HRP20110017T1 - Spojevi heteroarila korisni kao inhibitori e1 aktivirajućih enzima - Google Patents

Spojevi heteroarila korisni kao inhibitori e1 aktivirajućih enzima Download PDF

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Publication number
HRP20110017T1
HRP20110017T1 HR20110017T HRP20110017T HRP20110017T1 HR P20110017 T1 HRP20110017 T1 HR P20110017T1 HR 20110017 T HR20110017 T HR 20110017T HR P20110017 T HRP20110017 T HR P20110017T HR P20110017 T1 HRP20110017 T1 HR P20110017T1
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HR
Croatia
Prior art keywords
ring
optionally substituted
aliphatic
hydrogen
group
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HR20110017T
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English (en)
Inventor
F. Claiborne Christopher
Critchley Stephen
P. Langston Steven
J. Olhava Edward
Peluso Stephane
S. Weatherhead Gabriel
Vyskocil Stepan
Visiers Irache
Mizutani Hirotake
Cullis Courtney
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Millennium Pharmaceuticals
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Publication of HRP20110017T1 publication Critical patent/HRP20110017T1/hr

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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—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
    • 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
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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
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    • 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
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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
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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
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    • C07D213/02—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
    • 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
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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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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Spoj formule (1): ili njegova farmaceutski prihvatljiva sol, naznačen time što: Prsten A je 6-eročlani heteroarilni prsten koji sadrži dušik, izborno fuzioniran za 5- ili 6-eročlani aril, heteroaril, cikloalifatski ili heterociklički prsten, gdje je jedan od prstenova ili oba prstena izborno supstituirani i atom dušika iz jednog prstena je izborno oksidiran; W je -CH2-, -CHF-, -CF2-, -CH(R1)-, -CF(R1)-, -NH-, -N(R1)-, -O-, -S- ili -NHC(O)-; R1 je C1-4 alifatik ili C1-4 fluoroalifatik; ili R1 je C2-4 alkilenski lanac koji je vezan za položaj prstena na prstenu A da bi se formirao 5-, 6- ili 7-eročlani fuzionirani prsten, pri čemu je alkilenski lanac izborno supstituiran sa C1-4 alifatikom, C1-4 fluoroalifatikom, =O, -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 vodik, fluor, -CN, -N3, -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 alifatski ili C1-4 fluoroalifatski izborno supstituiran sa jednim ili dva supstituenta nezavisno izabrana iz grupe koju čine -OR3x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); ili Ra i Rc zajedno formiraju vezu; Rb je izabran iz grupe koju čine vodik, fluor, C1-4 alifatik i C1-4 fluoralifatik; Rc je izabran iz grupe koju čine vodik, fluor, -CN, -N3, -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 alifatik ili C1-4 fluoralifatik izborno supstituiran sa jednim ili dva supstituenta nezavisno izabrana iz grupe koju čine -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); ili Ra i Rc zajedno formiraju vezu; Rd je izabran iz grupe koju čine vodik, fluor, C1-4 alifatik i C1-4 fluoralifatik; Re je vodik, ili C1-4 alifatik; ili Re, uzet zajedno sa jednim Rf i ugljikovim atomima koji se nalaze između, formira 3- do 6-eročlani spirociklički prsten; ili Re; uzet zajedno sa Rm i ugljikovim atomima koji se nalaze između, formira fuzionirani ciklopropanski