DK2697198T3 - Substituerede benzenforbindelser - Google Patents

Substituerede benzenforbindelser Download PDF

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DK2697198T3
DK2697198T3 DK12716968.8T DK12716968T DK2697198T3 DK 2697198 T3 DK2697198 T3 DK 2697198T3 DK 12716968 T DK12716968 T DK 12716968T DK 2697198 T3 DK2697198 T3 DK 2697198T3
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alkyl
optionally substituted
cancer
membered heterocycloalkyl
cycloalkyl
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Timothy James Nelson Wigle
Kevin Wayne Kuntz
Richard Chesworth
Kenneth William Duncan
Heike Keilhack
Natalie Warholic
Christine Klaus
Masashi Seki
Sarah K Knutson
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Epizyme Inc
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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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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/10—Spiro-condensed systems
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Claims (15)

1. Forbindelse med formel (le) eller et farmaceutisk acceptabelt salt deraf:
hvor Z er NR7R8 eller S(0)aR7, hvori a er 0; Ri er H eller Ci-Cgalkyl, der eventuelt er substitueret med en eller flere substituenter udvalgt blandt hydroxyl, CR-Cealkoxyl, amino, mono-Ci-C6alkylamino, di-Ci-C6alkylamino og Ce-Cioaryl; hver af R2 og R4 uafhængigt er -Q1-T1, hvori Qi er en binding eller en Ci-C3alkyllinker, der eventuelt er substitueret med en eller flere substituenter udvalgt blandt halogen og hydroxyl, og Ti er H, halogen eller azido; R3 er H eller halogen; R5 er H eller Ci-C6alkyl; R6 er H, halogen, cyano, azido, ORa, -NRaRb, -C(0)NRaRb, S(0)bRa, hvor b er 0, 1 eller 2, eller Rs2; hvor Rs2 er Ci~ Cealkyl, C2-C6alkenyl, C2-C6alkynyl eller en 4 til 12-leddet heterocycloalkyl, og hvor hver af Ra og Rb uafhængigt er H, Ci-Cealkyl eller en 4 til 12-leddet heterocycloalkyl; eller Ra og Rb sammen med N-atomet, hvortil de er bundet, danner en 4 til 12-leddet heterocycloalkylring, der har 0 eller 1 yderligere heteroatom; og hver af Ra, Rs2 og den 4 til 12-leddede heterocycloalkylring dannet af Ra og Rb eventuelt er substitueret med en eller flere -Q2-T2; hvor Q2 er en binding eller en Ci-C3alkyllinker, og T2 er H, halogen, -ORc, -NRcRd, -C(0)0Rc, Ci-C6alkyl eller RS4, hvori hver af Rc og Rd uafhængigt er H eller Ci-C6alkyl, Rs4 er Cs-Cscycloalkyl, Cg-Cioaryl, en 4 til 12-leddet heterocycloalkyl eller en 5 eller 6-leddet heteroaryl, og Rs4 eventuelt er substitueret med en eller flere _Q3_T3, hvor Q3 er en binding eller en Ci-C3alkyllinker, der hver eventuelt er substitueret med halogen, cyano, hydroxyl eller Ci-C6alkoxyl, og T3 er udvalgt fra gruppen, der består af halogen, cyano, Ci-C6alkyl, C3-C8cycloalkyl, C6-Cioaryl, en 4 til 12-leddet heterocycloalkyl, en 5 eller 6-leddet heteroaryl, 