikloalkil;gde navedenii navedenisu uzeti zajedno sa jednim navedenim supstituentom R1 i jednim navedenim supstituentom R2 da bi se firmirao 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:i gdeW 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-, gde je W supstituisan sa od 0 do 4 Rw, gde 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 gde V je -CH2-, V je supstituisan sa od 0 do 2 Rv, gde je svaki Rv nezavisno izabran iz grupe koja se sastoji od C1-6alkil i C3-8cikloalkil;svako D je grupa nezavisno izabrana odi 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:i I je bivalentna grupa izabrana od -C(O)-, -CO2- i -C(O)N(R7)-,J je fuzionisani sistem 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 supstituisanih na C ili N atomima sa supstituentima R9,svaki R8a je nezavisno izabran iz grupe koja se sastoji od vodonika, 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 vodonika, 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 vodonika i C1-6alkil, ili bilo koje dve grupe izabrane od R8a, R8b i R8c mogu biti uzete zajedno tako da formiraju spiro-bicikličan ili premošćen bicikličan prsten;svaki R9 je nezavisno izabran iz grupe koja se sastoji od vodonika, 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 vodonika, C1-6alkil i fenil, i C1-6alkil i fenil su susptituisani sa od 0 do 3 supstituenta izabrana nezavisno iz grupe koja se sastoji od vodonika, halogena, C1-6alkil, -O-C1-6alkil i -S-C1-6alkil; i svaki G je nezavisno izabran iz grupe koja se sastoji od:(a) vodonika,(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 vodonika, 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 vodonika, 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 sistema prstenova G’ izabranih iz grupe koja se sastoji od:(i) 5- do 7-članih monocikličnih sistema prstenova i (ii) 8- do 10-članih bicikličnih sistema prstenova,i aril sistema prstenova G’ koji sadrži od 0 do 4 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N, O i S, i supstituisan na C ili N atomima sa 0 do 3 supstituenta R10;svaki R10 je nezavisno izabran iz grupe koja se sastoji od (i) vodonika,(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) vodonika,(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 dve R10 ili R10a grupe mogu biti uzete zajedno sa N za koji su vezani tako da formiraju prsten, koji može biti supstituisan sa od 0 do 3 supstituenta R14, isvaki R14 je nezavisno izabran iz grupe koja se sastoji od vodonika, C1-6alkil, C3-8cikloalkil, -(CH2)0-3C3-8cikloalkil i fenil; ili jedinjenje 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. Jedinjenje prema patentnom zahtevu 1, naznačeno time što navedeni i navedeni , uzeti zajedno sa jednim navedenim supstituentom R1 i jednim navedenim supstituentom R2, su predstavljeni grupom izabranom iz grupe koja se sastoji od: i
3. Jedinjenje prema patentnom zahtevu 2, naznačeno 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. Jedinjenje prema patentnom zahtevu 1, 2 ili 3, naznačeno 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-, i gde, jedan od R8a i R8b je -OH ili fluor.
5. Jedinjenje prema patentnom zahtevu 7, naznačeno time što svako E je nezavisno izabrano iz grupe koja se sastoji od jednogube veze, i gde jedan od R8a i R8b je -OH ili fluor.
6. Jedinjenje prema bilo kom od patentnih zahteva 1-5, naznačeno 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 sistema prstenova G’ izabranih iz grupe koja se sastoji od: (i) 5- do 7-članih monocikličnih sistema prstenova i (ii) 8- do 10-članih bicikličnih sistema prstenova, i aril sistema prstenova G’ koji sadrže od 0 do 4 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N, O i S, i supstituisanih na C ili N atomima sa 0 do 3 supstituenta R10.
7. Jedinjenje prema bilo kom od patentnih zahteva 1-6, naznačeno time što svako G je nezavisno izabrano iz grupe koja se sastoji od (a) vodonika, (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, gde su ciklopropil, ciklobutil, ciklopentil, cikloheksil, piranil, pirolidinil, piperidinil, oksaciklopentil i oksacikloheksil supstituisani sa od 0 do 2 supstituenta R12 na N ili C atomima, i svaki R12 je nezavisno izabran iz grupe koja se sastoji od vodonika, halogena, karboksi, C1-6alkil, -O-C1-6alkil i -S-C1-6alkil; i fenil, piridinil, pirimidinil i pirolil su supstituisani sa od 0 do 3 supstituenta R13 na N ili C atomima, i svaki R13 je nezavisno izabran iz grupe koja se sastoji od vodonika, 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 vodonika, halogena, karboksi, C1-6alkil, -O-C1-6alkil, -S-C1-6alkil, fenil i benzil, i (e) aril sistema prstenova G’ izabranih iz grupe koja se sastoji od: fenil, piridinil i 9-članih bicikličnih sistema prstenova koji sadrže od 0 do 2 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N i O.