prsten, koji je izborno supstituiran sa jednim ili dva supstituenta nezavisno izabrana između fluora ili C1-4 alifatika; Re' je vodik ili C1-4 alifatik; ili Re', uzet zajedno sa Rm i ugljikovim atomima koji se nalaze između, formira fuzionirani ciklopropan prsten, koji je izborno supstituiran sa jednim ili dva supstituenta nezavisno izabrana između fluora ili C1-4 alifatika; svaki Rf nezavisno je vodik, fluor, C1-4 alifatik ili C1-4 fluoralifatik; ili dva Rf uzeta zajedno formiraju =O; ili dva Rf, uzeta zajedno sa atomom ugljika za koji su vezani, formiraju 3- do 6-eročlani karbociklički prsten; ili jedan Rf, uzet zajedno sa Re i ugljikovim atomima koji se nalaze između, formira 3- do 6-eročlani spirociklički prsten; Rm je vodik, fluor, -N(R4)2, ili izborno supstituirana C1-4 alifatična grupa; ili Rm i Rn zajedno formiraju =O ili =C(R5)2; ili Rm i Re, uzeti zajedno sa ugljikovim atomima koji se nalaze između, formiraju fuzionirani ciklopropanski prsten, koji je izborno supstituiran sa jednim ili dva supst

Claims (30)

1. Spoj formule (1): [image] ili njegova farmaceutski prihvatljiva sol, naznačen time što: Prsten A je 6-eročlani heteroarilni prsten koji sadrži dušik, izborno fuzioniran za 5- ili 6-eročlani aril, heteroaril, cikloalifatski ili heterociklički prsten, gdje je jedan od prstenova ili oba prstena izborno supstituirani i atom dušika iz jednog prstena je izborno oksidiran; W je -CH2-, -CHF-, -CF2-, -CH(R1)-, -CF(R1)-, -NH-, -N(R1)-, -O-, -S- ili -NHC(O)-; R1 je C1-4 alifatik ili C1-4 fluoroalifatik; ili R1 je C2-4 alkilenski lanac koji je vezan za položaj prstena na prstenu A da bi se formirao 5-, 6- ili 7-eročlani fuzionirani prsten, pri čemu je alkilenski lanac izborno supstituiran sa C1-4 alifatikom, C1-4 fluoroalifatikom, =O, -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 vodik, fluor, -CN, -N3, -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 alifatski ili C1-4 fluoroalifatski izborno supstituiran sa jednim ili dva supstituenta nezavisno izabrana iz grupe koju čine -OR3x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); ili Ra i Rc zajedno formiraju vezu; Rb je izabran iz grupe koju čine vodik, fluor, C1-4 alifatik i C1-4 fluoralifatik; Rc je izabran iz grupe koju čine vodik, fluor, -CN, -N3, -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 alifatik ili C1-4 fluoralifatik izborno supstituiran sa jednim ili dva supstituenta nezavisno izabrana iz grupe koju čine -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); ili Ra i Rc zajedno formiraju vezu; Rd je izabran iz grupe koju čine vodik, fluor, C1-4 alifatik i C1-4 fluoralifatik; Re je vodik, ili C1-4 alifatik; ili Re, uzet zajedno sa jednim Rf i ugljikovim atomima koji se nalaze između, formira 3- do 6-eročlani spirociklički prsten; ili Re; uzet zajedno sa Rm i ugljikovim atomima koji se nalaze između, formira fuzionirani ciklopropanski prsten, koji je izborno supstituiran sa jednim ili dva supstituenta nezavisno izabrana između fluora ili C1-4 alifatika; Re’ je vodik ili C1-4 alifatik; ili Re’, uzet zajedno sa Rm i ugljikovim atomima koji se nalaze između, formira fuzionirani ciklopropan prsten, koji je izborno supstituiran sa jednim ili dva supstituenta nezavisno izabrana između fluora ili C1-4 alifatika; svaki Rf nezavisno je vodik, fluor, C1-4 alifatik ili C1-4 fluoralifatik; ili dva Rf uzeta zajedno formiraju =O; ili dva Rf, uzeta zajedno sa atomom ugljika za koji su vezani, formiraju 3- do 6-eročlani karbociklički prsten; ili jedan Rf, uzet zajedno sa Re i ugljikovim atomima koji se nalaze između, formira 3- do 6-eročlani spirociklički prsten; Rm je vodik, fluor, -N(R4)2, ili izborno supstituirana C1-4 alifatična grupa; ili Rm i Rn zajedno formiraju =O ili =C(R5)2; ili Rm i Re, uzeti zajedno sa ugljikovim atomima koji se nalaze između, formiraju fuzionirani ciklopropanski prsten, koji je izborno supstituiran sa jednim ili dva supstituenta nezavisno izabrana između fluora ili C1-4 alifatika; ili Rm i Re’, uzeti zajedno sa ugljikovim atomima koji se nalaze između, formiraju