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HRP20200274T1 - Terapeutski aktivni spojevi i postupci njihove uporabe - Google Patents

Terapeutski aktivni spojevi i postupci njihove uporabe Download PDF

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HRP20200274T1
HRP20200274T1 HRP20200274TT HRP20200274T HRP20200274T1 HR P20200274 T1 HRP20200274 T1 HR P20200274T1 HR P20200274T T HRP20200274T T HR P20200274TT HR P20200274 T HRP20200274 T HR P20200274T HR P20200274 T1 HRP20200274 T1 HR P20200274T1
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alkyl
image
optionally substituted
pharmaceutically acceptable
hydrate
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HRP20200274TT
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Zenon D. Konteatis
Janeta Popovici-Muller
Jeremy M. Travins
Robert Zahler
Zhenwei CAI
Ding Zhou
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Agios Pharmaceuticals, Inc.
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Application filed by Agios Pharmaceuticals, Inc. filed Critical Agios Pharmaceuticals, Inc.
Publication of HRP20200274T1 publication Critical patent/HRP20200274T1/hr

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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Claims (28)

1. Spoj koji ima formulu Ia ili njegova farmaceutski prihvatljiva sol ili hidrat, naznačen time što: [image] prsten A je izabran od fenila, pirazolila, oksazolila, izoksazolila, piridinila, pirimidinila, pirazinila i tiazolila, pri čemu je prsten A izborno supstituiran sa do dva supstituenta nezavisno izabrana od halo, -C1-C4 alkila, -C1-C4 haloalkila, -C1-C4 hidroksialkila, -NH-S(O)2-(C1-C4 alkil), -S(O)2NH(C1-C4 alkil), -CN, -S(O)2-(C1-C4 alkil), C1-C4 alkoksi, -NH(C1-C4 alkil), -OH, -OCF3, -CN, -NH2, -C(O)NH2, -C(O)NH(C1-C4 alkil), -C(O)-N(C1-C4 alkil)2 i ciklopropila izborno supstituiranog sa OH; R1, R3, R4 i R6 su svaki nezavisno izabrani od vodika, C1-C4 alkila, C1-C4 haloalkila, -O-C1-C4 alkila i CN, pri čemu je svaka navedena alkil grupa od R1, R3, R4, i R6 nezavisno izborno supstituirana sa -OH, -NH2, -CN, -O-C1-C4 alkil, -NH(C1-C4 alkil) ili -N(C1-C4 alkil)2; R2 i R5 su svaki nezavisno izabrani od: -(C1-C6 alkil), -(C1-C6 alkil)-C(O)-NH2, -(C1-C6 alkil)-CO2H, -(C2-C6 alkenil ili alkinil), -(C1-C6 alkilen)-O-(C1-C6 alkil), -(C0-C6 alkilen)-C(O)N(R6)-(C1-C6 alkil) i -(C0-C6 alkilen)-C(O)-(C1-C6 alkil) gdje: svaka alkil ili alkilen grupa prisutna u R2 i R5 je izborno supstituirana s jednim ili više -OH, -O(C1-C4 alkil), -CO2H ili halo; svaka terminalna metil grupa prisutna u R2 i R5 je izborno zamijenjena sa -CH2OH, CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN ili CO2H; R7 i R8 su svaki nezavisno izabrani od vodika i C1-C6 alkila; gdje R1 i R2 su izborno uzeti zajedno tako da formiraju karbociklil ili heterociklil od kojih je bilo koji izborno supstituiran sa do 3 supstituenta nezavisno izabrana od halo, npr., fluoro, C1-C4 alkila, C1-C4 haloalkila, C1-C4 