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Application filed by Millennium Pharm IncfiledCriticalMillennium Pharm Inc
Priority claimed from US11/890,338external-prioritypatent/US8008307B2/en
Priority claimed from PCT/US2007/017463external-prioritypatent/WO2008019124A1/en
Publication of ME01939BpublicationCriticalpatent/ME01939B/en
Pharmaceuticals Containing Other Organic And Inorganic 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 R je C2-4 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)R5, -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 alifatik ili C1-4 fluoroalifatik izborno supstituisan sa jodnim 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 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 C1-4 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 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 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 3.1. A compound of formula (1): or a pharmaceutically acceptable salt thereof, in which: Ring A is a 6-membered nitrogen-containing heteroaryl ring, optionally fused to a 5- or 6-membered aryl, heteroaryl, cycloaliphatic or heterocyclic ring, in which one of the rings or both rings optionally substituted and one ring nitrogen atom optionally oxidized; W is -CH2-, -CHF-, -CF2-, -CHCR1)-, -CFCR1)-, -NH-, -NCR1)-, -O-, -S- or -NHC(O)-; R1 is C1-4 aliphatic or C1-4 fluoroaliphatic, or R is a C2-4 alkylene chain attached to a ring position on ring A to form a 5-, 6-, or 7-membered fused ring, wherein the alkylene chain is optionally substituted with C1-4 aliphatic, C1-4 fluoroaliphatic, =O, -CN or -C(O)N(R4)2; X is -CH2-, -CHF-, -CF2-, -NH- or -O-; Y is -O-, -S- or -C(Rm)(Rn)-; Ra is selected from the group consisting of hydrogen, fluoro, -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 or C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from the group consisting of -0R3x , -N(R4x)(R4y), -CO2R5x or -C(O)N(R4x)(R4y); or Ra and Rc together form a bond; Rb is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic and C1-4 fluoroaliphatic; Rc is selected from the group consisting of hydrogen, 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 or C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with iodine or two substituents independently selected from the group consisting of -OR5x, -N(R4x)(R4y), -CO2R5x or -C(O)N(R4x)(R4y); or Ra and Rc together form a bond; Rd is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic and C1-4 fluoroaliphatic; Re is hydrogen, or C1-4 aliphatic; or Re, taken together with one Rf and intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring; or Re; taken together with Rm and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic; Re is hydrogen or C1-4 aliphatic; or Re, taken together with Rm and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic; each Rf is independently hydrogen, fluoro, C1-4 aliphatic or C1-4 fluoroaliphatic; or two R's taken together form =0; or two Rf, taken together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring; or one Rf, taken together with Re and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring; Rm is hydrogen, fluoro, -N(R4)2, or an optionally substituted C1-4 aliphatic group; or Rm and Rn together form =O or =C(R5)2; or Rm and Re, taken together with the intervening carbon atoms, form a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic; or Rm and Re, taken together with the intervening carbon atoms, form a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic; Rn is hydrogen, fluoro, or an optionally substituted C1-4 aliphatic group; or Rm and Rn together form =O or =C(R5)2; each R 4 is independently hydrogen or an optionally substituted aliphatic, aryl, heteroaryl or heterocyclyl group; or two R 4 on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O and S; R 4x is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl or C 6-10 ar(C 1-4 )alkyl, the aryl part of which may be optionally substituted; R4y is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C6-10 ar(C1-4)alkyl, the aryl part of which can be optionally substituted, or an optionally substituted 5- or 6-membered aryl, heteroaryl or heterocyclyl ring; or R4x and R4y, taken together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O and S; and each R 5 is independently hydrogen or an optionally substituted aliphatic, aryl, heteroaryl or heterocyclyl group; each R 5x is independently hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or optionally substituted C 6-10 aryl or C 6-10 ar(C 1-4 )alkyl; each R 6 is independently an optionally substituted aliphatic, aryl or heteroaryl group; and m is 1, 2, or 3.2. Jedinjenje prema patentnom zahtevu 1, u