fuzionirani ciklopropan prsten, koji je izborno supstituiran sa jednim ili dva supstituenta koji su nezavisno izabrani između fluora ili C1-4 alifatika; Rn je vodik, fluor, ili izborno supstituirana C1-4 alifatična grupa; ili Rm i Rn zajedno formiraju =O ili =C(R5)2; svakio R4 nezavisno je vodik ili izborno supstituirana alifatična, aril, heteroaril ili heterociklil grupa; ili dva R4 na istom atomu dušika, uzeti zajedno sa atomom dušika, formiraju izborno supstituirani 4- do 8-eročlani heterociklil prsten koji ima, pored atoma dušika, 0-2 heteroatoma u prstenu nezavisno izabrana između N, O i S; R4x je vodik, C1-4 alkil, C1-4 fluoralkil ili C6-10 ar(C1-4)alkil, čiji arilni dio može biti izborno supstituiran; R4y je vodik, C1-4 alkil, C1-4 fluoralkil, C6-10 ar(C1-4)alkil, čiji arilni dio može biti izborno supstituiran, ili izborno supstituirani 5- ili 6-eročlani aril, heteroaril ili heterociklil prsten; ili R4x i R4y, uzeti zajedno sa atomom dušika za koji su vezani, formiraju izborno supstituirani 4- do 8-eročlani heterociklil prsten koji ima, pored atoma dušika, 0-2 heteroatoma u prstenu nezavisno izabrana između N, O i S; i svaki R5 nezavisno je vodik ili izborno supstituirana alifatična, aril, heteroaril ili heterociklil grupa; svaki R5x nezavisno je vodik, C1-4 alkil, C1-4 fluoralkil, ili izborno supstituirani C6-10 aril ili C6-10 ar(C1-4)alkil; svaki R6 nezavisno je izborno supstituirana alifatična, aril ili heteroaril grupa; i m je 1, 2 ili 3.
2. Spoj prema patentnom zahtjevu 1, naznačen time što W je -CH2-, -CHF-, -CF2-, -NH-, -O-, -S- ili -NHC(O)-.
3. Spoj prema patentnom zahtjevu 2, naznačen jednom ili više od sljedećih karakteristika: (a) X je -O-; (b) Y je -CH2-; (c) W je -NH-; (d) Ra je -OH; (e) svaki Rb i Rd su nezavisno vodik ili C1-4 alifatik; (f) Rc je vodik, fluor, ili -OR5; (g) svaki Re i Re’ su vodik; (h) svaki Rf je vodik; i (i) m je 1.
4. Spoj prema patentnom zahtjevu 2 ili 3, naznačen formulom (II): [image] ili njegova farmaceutski prihvatljiva sol, gdje: D je -N= ili -C(Rh)=; E je -N= ili -C(Rh)=; Rg je vodik, halogen, cijano, -C(R5)=C(R5)2, -C≡C-R5, -OR5, -SR6, -S(O)R6, -SO2R6, -SO2N(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)SO2Rb, -N(R4)SO2N(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)-OR5,-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 supstituiran alifatik, aril, heteroaril ili heterociklil; i svaki Rh nezavisno je vodik, halogen, -CN-, -OR5, -N(R4)2, -SR6, ili izborno supstituirana C1-4 alifatična grupa.
5. Spoj prema patentnom zahtjevu 4, naznačen time što: Rg je vodik, C1-6 alifatik, C1-6 fluoralifatik, halogen, -R1g, -R2g, -T1-R1g, -T1-R2g, -V1-T1-R1g, -V1-T1-R2g, -V1-R1g ili -T1-V1-R1g; T1 je C1-6 alkilenski lanac supstituiran sa 0-2 nezavisno izabrana R3a ili R3b, pri čemu je alkilenski lanac izborno prekinut sa -C(R5)=C(R5)-, -C≡C-, -O-, -S-, -S(O)-, -S(O)2-, -SO2N(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)SO2-, -N(R4)SO2N(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 dio izborno formira dio 3-7-eročlanog prstena; V1 je -C(R5)=C(R5)-, -C≡C-, -O-, -S-, -S(O)-, -S(O)2-, -SO2N(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)SO2-, -N(R4)SO2N(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-; svaki R1g nezavisno je izborno supstituirani aril, heteroaril, heterociklil ili cikloalifatični prsten; svaki R2g nezavisno je -NO2, -CN, -C(R5)=C(R5)2, -C≡C-R5, -OR5, -SR6, -S(O)R6, -SO2R6, -SO2N(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)SO2R6, -N(R4)SO2N(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)-OR5, -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; svaki R3a nezavisno je izabran iz grupe koju čine -F, -OH, -O(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); svaki R3b nezavisno je C1-3 alifatik izborno supstituiran sa R3a ili R7, ili dva supstituenta R3b na istom atomu ugljika, uzeti zajedno sa atomom ugljika za koji su vezani, formiraju 3- do 6-eročlani cikloalifatični prsten; i svaki R7 nezavisno je izborno supstituirani aril ili heteroaril prsten.
