ME02789B - Jedinjenja heteroarila korisna kao inhibitori e1 aktivirajućih enzima - Google Patents

Jedinjenja heteroarila korisna kao inhibitori e1 aktivirajućih enzima

Info

Publication number
ME02789B
ME02789B MEP-2011-568A MEP56811A ME02789B ME 02789 B ME02789 B ME 02789B ME P56811 A MEP56811 A ME P56811A ME 02789 B ME02789 B ME 02789B
Authority
ME
Montenegro
Prior art keywords
optionally substituted
ring
aliphatic
hydrogen
group
Prior art date
Application number
MEP-2011-568A
Other languages
English (en)
French (fr)
Inventor
Edward J Olhava
Stephen Critchley
Stephane Peluso
Hirotake Mizutani
Courtney Cullis
Christopher F Claiborne
Steven P Langston
Gabriel S Weatherhead
Stepan Vyskocil
Irache Visiers
Original Assignee
Millennium Pharm Inc
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
Application filed by Millennium Pharm Inc filed Critical Millennium Pharm Inc
Publication of ME02789B publication Critical patent/ME02789B/me

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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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  • Pyridine Compounds (AREA)

Claims (30)

1. Jedinjenje formule (1): ili njegova farmaceutski prihvatljiva so, u kome: Prsten A je 6-člani heteroaril prsten koji sadrži azot, izborno fuzionisan za 5- ili 6-člani aril, heteroaril, cikloalifatičan ili heterocikličan prsten, u kome su jedan od prstenova ili oba prstena izborno supstituisani i jedan atom azota iz prstena je izborno oksidovan; W je -CH2-, -CHF-, -CF2-, -CHCR1)-, -CFCR1)-, -NH-, -NCR1)-, -O-, -S- ili - NHC(O)-; R1 je C1-4 alifatik ili C1-4 fluoroalifatik; ili R1 je C1-4 alkilen lanac koji je vezan za položaj prstena na prstenu A da bi se formirao 5-, 6- ili 7-člani fuzionisani prsten, pri čemu je alkilen lanac izborno supstituisan sa C1-4alifatikom, C1-4 fluoroalifatikom, =0, -CN ili -C(O)N(R4)2; X je -CH2-, -CHF-, -CF2-, -NH- ili -O-; Y je -O-, -S- ili -C(Rm)(Rn)-; Ra je izabran iz grupe koju čine vodonik, fluoro, -CN, -N3, -OR5, -N(R4)2, - NR4CO2R6, -NR4C(O)Rs, -C(O)N(R4)2, -C(O)R5, -OC(O)N(R4)2, -OC(O)R5, -OCO2R6 ili C1-4 alifatičan ili C1-4 fluoroalifatičan izborno supstituisan sa jednim ili dva supstituenta nezavisno izabrana iz grupe koju čine -0R3x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); ili Ra i Rc zajedno formiraju vezu; Rb je izabran iz grupe koju čine vodonik, fluoro, C1-4 alifatik i C1-4 fluoroalifatik; Rc je izabran iz grupe koju čine vodonik, fluoro, -CN, -Ny -OR5, -N(R4)2, - NR4CO2R6, -NR4C(O)R5, -C(O)N(R4)2, -C(O)R5, -OC(O)N(R4)2, -OC(O)R5, -OCO2R6 ili C1-4 slifatik ili C1-4 fluoroslifstik izborno supstituisan sa jednim ili dva supstituenta nezavisno izabrana iz grupe koju čine -ORSx, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); ili Ra i Rc zajedno formiraju vezu; Rd je izabran iz grupe koju čine vodonik, fluoro, C1-4 alifatik i C1-4 fluoroalifatik; Re je vodonik, ili C1-4 alifatik; ili Re, uzet zajedno sa jednim Rf i ugljenikovim atomima koji se nalaze između, formira 3- do 6-člani spirocikličan prsten; ili Re; uzet zajedno sa Rm i ugljenikovim atomima koji se nalaze