kome, W je -CH2-, -CHF-, -CF2-, -NH-, -O-, -S-ili -NHC(O)-.2. A compound according to claim 1, wherein W is -CH2-, -CHF-, -CF2-, -NH-, -O-, -S-or -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 1.3. A compound according to claim 2, characterized by one or more of the following characteristics: (a) X is -O-; (b) Y is -CH2-; (c) W is -NH-; (d) Ra is -OH; (e) each Rb and Rd are independently hydrogen or C1-4 aliphatic; (f) R c is hydrogen, fluoro, or -OR 5 ; (g) each R e and R e are hydrogen; (h) each Rf is hydrogen; and (i) m is 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, - SO2N(R4)2, -N(R4)2, -NR4C(O)Rs, -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(0)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.4. Jedinjenje prema patentnom zajekumu 2 ili 3, indicated by formula (II): ili njega pharmaceutics acceptable so, u kojima: D je -N= ili -C(Rh)=; E is -N= ili -C(Rh)=; R8 is hydrogen, halo, cyano, -C(R5)=C(R5)2, -C≡C-R5, -OR5, -SR6, -S(O)R6, -SO2R6, - SO2N(R4)2, -N(R4)2, -NR4C(O)Rs, -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( 0)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, or optionally substituted aliphatic, aryl, heteroaryl or heterocyclyl; and each Rh independently is hydrogen, halo, -CN-, -OR5, -N(R4)2, -SR6, or optionally substituted C1-4 aliphatic group.5. Jedinjenje prema patentnom zahtevu 4, u kome: Rg je vodonik, C1-6 alifatik, C1-6 fluoroalifatik, halo, -Rlg, -R2g, -T1-R1g, -T1-R28, -V1-T1-R1g, - V1-T1-R2g, -V1-R1g ili -T1-V1-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(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 deo izborno formira deo 3-7-članog prstena; V1 je -C(R5)=C(R5)-, -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)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-; svako R1g nezavisno je izborno supstituisani aril, heteroaril, heterociklil ili cikloalifatični prsten; svako 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)Rs, -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; svako 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); 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.5. Combination according to patent claim 4, in which: Rg is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, halo, -Rlg, -R2g, -T1-R1g, -T1-R28, -V1-T1-R1g, - V1-T1-R2g, -V1-R1g or -T1-V1-R1g; T1 is a C1-6 alkylene chain substituted with 0-2 independently selected R3a or R3b, wherein the alkylene chain is optionally terminated with -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- or -C(R6)=N-O-, and where T1 or V1 is -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- or -C(R6)=N-O-; each R1g is independently optionally substituted aryl, heteroaryl, heterocyclyl or a cycloaliphatic ring; each R2g independently is -NO2, -CN, -C(R5)=C(R5)2, -C≡C-R5, -OR5, -SR6, -S(O)R6, -SO2R6, -SO2N(R4) 2, -N(R4)2, -NR4C(O)Rs, -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 or -C(R6)=N-OR5; each R3a is independently selected from the group consisting of -F, -OH, -O(C1-4 alkyl), -CN, -N(R4)2, -C(O)(C1-4 alkyl), -CO2H, - CO2(C1-4 alkyl), -C(O)NH2 i -C(O)NH(C1-4 alkyl); each R3b independently is a C1-3 aliphatic optionally substituted with R3a or R7, or two R3b substituents on the same carbon atom, taken together with the carbon atom to which they are attached, form a 3- to 6-membered cycloaliphatic ring; and each R7 is independently optionally substituted with an aryl or heteroaryl ring.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, -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 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.6. The compound according to patent claim 5, indicated by formula (III): or its pharmaceutically acceptable salt, in which: Q is -T1- or -V1-T1-; V 1 is -N(R 8 )-, -O- or -S-; R8 is hydrogen or C1-4 aliphatic; T 1 is a C 1-4 alkylene chain optionally substituted with one or two groups independently selected from fluoro, C 1-4 aliphatic and C 1-4 fluoroaliphatic; and Ring C is a 3- to 8-membered heterocyclyl or cycloaliphatic ring, or a 5- or 6-membered aryl or heteroaryl ring, each of said rings being substituted with 0-2 R° and 0-2 R 80 ; each R° is independently halo, -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, or an optionally substituted aliphatic, or optionally substituted aryl, heterocyclyl or heteroaryl group; or two R° on the same saturated ring carbon atom, taken together with the carbon atom, form an optionally substituted 3- to 8-membered spirocyclic cycloaliphatic or heterocyclyl ring; or two adjacent R°, taken together with the intervening ring atoms, form an optionally substituted fused 4- to 8-membered aromatic or non-aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N