alkoksi, -CN, =O, -OH, arila, heteroarila, -SO2C1-C4 alkila, -CO2C1-C4 alkila, -C(O)arila i -C(O)C1-C4 alkila; ili R4 i R5 su izborno uzeti zajedno tako da formiraju karbociklil ili heterociklil od kojih je bilo koji izborno supstituiran sa do 3 supstituenta nezavisno izabrana od halo, npr., fluoro, C1-C4 alkila, C1-C4 haloalkila, C1-C4 alkoksi, -CN, =O, -OH, arila, heteroarila, -SO2C1-C4 alkila, -CO2C1-C4 alkila, -C(O)arila i -C(O)C1-C4 alkila; gdje: (i) kada je A jednak piridil izborno supstituiran kao što je opisano u prethodnom tekstu, tada (A) N(R7)C(R4)(R5)(R6) i N(R8)C(R1)(R2)(R3) nisu oba NHCH2CH2OH, ili NH-cikloheksil, i (B) kada je N(R7)C(R4)(R5)(R6) jednak NHC(CH3)3, tada N(R8)C(R1)(R2)(R3) nije NH-CH2CH3; (ii) kada je A jednak pirazolil, oksazolil, izoksazolil, piridinil, pirimidinil, pirazinil ili tiazolil izborno supstituiran kao što je opisan u prethodnom tekstu, tada N(R7)C(R4)(R5)(R6) i N(R8)C(R1)(R2)(R3) nisu oba N(CH2CH3)2, NHCH2CH2-i-propil ili NHCH2CH(CH3)2; (iii) kada je A jednak 1-pirazolil izborno supstituiran kao što je opisano u prethodnom tekstu, tada ni N(R7)C(R4)(R5)(R6) ni N(R8)C(R1)(R2)(R3) nisu NH-izopropil, NHCH2CH3, ili N(CH2CH3)2, (iv) kada je A jednako fenil izborno supstituiran kao što je opisano u prethodnom tekstu, tada N(R7)C(R4)(R5)(R6) nije isti kao N(R8)C(R1)(R2)(R3), (v) spoj nije: N2-izopropil-6-fenil-N4-(tetrahidro-2H-piran-4-il)-1,3,5-triazin-2,4-diamin.
2. Spoj ili njegova farmaceutski prihvatljiva sol ili hidrat prema patentnom zahtjevu 1, naznačeno time što prsten A je izborno supstituiran sa do dva supstituenta nezavisno izabrana od halo, -C1-C4 alkila, -C1-C4 haloalkila, -C1-C4 hidroksialkila, -NH-S(O)2-(C1-C4 alkil), -S(O)2NH(C1-C4 alkil), -CN, -S(O)2-(C1-C4 alkil), C1-C4 alkoksi, -NH(C1-C4 alkil), -OH, -CN i -NH2.
3. Spoj ili njegova farmaceutski prihvatljiva sol ili hidrat prema patentnom zahtjevu 1, naznačen time što: R1, R3, R4 i R6 su svaki nezavisno izabrani od vodika, C1-C4 alkila, C1-C4 haloalkila, -O-C1-C4 alkila i CN, pri čemu je svaka navedena alkil grupa od R1, R3, R4 i R6 nezavisno izborno supstituirana sa -OH, -NH2, -CN, -O-C1-C4 alkilom, -NH(C1-C4 alkil) ili -N(C1-C4 alkil)2; R2 i R5 su svaki nezavisno izabrani od: -(C1-C6 alkil), -(C1-C6 alkil)-C(O)-NH2, -(C1-C6 alkil)-CO2H, -(C2-C6 alkenil ili alkinil), -(C1-C6 alkilen)-O-(C1-C6 alkil), -(C0-C6 alkilen)-C(O)N(R6)-(C1-C6 alkil) i -(C0-C6 alkilen)-C(O)-(C1-C6 alkil), gdje: bilo koja alkil ili alkilen grupa prisutna u R2 i R5 je izborno supstituirana jednim ili više -OH, -O(C1-C4 alkil), -CO2H ili halo; bilo koja terminalna grupa prisutna u R2 i R5 je izborno zamijenjena sa -CH2OH, CF3, -CH2F, -CH2Cl,C(O)CH3, C(O)CF3, CN ili CO2H.
4. Spoj ili njegova farmaceutski prihvatljiva sol ili hidrat prema patentnom zahtjevu 1, naznačeno time što prsten A je piridinil izborno supstituiran sa halo ili -C1-C4 haloalkil.
5. Spoj ili njegova farmaceutski prihvatljiva sol ili hidrat prema patentnom zahtjevu 1, naznačen time što oba R7 i R8 su H.