između, formira fuzionisani ciklopropan prsten, koji je izborno supstituisan sa jednim ili dva supstituenta nezavisno izabrana od fluoro ili C1-4 alifatik; Re je vodonik ili C1-4 alifatik; ili Re, uzet zajedno sa Rm i ugljenikovim atomima koji se nalaze između, formira fuzionisani ciklopropan prsten, koji je izborno supstituisan sa jednim ili dva supstituenta nezavisno izabrana od fluoro ili Cm alifatika; svako Rf nezavisno je vodonik, fluoro, C1-4 alifatik ili C1-4 fluoroalifatik; ili dva R uzeta zajedno formiraju =0; ili dva Rf, uzeta zajedno sa atomom ugljenika za koji su vezani, formiraju 3- do 6-člani karbocikličan prsten; ili jedan Rf, uzet zajedno sa Re i ugljenikovim atomima koji se nalaze između, formira 3- do 6-člani spirocikličan prsten; Rm je vodonik, fluoro, -N(R4)2, ili izborno supstituisana C1-4 alifatična grupa; ili Rm i Rn zajedno formiraju =0 ili =C(R5)2; ili Rm i Re, uzeti zajedno sa ugljenikovim atomima koji se nalaze između, formiraju fuzionisani ciklopropan prsten, koji je izborno supstituisan sa jednim ili dva supstituenta nezavisno izabrana od fluoro ili C1-4 alifatika; ili Rm i Re, uzeti zajedno sa ugljenikovim atomima koji se nalaze između, formiraju fuzionisani ciklopropan prsten, koji je izborno supstituisan sa jednim ili dva supstituenta koji su nezavisno izabrani od fluoro ili C1-4 alifatika; Rn je vodonik, fluoro, ili izborno supstituisana C1-4 alifatična grupa; ili Rm i Rn zajedno formiraju =0 ili =C(R5)2; svako R4 nezavisno je vodonik ili izborno supstituisana alifatična, aril, heteroaril ili heterociklil grupa; ili dva R4 na istom atomu azota, uzeti zajedno sa atomom azota, formiraju izborno supstituisani 4- do 8-člani heterociklil prsten koji ima, pored atoma azota, 0-2 heteroatoma u prstenu nezavisno izabrana od N, O i S; R4x je vodonik, C1-4 alkil, C1-4 fluoroalkil ili (C1-4) ar(C1-4)alkil, čiji aril deo može biti izborno supstituisan; R4y je vodonik, C1-4 alkil, C1-4 fluoroalkil, (C1-4) ar(C1-4)alkil, čiji aril deo može biti izborno supstituisan, ili izborno supstituisani 5- ili 6-člani aril, heteroaril ili heterociklil prsten; ili R4x i R4y, uzeti zajedno sa atomom azota za koji su vezani, formiraju izborno supstituisani 4- do 8-člani heterociklil prsten koji ima, pored atoma azota, 0-2 heteroatoma u prstenu nezavisno izabrana od N, O i S; i svako R5 nezavisno je vodonik ili izborno supstituisana alifatična, aril, heteroaril ili heterociklil grupa; svako R5x nezavisno je vodonik, C1-4 alkil, C1-4 fluoroalkil, ili izborno supstituisani (C6-10) aril ili (C6-10) ar(C1-4)alkil; svako R6 nezavisno je izborno supstituisana alifatična, aril ili heteroaril grupa; i m je 1,2 ili 3.
2.    Jedinjenje prema patentnom zahtevu 1, u kome, W je -CH2-, -CHF-, -CF2-, -NH-, -O-, -S-ili -NHC(O)-.
3.    Jedinjenje prema patentnom zahtevu 2, naznačeno jednom ili više od sledećih karakteristika: (a)    X je -O-; (b)    Y je -CH2-; (c)    W je -NH-; (d)    Ra je -OH; (e)    svako Rb i Rd su nezavisno vodonik ili C1-4 alifatik; (f)    Rc je vodonik, fluoro, ili -OR5; (g)    svako Re i Re su vodonik; (h)    svaki Rf je vodonik; i (i)    m je 1.