and S; each R80 is independently selected from the group consisting of C1-4 aliphatic, C1-4 fluoroaliphatic, halo, -OR5x, -N(R4x)(R4y) or C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with -OR5x, -N (R4x)(R4y), -CO2R5x or -C(O)N(R4x)(R4y); R 4x is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl or C 6-10 ar(C 1-4 )alkyl, the aryl part of which may be optionally substituted; R4y is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C6-10 ar(C1-4)alkyl, the aryl part of which can be optionally substituted, or an optionally substituted 5- or 6-membered aryl, heteroaryl or heterocyclyl ring; or R4x and R4y, taken together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O and S; and each R 5x is independently hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or optionally substituted C 6-10 aryl or C 6-10 ar(C 1-4 )alkyl.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 R80.7. A compound according to patent claim 6, in which ring C is C3-6 cycloaliphatic, phenyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or tetrahydropyrimidinyl ring, pri čemu je bilo koji od nij 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 R8° i izborno je fiizionisan za izborno supstituisani benzen, dioksolan ili dioksan prsten.8. A compound according to claim 6, wherein ring C is a C3-6 cycloaliphatic, phenyl, oxazolyl or isoxazolyl ring, any of which is substituted with 0-2 R8° and is optionally fissioned to an optionally substituted benzene, dioxolane or dioxane ring.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.9. A compound according to patent claim 5, indicated by formula (IV): or a pharmaceutically acceptable salt thereof, in which: V1 is -N(R8)-, -O- or -S-; R8 is hydrogen or C1-4 aliphatic; and Ring D is an optionally substituted mono- or bicyclic ring system.10. Jedinjenje prema patentnom zahtevu 9, naznačeno formulom (IV-A) ili (IV-B):10. Compound according to claim 9, indicated by formula (IV-A) or (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.11. Compound according to patent claim 9 or 10, wherein ring D is selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienil, benzofuranil, purinyl, hinolyl, isohinolyl, cinolinyl, phthalazinyl, hinazolinyl, hinoxalinyl, naphthiridinyl, pteridinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidinyl, piperidinyl, pyrolinyl, tetrahydrohinolinyl, tetrahydroisohinolinyl, dekahydrohinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, tiazepinyl, morpholinyl, hinuclidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, phenanthridinyl, tetrahydronaphthyl, indolinyl, benzodioxanyl, benzodioxolyl, chromanil, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, bicycloheptanil, and bicyclooctanil, wherein any one of these groups is optionally substituted.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 =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 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, -NO2, -CN, -C(R5)=C(R5)2, -OC-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 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, -SO2R6, -SO2N(R4)2 ili C1-4 alifatik izborno supstituisan sa R3 ili R7.12. A compound according to claim 11, wherein: each saturated ring carbon atom substitutable in ring D is unsubstituted or substituted with =O, =S, =C(R5)2, =N-N(R4)2, = N-OR5, =N-NHC(O)R5, =N-NHCO2R6, =N-NHSO2R6, =N-R5 or -Rp; each unsaturated substitutable ring carbon atom in ring D is unsubstituted or substituted with -Rp; each substitutable ring nitrogen atom in ring D is unsubstituted or substituted with -R 9p ; each Rp is independently halo, -NO2, -CN, -C(R5)=C(R5)2, -OC-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( =NR 4 )-N(R 4 )-OR 5 , -C(R 6 )=NOR 5 , or an optionally substituted aliphatic, or optionally substituted aryl, heterocyclyl or heteroaryl group; or two Rp on the same saturated carbon atom, taken together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered spirocyclic cycloaliphatic ring, and each R9p is independently -C(O)R5, -C(O)N (R4)2, -CO2R6, -SO2R6, -SO2N(R4)2 or C1-4 aliphatic optionally substituted with R3 or R7.13. Jedinjenje prema patentnom zahtevu 12, u kome: svako Rp nezavisno je izabran iz grupe koju čine halo, C1-6 alifatik, C1-6 fluoroalifatik, -Rlp, -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 -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)=NOR5.13. The compound of claim 12, wherein: each Rp is independently selected from the group consisting of halo, C1-6 aliphatic, C1-6 fluoroaliphatic, -Rlp, -R2p, -T2-Rlp and -T2-R2p; or two Rp on the same saturated carbon atom, taken together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered spirocyclic cycloaliphatic ring; T2 is a C1-6 alkylene chain optionally substituted with 0-2 independently selected R3a or R3b; each Rlp is independently an optionally substituted aryl, heteroaryl or heterocyclyl group; and each R2p is independently -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 (=NR 4 )-N(R 4 )-OR 5 or -C(R 6 )=NOR 5 .14. Jedinjenje prema patentnom zahtevu 13, u kome je prsten D izborno supstituisani indanil, tetrahidronaftil ili hromanil.14. A compound according to claim 13, wherein ring D is optionally substituted indanyl, tetrahydronaphthyl or chromanyl.