6. Spoj koji ima formulu B, ili njegova farmaceutski prihvatljiva sol ili hidrat naznačen time što: [image] X je N, CH ili C-halo; Xa je N ili C-R9a, uz uvjet kada je jedan Xa jednak N, tada su druga dva Xa oba jednaki C-R9a; R9 je halo, -C1-C4 alkil, -C1-C4 haloalkil, -C1-C4 hidroksialkil, -NH-S(O)2-(C1-C4 alkil), -S(O)2NH(C1-C4 alkil), -CN, -S(O)2-(C1-C4 alkil), C1-C4 alkoksi, -NH(C1-C4 alkil), -N(C1-C4 alkil)2, -OH, -OCF3, -CN, -NH2, -C(O)NH2, -C(O)NH(C1-C4 alkil), -C(O)-N(C1-C4 alkil)2, -(C1-C6 alkilen)-O-(C1-C6 alkil), aril i ciklopropil izborno supstituiran sa OH; svaki R9a je nezavisno izabran od vodika, halo, -C1-C4 alkila, -C1-C4 haloalkila, -C1-C4 hidroksialkila, -NH-S(O)2-(C1-C4 alkil), -S(O)2NH(C1-C4 alkil), -CN, -S(O)2-(C1-C4 alkil), C1-C4 alkoksi, -NH(C1-C4 alkil), -N(C1-C4 alkil)2, -OH, -OCF3, -CN, -NH2, -C(O)NH2,-C(O)NH(C1-C4 alkil), -C(O)-N(C1-C4 alkil)2, -(C1-C6 alkilen)-O-(C1-C6 alkil), aril i ciklopropila izborno supstituiranog sa OH; R1, R3, R4 i R6 su svaki nezavisno izabrani od vodika, C1-C4 alkila, C1-C4 haloalkila, -O-C1-C4 alkila i CN, pri čemu je svaka navedena alkil grupa od R1, R3, R4 i R6 nezavisno izborno supstituirana sa -OH, -NH2, -CN, -O-C1-C4 alkil, -NH(C1-C4 alkil) ili -N(C1-C4 alkil)2; R2 i R5 su svaki nezavisno izabrani od: -(C1-C6 alkil), -(C1-C6 alkil)-C(O)-NH2, -(C1-C6 alkil)-CO2H, -(C2-C6 alkenil ili alkinil), -(C1-C6 alkilen)-O-(C1-C6 alkil), -(C0-C6 alkilen)-C(O)N(R6)-(C1-C6 alkil), -(C0-C6 alkilen)-Q, -(C0-C6 alkilen)-C(O)-(C1-C6 alkil) i -(C0-C6 alkilen)-C(O)-(C0-C6 alkilen)-Q, gdje: bilo koja alkil ili alkilen grupa prisutna u R2 i R5 je izborno supstituirana jednim ili više -OH, -O(C1-C4 alkil), -CO2H ili halo; bilo koja terminalna metil grupa prisutna u R2 i R5 je izborno zamijenjena sa -CH2OH, CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN ili CO2H; R7 i R8 su svaki nezavisno izabrani od vodika i C1-C6 alkila; i Q je izabran od arila, heteroarila, karbociklila i heterociklila, od kojih je bilo koji izborno supstituiran; gdje R1 i R3 su izborno uzeti zajedno sa atomom ugljika za koji su vezani tako da formiraju C(=O); ili R4 i R6 su izborno uzeti zajedno sa atomom ugljika za koji su vezani tako da formiraju C(=O); ili R1 i R2 su izborno uzeti zajedno tako da formiraju izborno supstituiran karbociklil ili izborno supstituiran i heterociklil; ili R4 i R5 su izborno uzeti zajedno tako da formiraju izborno supstituiran i karbociklil ili izborno supstituiran heterociklil; pri čemu spoj nije izabran iz grupe koju čine: (1) 4,6-Pirimidindiamin, 2-(6-metil-2-piridinil)-N4,N6-dipropil-; (2) 4,6-Pirimidindiamin, N4-etil-2-(6-metil-2-piridinil)-N6-propil-; i (3) 4,6-Pirimidindiamin, N4,N4-dietil-2-(6-metil-2-piridinil)-N6-propil-.