4. Jedinjenje prema patentnom zahtevu 2 ili 3, naznačeno formulom (II): ili njegova farmaceutski prihvatljiva so, u kojima: D je -N= ili -C(Rh)=; E je -N= ili -C(Rh)=; R8 je vodonik, halo, cijano, -C(R5)=C(R5)2, -C=C-R5, -OR5, -SR6, -S(O)R6, -SO2R6, - S02N(R4)2,-N(R4)2,-NR4C(O)R5,-NR4C(O)N(R4)2,-N(R4)C(=NR4)-N(R4)2,-N(R4)C(=NR4)-R6, -NR4CO2Rb, -N(R4)S02Rb, -N(R4)S02N(R4)2, -O-C(O)R5, -OCO2R6, - OC(O)N(R4)2, -C(O)R5, -CO2R5, -C(O)N(R4)2, -C(O)N(R4)-0R5,- C(O)N(R4)C(=NR4)- N(R4)2, -N(R4)C(=NR4)-N(R4)-C(O)R5, -C(=NR4)-N(R4)2, -C(=NR4)-OR5, -N(R4)-N(R4)2, - N(R4)-OR5, -C(=NR4)-N(R4)-OR5, -C(R6)=N-OR5, ili izborno supstituisan alifatik, aril, heteroaril ili heterociklil; i svako Rh nezavisno je vodonik, halo, -CN-, -OR5, -N(R4)2, -SR6, ili izborno supstituisana C1-4 alifatična grupa
5. Jedinjenje prema patentnom zahtevu 4, u kome: Rg je vodonik, C1-6 alifatik, C1-6 fluoroalifatik, halo, -Rlg, -R2g, -T1-R1g, -T1-R2g, -V1-T1-R18, -V1-T1-R2g, -V1-R1g ili -V1-T1-R1g; T1 je C1-6 alkilen lanac supstituisan sa 0-2 nezavisno izabrana R3a ili R3b, pri čemu je alkilen lanac izborno prekinut sa -C(R1)=C(R1)-, -C=C-, -O-, -S-, -S(O)-, -S(O)2-, -S02N(R4)-, -N(R4)-, -N(R4)C(O)-,    -NR4C(O)N(R4)-,    -N(R4)C(=NR4)-N(R4)-, -N(R4)-C(=NR4)-,-N(R4)CO2-, -N(R4)S02-, -N(R4)S02N(R4)-, -OC(O)-, -OC(O)N(R4)-, -C(O)-, -co2-, -C(O)N(R4)-, -C(=NR4>-N(R4)-, -C(NR4)=N(R4)-, -C(=NR4)-O- ili -C(R6)=N-O-, i pri čemu T1 ili njegov deo izborno formira deo 3-7-članog prstena; V1 je -C(R1)=C(R1)-, -C=C-, -O-, -S-, -S(O)-, -S(O)2-, -S02N(R4)-, -N(R4)-, -N(R4)C(O)-, -NR4C(O)N(R4)-, -N(R4)C(=NR4)-N(R4)-, -N(R4)C(=NR4)-, -N(R4)CO2-, -N(R4)S02-, -N(R4)S02N(R4)-, -OC(O)-, -OC(O)N(R4)-, -C(O)-, -CO2-, -C(O)N(R4)-, -C(O)N(R4)-O-, -C(O)N(R4)C(=NR4)-N(R4)-, -N(R4)C(=NR4)-N(R4)-C(O)-,-C(=NR4)-N(R4)-,C(NR4)=N(R4)-, -C(=NR4)-O- ili -C(R6)=N-O-; svako R1g nezavisno je izborno supstituisani aril, heteroaril, heterociklil ili cikloalifatični prsten; svako R2g nezavisno je -N02, -CN, -C(R5)=C(R5)2, -C=C-R5, -OR5, -SR6, -S(O)R6, -S02R6, - S02N(R4)2,-N(R4)2,-NR4C(O)R5,-NR4C(O)N(R4)2,-N(R4)C(=NR4)-N(R4)2,-N(R4)C(=NR4)-R6, -NR4CO2R6, -N(R4)S02R6, -N(R4)S02N(R4)2, -O-C(O)R5, -oco2r6, - OC(O)N(R4)2, -C(O)R5, -CO2R5, -C(O)N(R4)2, -C(O)N(R4)-0R5, -C(O)N(R4)C(=NR4)- N(R4)2, -N(R4)C(=NR4)-N(R4)-C(O)R5, -C(=NR4)-N(R4)2, -C(=NR4)-OR5, -N(R4)-N(R4)2, - N(R4)-OR5, -C(=NR4)-N(R4)-OR5 ili -C(R6)=N-OR5; svako R3a nezavisno je izabran iz grupe koju čine -F, -OH, -0(C1-4 alkil), -CN, -N(R4)2, - C(O)(C1-4 alkil), -CO2H, -CO2(C1-4 alkil), -C(O)NH2 i -C(O)NH(C1-4 alkil); svako R3b nezavisno je C1-3 alifatik izborno supstituisan sa R3a ili R7, ili dva supstituenta R3b na istom atomu ugljenika, uzeti zajedno sa atomom ugljenika za koji su vezani, formiraju 3- do 6-člani cikloalifatični prsten; i svako R7 nezavisno je izborno supstituisani aril ili heteroaril prsten.