6. Spoj prema patentnom zahtjevu 5, naznačen formulom (III): [image] ili njegova farmaceutski prihvatljiva sol, gdje: Q je -T1- ili -V1-T1-; V1 je -N(R8)-, -O- ili -S-; R8 je vodik ili C1-4 alifatik; T1 je C1-4 alkilenski lanac izborno supstituiran sa jednom ili dvije grupe nezavisno izabrane između fluora, C1-4 alifatika i C1-4 fluoralifatika; i Prsten C je 3- do 8-eročlani heterociklil ili cikloalifatični prsten, ili 5- ili 6-eročlani aril ili heteroaril prsten, pri čemu je svaki od tih prstena supstituiran sa 0-2 Ro i 0-2 R8o; svaki Ro nezavisno je halogen, -NO2, -CN, -C(R5)=C(R5)2, -C≡C-R5, -OR5, -SR6, -S(O)R6, -SO2R6, -SO2N(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)SO2R6, -N(R4)SO2N(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)-OR5, -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 supstituirana alifatična, ili izborno supstituirana aril, heterociklil ili heteroaril grupa; ili dva Ro na istom zasićenom atomu ugljika u prstenu, uzeti zajedno sa atomom ugljika, formiraju izborno supstituirani 3- do 8-eročlani spirociklički cikloalifatski ili heterociklil prsten; ili dva susjedna Ro, uzeti zajedno sa atomima prstena koji se nalaze između, formiraju izborno supstituirani fuzionirani 4- do 8-eročlani aromatični ili nearomatični prsten koji ima 0-3 heteroatoma u prstenu izabrana iz grupe koju čine O, N i S; svaki R8o nezavisno je izabran iz grupe koju čine C1-4 alifatik, C1-4 fluoralifatik, halogen, -OR5x, -N(R4x)(R4y) ili C1-4 alifatik ili C1-4 fluoralifatik izborno supstituiran sa -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); R4x je vodik, C1-4 alkil, C1-4 fluoralkil ili C6-10 ar(C1-4)alkil, čiji arilni dio može biti izborno supstituiran; R4y je vodik, C1-4 alkil, C1-4 fluoralkil, C6-10 ar(C1-4)alkil, čiji arilni dio može biti izborno supstituiran, ili izborno supstituiran 5- ili 6-eročlani aril, heteroaril ili heterociklil prsten; ili R4x i R4y, uzeti zajedno sa atomom dušika za koji su vezani, formiraju izborno supstituirani 4- do 8-eročlani heterociklil prsten koji ima, pored atoma dušika, 0-2 heteroatoma u prstenu nezavisno izabrana između N, O i S; i svaki R5x nezavisno je vodik, C1-4 alkil, C1-4 fluoralkil, ili izborno supstituirani C6-10 aril ili C6-10 ar(C1-4)alkil.
7. Spoj prema patentnom zahtjevu 6, naznačen time što 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 supstituiran sa 0-2 Ro i 0-2 R8o.
8. Spoj prema patentnom zahtjevu 6, naznačen time što prsten C je C3-6 cikloalifatik, fenil, oksazolil ili izoksazolil prsten, pri čemu je bilo koji od njih supstituiran sa 0-2 R8o i izborno je fuzioniran za izborno supstituirani benzen, dioksolan ili dioksan prsten.