7. Spoj koji ima formulu C, ili njegova farmaceutski prihvatljiva sol ili hidrat, naznačen time što: [image] X je N, CH ili C-halo; svaki Xb je nezavisno N-R9b, O, S, C-H ili C-R9c, uz uvjet da najmanje jedan Xb je C-R9c, i kada je jedan Xb jednak C-H ili C-R9c i drugi je C-R9c tada je Xc jednak N, i kada je jedan Xb jednak N-R9b, O ili S, tada je Xc jednak C; R9b je vodik ili -C1-C4 alkil; R9c je halo, -C1-C4 alkil, -C1-C4 haloalkil, -C1-C4 hidroksialkil, -NH-S(O)2-(C1-C4 alkil), -S(O)2NH(C1-C4 alkil), -CN, -S(O)2-(C1-C4 alkil), C1-C4 alkoksi, -NH(C1-C4 alkil),-N(C1-C4 alkil)2, -OH, -OCF3, -CN, -NH2, -C(O)NH2, -C(O)NH(C1-C4 alkil), -C(O)-N(C1-C4 alkil)2, -(C1-C6 alkilen)-O-(C1-C6 alkil), aril i ciklopropil izborno supstituiran sa OH; R1, R3, R4 i R6 su svaki nezavisno izabrani od vodika, C1-C4 alkila, C1-C4 haloalkila, -O-C1-C4 alkila i CN, pri čemu je svaka navedena alkil grupa od R1, R3, R4 i R6 nezavisno izborno supstituirana sa -OH, -NH2, -CN, -O-C1-C4 alkil, -NH(C1-C4 alkil) ili -N(C1-C4 alkil)2; R2 i R5 su svaki nezavisno izabrani od: -(C1-C6 alkil), -(C1-C6 alkil)-C(O)-NH2, -(C1-C6 alkil)-CO2H, -(C0-C6 alkilen)-Q, -(C0-C6 alkilen)-C(O)-(C1-C6 alkil), -(C0-C6 alkilen)-C(O)-(C0-C6 alkilen)-Q, gdje: bilo koja alkil ili alkilen grupa prisutna u R2 i R5 je izborno supstituirana sa jednim ili više -OH, -O(C1-C4 alkil), -CO2H ili halo; bilo koja terminalna metil grupa prisutna u R2 i R5 je izborno zamijenjena sa -CH2OH, CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN ili CO2H; R7 i R8 su svaki nezavisno izabrani od vodika i C1-C6 alkila; i Q je izabran od arila, heteroarila, karbociklila i heterociklila, od kojih je bilo koji izborno supstituiran ; gdje R1 i R3 su izborno uzeti zajedno sa atomom ugljika za koji su vezani tako da formiraju C(=O); ili R4 i R6 su izborno uzeti zajedno sa atomom ugljika za koji su vezani tako da formiraju C(=O); ili R1 i R2 su izborno uzeti zajedno tako da formiraju izborno supstituiran karbociklil ili izborno supstituiran heterociklil; ili R4 i R5 su izborno uzeti zajedno tako da formiraju izborno supstituiran i karbociklil ili izborno supstituiran i heterociklil; gdje: (i) kada je X jednako CH i [image] je izborno supstituiran 1-imidazolil, izborno supstituiran i 1-pirolil ili izborno supstituiran i 1-pirazolil, tada ni N(R7)C(R4)(R5)(R6) ni N(R8)C(R1)(R2)(R3) nije NH(CH2)7CH3, ili NHCH2CH2OH; i (ii) kada su X i Xc oba jednaki N, tada ni N(R7)C(R4)(R5)(R6) ni N(R8)C(R1)(R2)(R3) nije N(CH2CH3)2.
8. Spoj ili njegova farmaceutski prihvatljiva sol ili hidrat prema patentnom zahtjevu 7 naznačeno time što: a) R9c je halo, -OH, CN, -NH2, -O-C1-C4 alkil, -NH(C1-C4 alkil), -N(C1-C4 alkil)2, -C1-C4 alkil, -C1-C4 haloalkil i -(C1-C6 alkilen)-O-(C1-C6 alkil); R1 i R4 su svaki vodik ; R3 i R6 su svaki nezavisno izabrani od C1-C4 alkila, C1-C4 haloalkila, -O-C1-C4 alkila i CN; i R2 i R5 su svaki -(C1-C6 alkil), gdje: alkil grupa prisutna u R2 i R5 je izborno supstituirana sa jednim ili više -OH, -O(C1-C4 alkil), -CO2H, ili halo; i bilo koja terminalna metil grupa prisutna u R2 i R5 je izborno zamijenjen sa -CH2OH, CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN, ili CO2H; ili b) R1 i R4 su svaki nezavisno izabrani od C1-C4 alkila i C1-C4 haloalkila, i R2 i R5 su svaki -(C1-C6 alkil).