6. Jedinjenje prema patentnom zahtevu 5, naznačeno formulom (III): ili njegova farmaceutski prihvatljiva so, u kome: Q je -T1- ili -V1-T1-; V1 je -N(R8)-, -O- ili -S-; R8 je vodonik ili C1-4 alifatik; T1 je C1-4 alkilen lanac izborno supstituisan sa jednom ili dve grupe nezavisno izabrane od fluoro, C1-4 alifatika i C1-4 fluoroalifatika; i Prsten C je 3- do 8-člani heterociklil ili cikloalifatični prsten, ili 5- ili 6-člani aril ili heteroaril prsten, pri čemu je svaki od tih prstena supstituisan sa 0-2 R° i 0-2 R80; svako R° nezavisno je halo, -N02, -CN, -C(R5)=C(R5)2, -C=C-R5, -OR5, -SR6, -S(O)R6, -S02R6, -S02N(R4)2, -N(R4)2, -NR4C(O)R5,-NR4C(O)N(R4)2,-N(R4)C(=NR4)-N(R4)2,-N(R4)C(=NR4)-R6,-NR4CO2R6,-N(R4)S02R6,-N(R4)S02N(R4)2,-O-C(O)R5,-oco2r6,-OC(O)N(R4)2,-C(O)R5,-CO2R5,-C(O)N(R4)2, -C(O)N(R4)-0R5, -C(O)N(R4)C(=NR4)-N(R4)2, -N(R4)C(=NR4)-N(R4)-C(O)R5, -C(=NR4)-N(R4)2,-C(=NR4)-OR5,-C(=NR4)-N(R4)-OR5,-C(R6)=N-OR5, ili izborno supstituisana alifatična, ili izborno supstituisana aril, heterociklil ili heteroaril grupa; ili dva R° na istom zasićenom atomu ugljenika u prstenu, uzeti zajedno sa atomom ugljenika, formiraju izborno supstituisani 3- do 8-člani spirocikličan cikloalifatičan ili heterociklil prsten; ili dva susedna R°, uzeti zajedno sa atomima prstena koji se nalaze između, formiraju izborno supstituisani fuzionisani 4- do 8-člani aromatični ili nearomatični prsten koji ima 0-3 heteroatoma u prstenu izabrana iz grupe koju čine O, N i S; svako R80 nezavisno je izabrano iz grupe koju čine C1-4 alifatik, C1-4 fluoroalifatik, halo, -OR5x, -N(R4x)(R4y) ili C1-4 alifatik ili C1-4 fluoroalifatik izborno supstituisan sa -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); R4x je vodonik, C1-4 alkil, C1-4 fluoroalkil ili C6-10 ar(C1-4)alkil, čiji aril deo može biti izborno supstituisan; R4y je vodonik, C1-4 alkil, C1-4 fluoroalkil, C6-10 ar(C1-4)alkil, čiji aril deo može biti izborno supstituisan, ili izborno supstituisan 5- ili 6-člani aril, heteroaril ili heterociklil prsten; ili R4x i R4y, uzeti zajedno sa atomom azota za koji su vezani, formiraju izborno supstituisani 4-do 8-člani heterociklil prsten koji ima, pored atoma azota, 0-2 heteroatoma u prstenu nezavisno izabrana od N, O i S; i svako R5x nezavisno je vodonik, C1-4 alkil, C1-4 fluoroalkil, ili izborno supstituisani C6-10 aril ili C6-10 ar(C1-4)alkil.
7. Jedinjenje prema patentnom zahtevu 6, u kome prsten C je C3-6 cikloalifatik, fenil, pirolil, imidazolil, oksazolil, tiazolil, izoksazolil, izotiazolil, pirazolil, triazolil, tetrazolil, oksadiazolil, tiadiazolil, pirolinil, imidazolinil, pirazolinil, pirolidinil, imidazolidinil, pirazolidinil, piperidinil, morfolinil, piperazinil, piridil, piridazinil, pirimidinil, pirazinil ili tetrahidropirimidinil prsten, pri čemu je bilo koji od njih supstituisan sa 0-2 R° i 0-2 R80.