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 C1-4 alifatik 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 Cl-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 2.15. A compound according to claim 13, wherein: V1 is -N(R8)-; Ring D is selected from the group consisting of: each Rp is independently halo, -OR5x, -N(R4x)(R4y), -CO2R5x or -C(O)N(R4x)(R4y), or C1-4 is aliphatic or C1-4 fluoroaliphatic optionally substituted with -OR5x, -N(R4x)(R4y), -CO2R5x or -C(O)N (R4x)(R4y); each R8p is independently fluoro, -OR5x, -N(R4x)(R4y), -CO2R5x, or -C(O)N(R4x)(R4y), or is C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with - OR5x, -N(R4x)(R4y), -CO2R5x or -C(O)N(R4x)(R4y); or two R8p on the same carbon atom together form =0 or =C(R5x)2; with the proviso that when two R8p are attached to the same carbon atom, one must be selected from the group consisting of fluoro, - CO2R5x, -C(O)N(R4x)(R4y), or C1-4 aliphatic or Cl-4 fluoroaliphatic optionally substituted with -OR5x, -N(R4x)(R4y), -CO2R5x, or -C(O)N(R4x)(R4y); and further provided that R8p is different from -OR5x or -N(R4x)(R4y) when positioned next to a ring oxygen atom; s is 0, 1, 2, 3 or 4; and t is 0, 1, or 2.16. Jedinjenje prema patentnom zahtevu 15, u kome, Rp je halo.16. The compound of claim 15, wherein Rp is halo.17. Jedinjenje prema patentnom zahtevu 15, u kome, R8p je -OR5x.17. The compound of claim 15, wherein R8p is -OR5x.18. Jedinjenje prema patentnom zahtevu 15, u kome je svako Rh nezavisno vodonik, fluoro, -CH3, -CF3 ili -OH.18. The compound of claim 15, wherein each Rh is independently hydrogen, fluoro, -CH3, -CF3 or -OH.19. Jedinjenje prema patentnom zahtevu 15, u kome su Rb i Rd istovremeno vodonik, Ra je -OH i Rc je vodonik ili -OH.19. A compound according to claim 15, wherein Rb and Rd are both hydrogen, Ra is -OH and Rc is hydrogen or -OH.20. Jedinjenje prema patentnom zahtevu 5, u kome: Rg je-N(R8)(R9); R8 je vodonik ili C1-6 alifatik; R9 je vodonik, C1-6 alifatik, -T3-R9a ili -T4-R9b; T3 je C1-6 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, -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 halo, -NO2, -CN, -OR5, -SR6, -N(R4)2, -N(R4)C(O)R5, -N(R4)C(O)N(R4)2, - N(R4)CO2R5, -O-CO2-Rs, -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, 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).20. A compound according to claim 5, wherein: R 8 is -N(R 8 )(R 9 ); R8 is hydrogen or C1-6 aliphatic; R9 is hydrogen, C1-6 aliphatic, -T3-R9a or -T4-R9b; T3 is a C1-6 alkylene chain substituted with 0-2 independently selected R3a or R3b; T4 is a C2-6 alkylene chain substituted with 0-2 independently selected R3a or R3b; R9a is -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 or -C(= NR 4 )-OR 5 ; and R9b is halo, -NO2, -CN, -OR5, -SR6, -N(R4)2, -N(R4)C(O)R5, -N(R4)C(O)N(R4)2, - N(R4)CO2R5, -O-CO2-Rs, -OC(O)N(R4)2, -OC(O)R5, -N(R4)N(R4)2, -N(R4)S( O)2R6 or - N(R4)SO2-N(R4)2, preferably, wherein R9 is hydrogen or C1-6 aliphatic or C1-6 fluoroaliphatic optionally substituted with one or two substituents independently selected from the group consisting of -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, -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 supstituisani alifatik, aril, heteroaril ili heterociklil; i nje 0, 1, 2 ili 3.21. A compound according to patent claim 2 or 3, indicated by formula (V): or its pharmaceutically acceptable salt, in which: ring E is a 5- or 6-membered aryl, heteroaryl, cycloaliphatic or heterocyclic ring; E is -N= ili -C(Rh)=; each Rh independently is hydrogen, halo, -CN-, -OR5, -N(R4)2, -SR6, or optionally substituted C1-4 aliphatic group; each Rk independently is hydrogen, halo, -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, or optionally substituted aliphatic, aryl, heteroaryl or heterocyclyl; i nje 0, 1, 2 or 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-; R8k 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, -SO2R6, -SO2N(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 ili C1-4 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.22. The compound according