9. Spoj ili njegova farmaceutski prihvatljiva sol ili hidrat prema patentnom zahtjevu 1, naznačeno time što R3 i R6 su oba vodik , R1 i R4 su svaki nezavisno izabrani od C1-C4 alkila i C1-C4 haloalkila, i R2 i R5 su svaki -(C1-C6 alkil).
10. Spoj formule (Ig) ili njegova farmaceutski prihvatljiva sol ili hidrat, naznačeno time što: [image] prsten A je izborno supstituiran 5-6 –člani monocikličan aril ili monocikličan heteroaril; R3 i R6 su oba vodik ; R1 i R4 su svaki nezavisno izabrani od C1-C4 alkila i C1-C4 haloalkila; i R2 i R5 su svaki -(C1-C6 alkil); ili R1 i R2 su izborno uzeti zajedno tako da formiraju izborno supstituiran i monocikličan karbociklil; ili R4 i R5 su izborno uzeti zajedno tako da formiraju izborno supstituiran monocikličan karbociklil; gdje: (i) prsten A nije izborno supstituiran triazolil, ili 3,5-dimetil-1H-pirazol-1-il, (ii) kada su R1 i R2 izborno uzeti zajedno tako da formiraju nesupstituiran i cikloheksil, i R4 i R5 su izborno uzeti zajedno tako da formiraju nesupstituiran i cikloheksil, tada A nije disupstituiran 1-pirazolil ili nesupstituiran fenil; (iii) spoj nije izabran iz grupe koju čine: (1) 6-(1H-imidazol-1-il)-N2,N4-bis(1-metiletil)-1,3,5-Triazin-2,4-diamin; (2) N2,N4-bis(1-metilpropil)-6-fenil-1,3,5-Triazin-2,4-diamin; ili (3) 1,3,5-triazin-2,4-diamin, 6-(4-hloro-3,5-dimetil-1H-pirazol-1-il)-N2,N4-bis(1-metiletil)-.
11. Spoj prema patentnom zahtjevu 10 ili njegova farmaceutski prihvatljiva sol ili hidrat, naznačen time što A je piridinil izborno supstituiran sa halo ili -C1-C4 haloalkilom.
12. Spoj ili njegova farmaceutski prihvatljiva sol ili hidrat, izabran iz grupe koja se sastoji od: [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image]
13. Spoj prema patentnom zahtjevu 12 ili njegova farmaceutski prihvatljiva sol ili hidrat, koji ima strukturu: [image]
14. Spoj prema patentnom zahtjevu 12 ili njegova farmaceutski prihvatljiva sol ili hidrat, koji ima strukturu: [image]
15. Spoj prema patentnom zahtjevu 12 ili njegova farmaceutski prihvatljiva sol ili hidrat, koji ima strukturu: [image]
16. Spoj prema patentnom zahtjevu 12 ili njegova farmaceutski prihvatljiva sol ili hidrat, koji ima strukturu: [image]
17. Spoj prema patentnom zahtjevu 12 ili njegova farmaceutski prihvatljiva sol ili hidrat, koji ima strukturu: [image]
18. Spoj prema patentnom zahtjevu 12 ili njegova farmaceutski prihvatljiva sol ili hidrat, koji ima strukturu: [image]
19. Spoj prema patentnom zahtjevu 12 ili njegova farmaceutski prihvatljiva sol ili hidrat, koji ima strukturu: [image]
20. Spoj prema patentnom zahtjevu 12 ili njegova farmaceutski prihvatljiva sol ili hidrat, koji ima strukturu: [image]
21. Spoj prema patentnom zahtjevu 12 ili njegova farmaceutski prihvatljiva sol ili hidrat, koji ima strukturu: [image]
22. Spoj prema patentnom zahtjevu 12 ili njegova farmaceutski prihvatljiva sol ili hidrat, koji ima strukturu: [image]
23. Farmaceutska kompozicija koja sadrži spoj ili njegovu farmaceutski prihvatljivu sol ili hidrat prema bilo kojem od patentnih zahtjeva 1 do 9 ili 11 do 22, i farmaceutski prihvatljiv nosač.