8.    Jedinjenje prema patentnom zahtevu 6, u kome prsten C je C3-6 cikloalifatik, fenil, oksazolil ili izoksazolil prsten, pri čemu je bilo koji od njih supstituisan sa 0-2 R80 i izborno je fuzionisan za izborno supstituisani benzen, dioksolan ili dioksan prsten.
9.    Jedinjenje prema patentnom zahtevu 5, naznačeno formulom (IV): ili njegova farmaceutski prihvatljiva so, u kome: V1 je -N(R8)-, -O- ili -S-; R8 je vodonik ili C1-4 alifatik; i Prsten D je izborno supstituisani mono- ili biciklični sistem prstena.
10. Jedinjenje prema patentnom zahtevu 9, naznačeno formulom (IV-A) ili (IV-B):
11. Jedinjenje prema patentnom zahtevu 9 ili 10, u kome je prsten D izabran iz grupe koju čine furanil, tienil, pirolil, oksazolil, tiazolil, imidazolil, pirazolil, izoksazolil, izotiazolil, oksadiazolil, triazolil, tiadiazolil, fenil, naftil, piranil, piridil, piridazinil, pirimidinil, pirazinil, triazinil, indolizinil, indolil, izoindolil, indazolil, benzimidazolil, benztiazolil, benzotienil, benzofuranil, purinil, hinolil, izohinolil, cinolinil, ftalazinil, hinazolinil, hinoksalinil, naftiridinil, pteridinil, tetrahidrofuranil, tetrahidrotienil, pirolidinil, pirolidonil, piperidinil, pirolinil, tetrahidrohinolinil, tetrahidroizohinolinil, dekahidrohinolinil, oksazolidinil, piperazinil, dioksanil, dioksolanil, diazepinil, oksazepinil, tiazepinil, morfolinil, hinuklidinil, tetrahidrohinolinil, tetrahidroizohinolinil, indanil, fenantridinil, tetrahidronaftil, indolinil, benzodioksanil, benzodioksolil, hromanil, ciklopropil, ciklobutil, ciklopentil, ciklopentenil, cikloheksil, cikloheksenil, cikloheptil, cikloheptenil, ciklooktil, ciklooktenil, ciklooktadienil, bicikloheptanil i biciklooktanil, pri čemu je bilo koja od tih grupa izborno supstituisana.
12.    Jedinjenje prema patentnom zahtevu 11, u kome: svaki zasićeni atom ugljenika iz prstena koji se može supstituisati u prstenu D je nesupstituisan ili supstituisan sa =0, =S, =C(R5)2, =N-N(R4)2, =N-OR5, =N-NHC(O)R5, =N-NHCO2R6, =N-NHS02R6, =N-R5 ili -Rp; svaki nezasićeni atom ugljenika iz prstena koji se može supstituisati u prstenu D je nesupstituisan ili supstituisan sa -Rp; svaki atom azota u prstenu koji se može supstituisati u prstenu D je nesupstituisan ili supstituisan sa -R9p; svaki Rp nezavisno je halo, -N02, -CN, -C(R5)=C(R5)2, -OC-R5, -OR5, -SR6, -S(O)R6, -S02R6, -S02N(R4)2, -N(R4)2, -NR4C(O)R5, -NR4C(O)N(R4)2, -N(R4)C(=NR4)-N(R4)2, -N(R4)C(=NR4)-R6, -NR4CO2R6, -N(R4)S02R6, -N(R4)S02N(R4)2, -O-C(O)R3, -OCO2R6,-OC(O)N(R4)2, -C(O)R5, -CO2R5, -C(O)N(R4)2, -C(O)N(R4)-0R5, -C(O)N(R4)C(=NR4)-N(R4)2, -N(R4)C(=NR4)-N(R4)-C(O)R5, -C(=NR4)-N(R4)2, -C(=NR4)-OR5, -C(=NR4)-N(R4)-OR5, -C(R6)=NOR5, ili izborno supstituisana alifatična, ili izborno supstituisana aril, heterociklil ili heteroaril grupa; ili dva Rp na istom zasićenom atomu ugljenika, uzeti zajedno sa atomom ugljenika za koji su vezani, formiraju izborno supstituisati 3- do 6-člani spirocikličan cikloalifatični prsten, i svako R9p nezavisno je -C(O)R5, -C(O)N(R4)2, -CO2R6, -S02R6, -S02N(R4)2 ili C1-4 alifatik izborno supstituisan sa R3 ili R7.