0Re, COORe, — S (0) 2Rer ~NReRf og -C(0)NReRf, hvor hver af Re og Rf uafhængigt er H eller Ci-Cgalkyl, eller Re og Ra sammen med N-atomet, hvortil de er bundet, danner en 4 til 12-leddet heterocycloalkylring, der har 0 eller 1 yderligere heteroatom og eventuelt er substitueret med Ci-C6alkyl; R7 er -Q4-T4, hvori Q4 er en binding eller en Ci-C4alkyllinker, og T4 er H, Ci-C6alkyl, C3-C8cycloalkyl, C6_Cioaryl, C (0) -Ci_ 6alkyl, C (0) -C3_6cycloalkyl eller en 4 til 14-leddet heterocycloalkyl, der hver eventuelt er substitueret med en eller flere -Q5-T5, hvor Q5 er en binding, C (0) , C(0)NRk, NRkC(0), S (0)2 eller en Ci-C3alkyllinker, hvor Rk er H eller Ci~ C6alkyl, og T5 er H, halogen, Ci-C6alkyl, hydroxyl, cyano, Ci~ C6alkoxyl, amino, mono-Ci-C6alkylamino, di-Ci-C6alkylamino, C3-Cgcycloalkyl, C6-Ci0aryl, en 4 til 12-leddet heterocycloalkyl, en 5 eller 6-leddet heteroaryl eller S(0)qRq, hvori g er 0, 1 eller 2, og Rg er Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C6-Ci0aryl, en 4 til 12-leddet heterocycloalkyl eller en 5 eller 6-leddet heteroaryl, og T5 eventuelt er substitueret med en eller flere substituenter udvalgt fra gruppen, der består af halogen, Ci-C6alkyl, hydroxyl, cyano, Ci-C6alkoxyl, amino, mono-Ci-C6alkylamino, di-Ci-C6alkylamino, C3-C8cycloalkyl, C6-Ci0aryl, en 4 til 12-leddet heterocycloalkyl og en 5 eller 6-leddet heteroaryl, bortset fra når T5 er H, halogen, hydroxyl eller cyano; eller -Q5-T5 er oxo; Rg er H, Ci-C6alkyl, der eventuelt er substitueret med halogen, hydroxyl eller Ci-C6alkoxyl, C2-C6alkenyl, C3-C8cycloalkyl eller en 4 til 7-leddet heterocycloalkyl; eller R7 og R8 sammen med N-atomet, hvortil de er bundet, danner en 4 til 12-leddet heterocycloalkylring, der har 0 til 2 yderligere heteroatomer, og den 4 til 12-leddede heterocycloalkylring dannet af R7 og Rg eventuelt er substitueret med en eller flere -Qi-Te, hvor Q6 er en binding, C(0), C(0)NRm, NRmC(0), S(0)2 eller en Ci~ C3al kyl linker, hvor Rm er H eller Ci-C6alkyl, og T6 er H, halogen, Ci-C6alkyl, hydroxyl, cyano, Ci-C6alkoxyl, amino, mono-Ci-C6alkylamino, di-Ci-C6alkylamino, C3-C8cycloalkyl, C6-Ci0aryl, en 4 til 12-leddet heterocycloalkyl, en 5 eller 6-leddet heteroaryl eller S(0)pRp, hvori p er 0, 1 eller 2, og Rp er Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C6-Ci0aryl, en 4 til 12-leddet heterocycloalkyl eller en 5 eller 6-leddet heteroaryl, og T6 eventuelt er substitueret med en eller flere substituenter udvalgt fra gruppen, der består af halogen, C3-Cealkyl, hydroxyl, cyano, Ci-C6alkoxyl, amino, mono-Ci-Cealkylamino, di-Ci-C6alkylamino, C3-C8cycloalkyl, C6-Cioaryl, en 4 til 12-leddet heterocycloalkyl og en 5 eller 6-leddet heteroaryl, bortset fra når T6 er H, halogen, hydroxyl eller cyano; eller -Q6-T6 er oxo; og Ri2 er halogen, Ci-C6alkoxyl, C2-C6alkenyl eller Ci-C6alkyl, der eventuelt er substitueret med halogen.