24. Farmaceutska kompozicija koja sadrži spoj koji ima formulu Ig ili njegovu farmaceutski prihvatljivu sol ili hidrat: [image] gdje prsten A je izborno supstituiran 5-6 –člani monocikličan aril ili monocikličan heteroaril; R3 i R6 su oba vodik ; R1 i R4 su svaki nezavisno izabrani od C1-C4 alkila i C1-C4 haloalkila; i R2 i R5 su svaki -(C1-C6 alkil); ili R1 i R2 su izborno uzeti zajedno tako da formiraju izborno supstituiran monocikličan karbociklil; ili R4 i R5 su izborno uzeti zajedno tako da formiraju izborno supstituiran monocikličan karbociklil; gdje: (i) prsten A nije izborno supstituiran triazolil ili 3,5-dimetil-1H-pirazol-1-il, (ii) kada su R1 i R2 izborno uzeti zajedno tako da formiraju nesupstituiran i cikloheksil, i R4 i R5 su izborno uzeti zajedno tako da formiraju nesupstituiran i cikloheksil, tada A nije disupstituiran i 1-pirazolil ili nesupstituiran i fenil; (iii) spoj nije izabran iz grupe koju čine: (1) 6-(1H-imidazol-1-il)-N2,N4-bis(1-metiletil)-1,3,5-Triazin-2,4-diamin; ili (2) N2,N4-bis(1-metilpropil)-6-fenil-1,3,5-Triazin-2,4-diamin; i farmaceutski prihvatljiv nosač.
25. Farmaceutska kompozicija prema bilo kojem od patentnih zahtjeva 23 do 24, naznačena time što dodatno sadrži drugo terapeutsko sredstvo korisno u liječenju karcinoma.
26. Spoj, ili njegova farmaceutski prihvatljiva sol ili hidrat, ili farmaceutska kompozicija prema bilo kojem od patentnih zahtjeva 1 do 9 ili 11 do 25 za upotrebu u postupku za liječenje karcinoma naznačeno prisustvom IDH1 mutacije, pri čemu IDH1 mutacija rezultira u novoj sposobnosti enzima da katalizira NADPH-zavisnu redukciju α-ketoglutarata u R(-)-2-hidroksiglutarat u pacijentu.
27. Spoj koji ima formulu Ig ili njegova farmaceutski prihvatljiva sol ili hidrat: [image] gdje prsten A je izborno supstituiran 5-6 –člani monociklični aril ili monociklični heteroaril; R3 i R6 su oba vodik ; R1 i R4 su svaki nezavisno izabrani od C1-C4 alkila i C1-C4 haloalkila; i R2 i R5 su svaki -(C1-C6 alkil); ili R1 i R2 su izborno uzeti zajedno tako da formiraju izborno supstituiran monocikličan karbociklil; ili R4 i R5 su izborno uzeti zajedno tako da formiraju izborno supstituiran monocikličan karbociklil; gdje: (i) prsten A nije izborno supstituiran triazolil, ili 3,5-dimetil-1H-pirazol-1-il, (ii) kada su R1 i R2 izborno uzeti zajedno tako da formiraju nesupstituiran i cikloheksil, i R4 i R5 su izborno uzeti zajedno tako da formiraju nesupsupstituiran i cikloheksil, tada A nije disupstituiran 1-pirazolil ili nesupstituiran fenil; (iii) spoj nije izabran iz grupe koju čine: (1) 6-(1H-imidazol-1-il)-N2,N4-bis(1-metiletil)-1,3,5-Triazin-2,4-diamin; ili (2) N2,N4-bis(1-metilpropil)-6-fenil-1,3,5-Triazin-2,4-diamin; za upotrebu u postupku za liječenje karcinoma naznačeno prisustvom IDH1 mutacije, gdje IDH1 mutacija rezultira u novoj sposobnosti enzima da katalizira NADPH-zavisnu redukciju α-ketoglutarata u R(-)-2-hidroksiglutarat u pacijenta.
28. Spoj ili njegova farmaceutski prihvatljiva sol ili hidrat, ili farmaceutska kompozicija za upotrebu prema bilo kojem od patentnih zahtjeva 26 do 27, pri čemu IDH1 mutacija je IDH1 R132H ili R132C mutacija; i/ili pri čemu je karcinom izabran od glioma (glioblastoma), akutne mijelogene leukemije, sarkoma, melanoma, nesitnostaničnog karcinoma pluća (NSCLC), holangiokarcinoma, hondrosarkoma, mijelodisplastičnih sindroma (MDS), mijeloproliferativne neoplazme (MPN), karcinoma debelog crijeva ili angio-imunoblastičnog ne-Hodgkin-ovog limfoma (NHL) kod pacijenta, pri čemu, poželjno, karcinom je gliom.
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