13.    Jedinjenje prema patentnom zahtevu 12, u kome: svako Rp nezavisno je izabran iz grupe koju čine halo, C1-4 alifatik, C1-4 fluoroalifatik, -R1p, -R2p, -T2-Rlp i -T2-R2p; ili dva Rp na istom zasićenom atomu ugljenika, uzeti zajedno sa atomom ugljenika za koji su vezani, formiraju izborno supstituisani 3- do 6-člani spirocikličan cikloalifatičan prsten; T2 je C1-6 alkilen lanac izborno supstituisan sa 0-2 nezavisno izabrana R3a ili R3b; svako Rlp nezavisno je izborno supstituisana aril, heteroaril ili heterociklil grupa; i svako R2p nezavisno je -N02, -CN, -C(R5)=C(R5)2, -C=C-R5, -OR5, -SR6, -S(O)R6, -S02R6, -S02N(R4)2,    -N(R4)2,    -NR4C(O)R5,    -NR4C(O)N(R4)2,    -N(R4)C(=NR4)-N(R4)2,    - N(R4)C(=NR4)-R6, -NR4CO2R6, -N(R4)S02R6, -N(R4)S02N(R4)2, -O-C(O)R5, -oco2r6, -OC(O)N(R4)2, -C(O)R5, -CO2R5, -C(O)NC(R4)2, -C(O)N(R4)-0R5, -C(O)N(R4)C(=NR4)-N(R4)2, -N(R4)C(=NR4)-N(R4)-C(O)R5, -C(=NR4)-N(R4)2, -C(=NR4)-OR5, -C(=NR4)-N(R4)-OR5 ili -C(R6)=NOR5.
14.    Jedinjenje prema patentnom zahtevu 13, u kome je prsten D izborno supstituisani indanil, tetrahidronaftil ili hromanil.
15.    Jedinjenje prema patentnom zahtevu 13, u kome: V1 je -N(R8)-; Prsten D je izabran iz grupe koju čine: svako Rp nezavisno je halo, -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y), ili je C1-4 alifatik ili C1-4 fluoroalifatik izborno supstituisan sa -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N (R4x)(R4y); svako R8p nezavisno je fluoro, -OR5x, -N(R4x)(R4y), -CO2R5x, ili -C(O)N(R4x)(R4y), ili je C1-4alifatik ili C1-4 fluoroalifatik izborno supstituisan sa -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); ili dva R8p na istom atomu ugljenika zajedno formiraju =0 ili =C(R5x)2; uz uslov da kada su dva R8p vezana za isti atom ugljenika, jedan mora biti izabran iz grupe koju čine fluoro,- CO2R5x, -C(O)N(R4x)(R4y), ili C1-4 alifatik ili C1-4 fluoroalifatik izborno supstituisan sa -OR5x, -N(R4x)(R4y), -CO2R5x, ili -C(O)N(R4x)(R4y); i dodatno uz uslov da se R8p razlikuje od -OR5x ili -N(R4x)(R4y) kada se nalazi na položaju pored atoma kiseonika u prstenu; s je 0, 1, 2, 3 ili 4; i t je 0, 1 ili 2.