9. Spoj prema patentnom zahtjevu 5, naznačen formulom (IV): [image] ili njegova farmaceutski prihvatljiva sol, gdje: V1 je -N(R8)-, -O- ili -S-; R8 je vodik ili C1-4 alifatik; i Prsten D je izborno supstituirani mono- ili biciklički sustav prstena.
10. Spoj prema patentnom zahtjevu 9, naznačen formulom (IV-A) ili (IV-B): [image]
11. Spoj prema patentnom zahtjevu 9 ili 10, naznačen time što 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, kinolil, izokinolil, cinolinil, ftalazinil, kinazolinil, kinoksalinil, naftiridinil, pteridinil, tetrahidrofuranil, tetrahidrotienil, pirolidinil, pirolidonil, piperidinil, pirolinil, tetrahidrokinolinil, tetrahidroizokinolinil, dekahidrokinolinil, oksazolidinil, piperazinil, dioksanil, dioksolanil, diazepinil, oksazepinil, tiazepinil, morfolinil, kinuklidinil, tetrahidrokinolinil, tetrahidroizokinolinil, indanil, fenantridinil, tetrahidronaftil, indolinil, benzodioksanil, benzodioksolil, kromanil, ciklopropil, ciklobutil, ciklopentil, ciklopentenil, cikloheksil, cikloheksenil, cikloheptil, cikloheptenil, ciklooktil, ciklooktenil, ciklooktadienil, bicikloheptanil i biciklooktanil, pri čemu je bilo koja od tih grupa izborno supstituirana.
12. Spoj prema patentnom zahtjevu 11, naznačen time što: svaki zasićeni atom ugljika iz prstena koji se može supstituirati u prstenu D je nesupstituiran ili supstituiran sa =O, =S, =C(R5)2, =N-N(R4)2, =N-OR5, =N-NHC(O)R5, =N-NHCO2R6, =N-NHSO2R6, =N-R5 ili -Rp; svaki nezasićeni atom ugljika iz prstena koji se može supstituirati u prstenu D je nesupstituiran ili supstituiran sa -Rp; svaki atom dušika u prstenu koji se može supstituirati u prstenu D je nesupstituiran ili supstituiran sa -R9p; svaki Rp nezavisno je halogen, -NO2, -CN, -C(R5)=C(R5)2, -C≡C-R5, -OR5, -SR6, -S(O)R6, -SO2R6, -SO2N(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)SO2R6, -N(R4)SO2N(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)-OR5, -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 supstituirana alifatična, ili izborno supstituirana aril, heterociklil ili heteroaril grupa; ili dva Rp na istom zasićenom atomu ugljika, uzeti zajedno sa atomom ugljika za koji su vezani, formiraju izborno supstituirati 3- do 6-eročlani spirociklički cikloalifatični prsten, i svaki R9p nezavisno je -C(O)R5, -C(O)N(R4)2, -CO2R6, -SO2R6, -SO2N(R4)2 ili C1-4 alifatik izborno supstituiran sa R3 ili R7.
13. Spoj prema patentnom zahtjevu 12, naznačen time što: svaki Rp nezavisno je izabran iz grupe koju čine halogen, C1-6 alifatik, C1-6 fluoralifatik, -R1p, -R2p, -T2-R1p i -T2-R2p; ili dva Rp na istom zasićenom atomu ugljika, uzeti zajedno sa atomom ugljika za koji su vezani, formiraju izborno supstituirani 3- do 6-eročlani spirociklički cikloalifatski prsten; T2 je C1-6 alkilenski lanac izborno supstituiran sa 0-2 nezavisno izabrana R3a ili R3b; svaki R1p nezavisno je izborno supstituirana aril, heteroaril ili heterociklil grupa; i svaki R2p nezavisno je -NO2, -CN, -C(R5)=C(R5)2, -C≡C-R5, -OR5, -SR6, -S(O)R6, -SO2R6, -SO2N(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)SO2R6, -N(R4)SO2N(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)-OR5, -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. Spoj prema patentnom zahtjevu 13, naznačen time što je prsten D izborno supstituirani indanil, tetrahidronaftil ili kromanil.