to patent claim 21, indicated by a) formula (VI): or its pharmaceutically acceptable salt, in which: U is a covalent bond, C1-3 alkylene, -O-, -S-, -S(O)- or -S(O)2-; R8k is halo, C1-4 aliphatic or C1-4 fluoroaliphatic; and Ring F is an optionally substituted mono-, bi- or tricyclic ring system, preferably wherein Ring F is optionally substituted phenyl, naphthyl, tetrahydronaphthyl or dihydrobenzofuranyl, or b) of formula (VII): or a pharmaceutically acceptable salt thereof, wherein: E is -N= or -C(Rh)=; F is -N(R9k)-, -O- or -S-; and G is =N- or =C(Rk)-; and R9k is hydrogen, -C(O)R5, -C(O)N(R4)2, -CO2R6, -SO2R6, -SO2N(R4)2 or C1-4 aliphatic optionally substituted with R3 or R7, preferably indicated by the formula (VII-C) or (VII-D): or a pharmaceutically acceptable salt thereof, wherein: dashed lines indicate single or double bonds; each R2f is independently hydrogen, halo, -OR5x, -N(R4x)(R4y) or C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with -OR5x, -N(R4x)(R4y), -CO2R5x or -C( O)N(R4x)(R4y); or both R2f, taken together with the intervening ring carbon atoms, form an optionally substituted fused 5- or 6-membered cycloaliphatic, aryl, heteroaryl, or heterocyclic ring.23. Jedinjenje prema patentnom zahtevu 21, naznačeno formulom (VIII): ili njegova farmaceutski prihvatljiva so.23. The compound according to claim 21, indicated by formula (VIII): or its pharmaceutically acceptable salt.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)=; svako Rh nezavisno je vodonik, halo, -CN-, -OR5, -N(R4)2, -SR6, ili uzborno supstituisana C1-4 alifatična grupa; 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 C1-4 alifatik 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 -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 2.24. A compound according to claim 2 or 3, indicated by the formula (IX-A): or a pharmaceutically acceptable salt thereof, wherein the stereochemical configurations at the positions marked with asterisks show the absolute configuration, and wherein: D is -N= or -C(Rh )=; E is -N= or -C(Rh)=; each Rh is independently hydrogen, halo, -CN-, -OR5, -N(R4)2, -SR6, or an optionally substituted C1-4 aliphatic group; each Rp is independently halo, -OR5x, -N(R4x)(R4y), -CO2R5x or -C(O)N(R4x)(R4y), or is C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with -OR5x , -N(R4x)(R4y), -CO2R5x or -C(O)N(R4x)(R4y); each R8p is independently fluoro, -OR5x, -N(R4x)(R4y), -CO2R5x or -C(O)N(R4x)(R4y), or is C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with -OR5x , - N(R4x)(R4y), -CO2R5x, or -C(O)N(R4x)(R4y); or two R8p on the same carbon atom together form =0 or =C(R5x)2; provided that when two R8p are attached to the same carbon atom, one must be selected from the group consisting of fluoro, -CO2R5x, -C(O)N(R4x)(R4y) or C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with -OR5x, -N(R4x)(R4y), -CO2R5x or -C(O)N(R4x)(R4y); and further provided that R8p is different from -OR5x or -N(R4x)(R4y) when positioned next to a ring oxygen atom; s is 0, 1, 2, 3 or 4; and t is 0, 1, or 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.25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 and a pharmaceutically acceptable carrier, preferably wherein the composition is formulated for administration to a human patient.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.26. A method for reducing the activity of an E1 enzyme in a sample, comprising contacting the sample with a compound according to any one of claims 1 to 24, wherein the E1 enzyme is, for example, selected from the group consisting of NAE, UAE and SAE.27. Jedinjenje prema bilo kom od patentnih zahteva 1 do 24 za primenu u lečenju kancera.27. A compound according to any one of claims 1 to 24 for use in the treatment of cancer.28. Jedinjenje prema patentnom zahtevu 27, pri čemu je kancer - kancer pluća, kolorektalni kancer, kancer jajnika ili hematološki kancer.28. The compound of claim 27, wherein the cancer is lung cancer, colorectal cancer, ovarian cancer or hematological cancer.29. Jedinjenje prema bilo kom od patentnih zahteva 1 do 24 za primenu u lečenju poremećaja imunog odgovora ili poremećaja proliferacije vaskularnih ćelija.29. A compound according to any one of claims 1 to 24 for use in the treatment of an immune response disorder or a vascular cell proliferation disorder.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.30. Use of a compound according to any one of claims 1 to 24 in the production of a drug for the treatment of cancer, immune response disorders or vascular cell proliferation disorders.
MEP-2011-210A2006-08-082007-08-06Heteroaryl compounds useful as inhibitors of e1 activating enzymes
ME01939B
(en)