16.    Jedinjenje prema patentnom zahtevu 15, u kome, Rp je halo.
17.    Jedinjenje prema patentnom zahtevu 15, u kome, R8p je -OR5x.
18.    Jedinjenje prema patentnom zahtevu 15, u kome je svako Rh nezavisno vodonik, fluoro, -CH3, -CF3 ili -OH.
19.    Jedinjenje prema patentnom zahtevu 15, u kome su Rb i Rd istovremeno vodonik, Ra je -OH i Rc je vodonik ili -OH.
20.    Jedinjenje prema patentnom zahtevu 5, u kome: Rg je -N(R8)(R9); R8 je vodonik ili C1-4 alifatik; R9 je vodonik, C1-4 alifatik, -T3-R9a ili -T4R9b; T3 je C1-4 alkilen lanac supstituisan sa 0-2 nezavisno izabrana R3a ili R3b; T4 je C2-6 alkilen lanac supstituisan sa 0-2 nezavisno izabrana R3a ili R3b; R9a je -C(R5)=C(R5)2, -C=C-R5, -S(O)R6, -S02R6, -S02-N(R4)2, -C(R5)=N-OR5, -CO2R5, - C(O)-C(O)R5, -C(O)R5, -C(O)N(R4)2, -C(=NR4)-N(R4)2 ili -C(=NR4)-OR5; i R9b je halo, -N02, -CN, -OR5, -SR6, -N(R4)2, -N(R4)C(O)R5, -N(R4)C(O)N(R4)2, - N(R4)CO2R5, -O-CO2-R5, -OC(O)N(R4)2, -OC(O)R5, -N(R4)N(R4)2, -N(R4)S(O)2R6 ili - N(R4)S02-N(R4)2, poželjno, pri čemu R9 je vodonik ili C1-6 alifatik ili C1-6 fluoroalifatik izborno supstituisan sa jednim ili dva supstituenta nezavisno izabrana iz grupe koju čine -OR5x, -N(R4x)(R4y), -CO2R5x, -C(O)N(R4x)(R4y).
21.    Jedinjenje prema patentnom zahtevu 2 ili 3, naznačeno formulom (V): ili njegova farmaceutski prihvatljiva so, u kome: prsten E je 5- ili 6-člani aril, heteroaril, cikloalifatičan ili heterocikličan prsten; E je -N= ili -C(Rh)=; svako Rh nezavisno je vodonik, halo, -CN-, -OR5, -N(R4)2, -SR6, ili izborno supstituisana C1-4 alifatična grupa; svako Rk nezavisno je vodonik, halo, -N02, -CN, -OR5, -SR6, -S(O)R6, -SO2R6, -S02N(R4)2, -N(R4)2, -NR4C(O)R5, -NR4C(O)N(R4)2, -N(R4)C(=NR4)-N(R4)2, -N(R4)C(=NR4)-R6, -NR4CO2R6, -N(R4)S02R6, -N(R4)S02N(R4)2, -O-C(O)R5, -OCO2R6, -OC(O)N(R4)2, -C(O)R5, -CO2R5, -C(O)N(R4)2, -C(O)N(R4)-0R5, -C(O)N(R4)C(=NR4)-N(R4)2, -N(R4)C(=NR4)-N(R4)-C(O)Rs, -C(=NR4)-N(R4)2,- C(=NR4)-OR5, -N(R4)-N(R4)2, -N(R4)-OR5, -C(=NR4)-N(R4)-OR5, -C(R6)=N-OR5, ili izborno supstituisani alifatik, aril, heteroaril ili heterociklil; i nje 0,1,2 ili 3.
22. Jedinjenje prema patentnom zahtevu 21, naznačeno a) formulom (VI): ili njegova farmaceutski prihvatljiva so, u kome: U je kovalentna veza, C1-3 alkilen, -O-, -S-, -S(O)- ili -S(O)2-; R je halo, C1-4 alifatik ili C1-4 fluoroalifatik; i Prsten F je izborno supstituisani mono-, bi- ili triciklični sistem prstena, poželjno pri čemu je prsten F izborno supstituisani fenil, naftil, tetrahidronaftil ili dihidrobenzofuranil, ili b) formulom (VII): ili njegova farmaceutski prihvatljiva so, u kome: E je -N= ili -C(Rh)=; F je -N(R9k)-, -O- ili -S-; i G je =N- ili =C(Rk)-; i R9k je vodonik, -C(O)R5, -C(O)N(R4)2, -CO2R6, -S02R6, -S02N(R4)2 ili C1-4 alifatik izborno supstituisan sa R3 ili R7, poželjno naznačeno formulom (VII-C) ili (VII-D): ili njegova farmaceutski prihvatljiva so, u kome: isprekidane linije pokazuju jednogube ili dvogube veze; svako R2f nezavisno je vodonik, halo, -OR5x, -N(R4x)(R4y) ili C1-4 alifatik iliC1-4 fluoroalifatik izborno supstituisan sa -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); ili oba R2f, uzeta zajedno sa atomima ugljenika u prstenu koji se nalaze između, formiraju izborno supstituisani fuzionisani 5- ili 6-člani cikloalifatični, aril, heteroaril ili heterociklični prsten.