15. Spoj prema patentnom zahtjevu 13, naznačen time što: V1 je -N(R8)-; Prsten D je izabran iz grupe koju čine: [image] svaki Rp nezavisno je halogen, -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y), ili je C1-4 alifatik ili C1-4 fluoralifatik izborno supstituiran sa -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); svaki R8p nezavisno je fluor, -OR5x, -N(R4x)(R4y), -CO2R5x, ili -C(O)N(R4x)(R4y), ili je C1-4 alifatik ili C1-4 fluoralifatik izborno supstituiran sa -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); ili dva R8p na istom atomu ugljika zajedno formiraju =O ili =C(R5x)2; uz uvjet da kada su dva R8p vezana za isti atom ugljika, jedan mora biti izabran iz grupe koju čine fluor,- CO2R5x, -C(O)N(R4x)(R4y), ili C1-4 alifatik ili C1-4 fluoralifatik izborno supstituiran sa -OR5x, -N(R4x)(R4y), -CO2R5x, ili -C(O)N(R4x)(R4y); i dodatno uz uvjet da se R8p razlikuje od -OR5x ili -N(R4x)(R4y) kada se nalazi na položaju pored atoma kisika u prstenu; s je 0, 1, 2, 3 ili 4; i t je 0, 1 ili 2.
16. Spoj prema patentnom zahtjevu 15, naznačen time što Rp jehalogen.
17. Spoj prema patentnom zahtjevu 15, naznačen time što R8p je -OR5x.
18. Spoj prema patentnom zahtjevu 15, naznačen time što je svaki Rh nezavisno vodik, fluor, -CH3, -CF3 ili -OH.
19. Spoj prema patentnom zahtjevu 15, naznačen time što su Rb i Rd istovremeno vodik, Ra je -OH i Rc je vodik ili -OH.
20. Spoj prema patentnom zahtjevu 5, naznačen time što: Rg je -N(R8)(R9); R8 je vodik ili C1-4 alifatik; R9 je vodik, C1-4 alifatik, -T3-R9a ili -T4-R9b; T3 je C1-6 alkilenski lanac supstituiran sa 0-2 nezavisno izabrana R3a ili R3b; T4 je C2-6 alkilenski lanac supstituiran sa 0-2 nezavisno izabrana R3a ili R3b; R9a je -C(R5)=C(R5)2, -C≡C-R5, -S(O)R6, -SO2R6, -SO2-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 halogen, -NO2, -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)SO2-N(R4)2, poželjno da R9 je vodik ili C1-6 alifatik ili C1-6 fluoralifatik izborno supstituiran sa jednim ili dva supstituenta nezavisno izabrana iz grupe koju čine -OR5x, -N(R4x)(R4y), -CO2R5x, -C(O)N(R4x)(R4y).
21. Spoj prema patentnom zahtjevu 2 ili 3, naznačen formulom (V): [image] ili njegova farmaceutski prihvatljiva sol, gdje: prsten E je 5- ili 6-eročlani aril, heteroaril, cikloalifatski ili heterociklički prsten; E je -N= ili -C(Rh)=; svaki Rh nezavisno je vodik, halogen, -CN-, -OR5, -N(R4)2, -SR6, ili izborno supstituirana C1-4 alifatična grupa; svaki Rk nezavisno je vodik, halogen, -NO2, -CN, -OR5, -SR6, -S(O)R6, -SO2R6, -SO2N(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)SO2R6, -N(R4)SO2N(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)-OR5, -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 supstituirani alifatik, aril, heteroaril ili heterociklil; i n je 0, 1, 2 ili 3.