8. Jedinjenje prema patentnom zahtevu 7, naznačeno time što svako G je nezavisno izabrano iz grupe koja se sastoji od C1-4alkil koji ima 1 do 2 supstituenta R11, gde 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. Jedinjenje prema patentnom zahtevu 1, naznačeno time što jedinjenje koje ima strukturnu formulu (I) je jedinjenje koje ima strukturnu formulu (Ib): ili njegova farmaceutski prihvatljiva so, pri čemu navedeni i navedeni uzeti zajedno sa jednim navedenim supstituentom R1 i jednim navedenim supstituentom R2, su predstavljeni sa gde V je -CH2-, W je -(CH2)0-2O(CH2)0-2-, R1 je fluor, i oba slučaja G su
10. Jedinjenje prema patentnom zahtevu 1, naznačeno time što navedeni i navedeni uzeti zajedno sa jednim navedenim supstituentom R1 i jednim navedenim supstituentom R2, predstavljeni su grupom koja je izabrana iz grupe koja se sastoji od: i gde 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-, gde je W supstituisan sa od 0 do 4 Rw, gde 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 gde V je -CH2-, V je supstituisan sa od 0 do 2 Rv, gde 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 vodonika, 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 supstituisani sa od 0 do 3 supstituenta nezavisno izabrana iz grupe koja se sastoji od vodonika, 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 vodonika, C1-6alkil, -OH, -O-C1-6alkil i C3-8cikloalkil, i svaki R3a je nezavisno izabran iz grupe koja se sastoji od vodonika, C1-6alkil i C3-8cikloalkil; svaki R2 je nezavisno izabran iz grupe koja se sastoji od vodonika, 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 supstituisan sa od 0 do 4 R4 i C3-8cikloalkil supstituisan sa od 0 do 4 R4, svaki R4 je nezavisno izabran iz grupe koja se sastoji od vodonika, -OH, C1-6alkil i C3-8cikloalkil, i gde 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-, i gde, jedan od R8a i R8b je -OH ili fluor; gde je svaki G nezavisno izabran iz grupe koja se sastoji od (a) vodonika, (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, gde su ciklopropil, ciklobutil, ciklopentil, cikloheksil, piranil, pirolidinil, piperidinil, oksaciklopentil i oksacikloheksil supstituisani sa od 0 do 2 supstituenta R12 na N ili C atomima, i svaki R12 je nezavisno izabran iz grupe koja se sastoji od vodonika, halogena, karboksi, C1-6alkil, -O-C1-6alkil i -S-C1-6alkil; i fenil, piridinil, pirimidinil i pirolil su supstituisani sa od 0 do 3 supstituenta R13 na N ili C atomima, i svaki R13 je nezavisno izabran iz grupe koja se sastoji od vodonika, 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 vodonika, halogena, karboksi, C1-6alkil, -O-C1-6alkil, -S-C1-6alkil, fenil i benzil, i (e) aril sistema prstenova G’ izabranih iz grupe koja se sastoji od: fenil, piridinil i 9-članih bicikličnih sistema prstenova koji sadrže od 0 do 2 heteroatoma nezavisno izabrana iz grupe koja se sastoji od N i O.
11. Jedinjenje prema patentnom zahtevu 1 izabrano 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. Jedinjenje prema patentnom zahtevu 11 koje 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. Jedinjenje prema patentnom zahtevu 11 koje 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. Jedinjenje prema patentnom zahtevu 11 koje 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 jedinjenja prema bilo kom od patentnih zahteva 1-14 ili njegove farmaceutski prihvatljive soli, i farmaceutski prihvatljiv nosač.
16. Jedinjenje prema bilo kom od patentnih zahteva 1 do 14, ili njegova farmaceutski prihvatljiva so, za upotrebu u postupku za lečenje ljudskog tela putem terapije.
17. Jedinjenje za upotrebu prema patentnom zahtevu 16 naznačeno time što, terapija je lečenje HCV.
18. Upotreba jedinjenja prema bilo kom od patentnih zahteva 1 do 15, ili njegove farmaceutski prihvatljive soli, za proizvodnju leka za lečenje HCV.
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CN103880862B (zh) 2018-09-25

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