23. Jedinjenje prema patentnom zahtevu 21, naznačeno formulom (VIII): ili njegova farmaceutski prihvatljiva so.
24. Jedinjenje prema patentnom zahtevu 2 ili 3, naznačeno formulom (IX-A): ili njegova farmaceutski prihvatljiva so, u kome stereohemijske konfiguracije na položajima označenim zvezdicama pokazuju apsolutnu konfiguraciju, i pri čemu: D je -N= ili -C(Rh)=; E je -N= ili -C(Rh)=; svalco Rh nezavisno je vodonik, halo, -CN-, -OR5, -N(R4)2, -SR6, ili uzbomo supstituisana C1-4alifatična grupa; svako Rp nezavisno je halo, -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y), ili je C1-4alifatik ili C1-4 fluoroalifatik izborno supstituisan sa -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); svako R8p nezavisno je fluoro, -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y), ili je C1-4alifatik ili C1-4 fluoroalifatik izborno supstituisan sa -OR5x,- N(R4x)(R4y), -CO2R5x, ili -C(O)N(R4x)(R4y); ili dva R8p na istom atomu ugljenika zajedno formiraju =0 ili =C(R5x)2; uz uslov da kada su dva R8p vezani za isti atom ugljenika, jedan mora biti izabran iz grupe koju čine fluoro, -CO2R5x, -C(O)N(R4x)(R4y) ili C1-4 alifatik ili C1-4 fluoroalifatik izborno supstituisan sa -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); i dalje uz uslov da se R8p razlikuje od -0R5x ili -N(R4x)(R4y) kada se nalazi na položaju pored atoma kiseonika u prstenu; s je 0, 1, 2, 3 ili 4; i t je 0,1 ili 2.
25. Farmaceutska kompozicija koja sadrži jedinjenje prema bilo kom od patentnih zahteva 1 do 24 i farmaceutski prihvatljiv nosač, poželjno pri čemu je kompozicija formulisana za primenu na humanog pacijenta.
26.    Postupak za smanjenje aktivnosti E1 enzima u uzorku, koji sadrži dovođenje u dodir uzorka sa jedinjenjem prema bilo kom od patentnih zahteva 1 do 24, pri čemu E1 enzim je, na primer, izabran iz grupe koju čine NAE, UAE i SAE.
27.    Jedinjenje prema bilo kom od patentnih zahteva 1 do 24 za primenu u lečenju kancera.
28.    Jedinjenje prema patentnom zahtevu 27, pri čemu je kancer - kancer pluća, kolorektalni kancer, kancer jajnika ili hematološki kancer.
29.    Jedinjenje prema bilo kom od patentnih zahteva 1 do 24 za primenu u lečenju poremećaja imunog odgovora ili poremećaja proliferacije vaskulamih ćelija.
30.    Primena jedinjenja prema bilo kom od patentnih zahteva 1 do 24 u proizvodnji leka za lečenje kancera, poremećaja imunog odgovora ili poremećaja proliferacije vaskulamih ćelija.
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CA2659894C (en) 2018-03-27
CN103923021A (zh) 2014-07-16
IL254784A0 (en) 2017-12-31
BRPI0715176A8 (pt) 2018-04-10
HK1130803A1 (en) 2010-01-08
CN101516850B (zh) 2014-05-07
CY1111121T1 (el) 2015-06-11
DK2049491T3 (da) 2011-02-14
AU2007281993B2 (en) 2013-08-29
IL242112A0 (en) 2015-11-30
NZ574513A (en) 2012-02-24
TW201439065A (zh) 2014-10-16
NO20090434L (no) 2009-02-16
AU2007281993A1 (en) 2008-02-14
DE602007009998D1 (de) 2010-12-02
KR20140066753A (ko) 2014-06-02
EP2049491A1 (en) 2009-04-22
JP2015013904A (ja) 2015-01-22
JP5906297B2 (ja) 2016-04-20
KR20090038931A (ko) 2009-04-21
WO2008019124A1 (en) 2008-02-14
ATE485276T1 (de) 2010-11-15
CN103923021B (zh) 2018-03-30
EA201501088A1 (ru) 2017-01-30
KR101555258B1 (ko) 2015-09-24
JP5274460B2 (ja) 2013-08-28

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