22. Spoj prema patentnom zahtjevu 21, naznačen a) formulom (VI): [image] ili njegova farmaceutski prihvatljiva sol, gdje: U je kovalentna veza, C1-3 alkilen, -O-, -S-, -S(O)- ili -S(O)2-; R8k je halogen, C1-4 alifatik ili C1-4 fluoralifatik; i Prsten F je izborno supstituirani mono-, bi- ili triciklični sustav prstena, poželjno pri čemu je prsten F izborno supstituirani fenil, naftil, tetrahidronaftil ili dihidrobenzofuranil, ili b) formulom (VII): [image] ili njegova farmaceutski prihvatljiva sol, gdje: E je -N= ili -C(Rh)=; F je -N(R9k)-, -O- ili -S-; i G je =N- ili =C(Rk)-; i R9k je vodik, -C(O)R5, -C(O)N(R4)2, -CO2R6, -SO2R6, -SO2N(R4)2 ili C1-4 alifatik izborno supstituiran sa R3 ili R7, poželjno naznačen formulom (VII-C) ili (VII-D): [image] ili njegova farmaceutski prihvatljiva sol, gdje: isprekidane linije pokazuju jednostruke ili dvostruke veze; svaki R2f nezavisno je vodik, halogen, -OR5x, -N(R4x)(R4y) ili C1-4 alifatik ili C1-4 fluoralifatik izborno supstituiran sa -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); ili oba R2f, uzeta zajedno sa atomima ugljika u prstenu koji se nalaze između, formiraju izborno supstituirani fuzionirani 5- ili 6-eročlani cikloalifatični, aril, heteroaril ili heterociklični prsten.
23. Spoj prema patentnom zahtjevu 21, naznačen formulom (VIII): [image] ili njegova farmaceutski prihvatljiva sol.
24. Spoj prema patentnom zahtjevu 2 ili 3, naznačen formulom (IX-A): [image] ili njegova farmaceutski prihvatljiva sol, gdje stereokemijske konfiguracije na položajima označenim zvjezdicama pokazuju apsolutnu konfiguraciju, i pri čemu: D je -N= ili -C(Rh)=; E je -N= ili -C(Rh)=; svaki Rh nezavisno je vodik, halogen, -CN-, -OR5, -N(R4)2, -SR6, ili izborno supstituirana C1-4 alifatična grupa; svaki Rp nezavisno je halogen, -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y), ili je C1-4 alifatik ili C1-4 fluoralifatik izborno supstituiran sa -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); svaki R8p nezavisno je fluor, -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y), ili je C1-4 alifatik ili C1-4 fluoralifatik izborno supstituiran sa -OR5x,- N(R4x)(R4y), -CO2R5x, ili -C(O)N(R4x)(R4y); ili dva R8p na istom atomu ugljika zajedno formiraju =O ili =C(R5x)2; uz uvjet da kada su dva R8p vezani za isti atom ugljika, jedan mora biti izabran iz grupe koju čine fluor, -CO2R5x, -C(O)N(R4x)(R4y) ili C1-4 alifatik ili C1-4 fluoralifatik izborno supstituiran sa -OR5x, -N(R4x)(R4y), -CO2R5x ili -C(O)N(R4x)(R4y); i dalje uz uvjet da se R8p razlikuje od -OR5x ili -N(R4x)(R4y) kada se nalazi na položaju pored atoma kisika u prstenu; s je 0, 1, 2, 3 ili 4; i t je 0, 1 ili 2.
25. Farmaceutska smjesa, naznačena time što sadrži spoj prema bilo kojem od patentnih zahtjeva 1 do 24 i farmaceutski prihvatljiv nosač, poželjno pri čemu je smjesa oblikovana za primjenu kod ljudskog bolesnika.
26. Postupak za smanjenje aktivnosti E1 enzima u uzorku, naznačen time što obuhvaća dovođenje u dodir uzorka sa spojem prema bilo kojem od patentnih zahtjeva 1 do 24, pri čemu je E1 enzim, na primjer, izabran iz grupe koju čine NAE, UAE i SAE.
27. Spoj prema bilo kojem od patentnih zahtjeva 1 do 24, naznačen time što je za primjenu u liječenju raka.
28. Spoj prema patentnom zahtjevu 27, naznačen time što se radi o raku pluća, kolorektuma, jajnika ili hematološkom raku.
29. Spoj prema bilo kojem od patentnih zahtjeva 1 do 24, naznačen time što je za primjenu u liječenju poremećaja odgovora imunog sustava ili poremećaja proliferacije vaskularnih stanica.
30. Primjena spoja prema bilo kojem od patentnih zahtjeva 1 do 24, naznačena time što se radi o primjeni u proizvodnji lijeka za liječenje raka, poremećaja odgovora imunog sustava ili poremećaja proliferacije vaskularnih stanica.
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