2. Forbindelse ifølge krav 1, hvor Ri er H eller Ci-C6alkyl, der eventuelt er substitueret en eller flere gange med en substituent udvalgt blandt hydroxyl, Ci-C6alkoxyl og C6-Ci0aryl; R7 er -Q4-T4, hvori Q4 er en binding eller en Ci-C4alkyllinker, og T4 er Ci-C6alkyl, C3-Cscycloalkyl, C6-Cioaryl, C(O)-Ci-C6alkyl, C (O)-C3-C6cycloalkyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, pyrrolidinyl, azetidinyl og oxetanyl, der hver eventuelt er substitueret med en eller flere substituenter uafhængigt udvalgt blandt oxo og -Q5-T5; Rs er H eller Ci-C6alkyl, C1-C6 halogenalkyl, C2-Cgalkenyl eller C3-C8Cycloalkyl; og R12 er halogen, Ci-C6alkyl, C1-C6 halogenalkyl eller C7- Cealkoxyl.
3. Forbindelse ifølge krav 1 eller 2, hvor Z er NR7R8 eller SR7; R6 er H, halogen, cyano, ORa, -C(0)NRaRb, -S(0)2Ra eller Rs2; hvor Rs2 er Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl eller en 4 til 12-leddet heterocycloalkyl, og hvor hver af Ra og Rb uafhængigt er H eller Ci-C6alkyl; eller Ra og Rb sammen med N-atomet, hvortil de er bundet, danner en 4 til 12-leddet heterocycloalkylring, der har 0 eller 1 yderligere heteroatom; og hver af Rs2 og den 4 til 12-leddede heterocycloalkylring dannet af Ra og Rb eventuelt er substitueret med en eller flere -Q2-T2; hvor Q2 er en binding eller en Ci-C3alkyllinker, og T2 er H, halogen, -0RC, -NRcRd, -C (0) 0Ci-C6alkyl eller Ci-Csalkyl, hvori hver af Rc og Rd uafhængigt er H eller Ci-C6alkyl, eller Rc og Rd sammen med N-atomet, hvortil de er bundet, danner en 4 til 12-leddet heterocycloalkylring, der har 0 eller 1 yderligere heteroatom og 0 eller 1 Ci-C6alkylsubstituenter; R7 er Ci-C6alkyl, C3-Cscycloalkyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, pyrrolidinyl, azetidinyl og oxetanyl, der hver eventuelt er substitueret med en eller flere substituenter uafhængigt udvalgt blandt oxo og -Q5-T5; og Ri2 er halogen eller Ci-C6alkyl.
4. Forbindelse ifølge et hvilket som helst af kravene 1-3, hvor R2, R4 og R22 hver for sig er Ci-Cgalkyl, og R5 er H.
5. Forbindelse ifølge krav 1, hvor R7 er cyclohexyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, pyrrolidinyl, azetidinyl oxetanyl, 1,4-dioxaspiro [4.5] decan-8-yl, 1-oxaspiro [4.5] decan-8-yl, 3'il-spir o [cyclohexan-1,1'-isobenzofuran]-4-yl, 7'H- spiro [cyclohexan-1,5 ' - furo [3,4 —b] pyridin] - 4-yl, 3Ή- spiro[cyclohexan-1,1'-furo[3,4-c]pyridin]-4-yl eller 1- azaspiro[4.5]decan-8-yl, der hver er substitueret med en eller flere -Q5-T5.
6. Forbindelse ifølge et hvilket som helst af kravene 1-5, hvor Z er udvalgt fra gruppen, der består af piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrrolidinyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl og l,4-dioxa-8- azaspiro[4.5]decan-8-yl, der hver eventuelt er substitueret med én -Q6-T6.
7. Forbindelse ifølge et hvilket som helst af kravene 1-5, hvor R-6 er halogen, og Z er SR7, hvori R7 er Ci-C6alkyl, C3-Cscycloalkyl eller en 4 til 7-leddet heterocycloalkyl, og R7 eventuelt er substitueret med en eller flere -Q5-T5.
8. Forbindelse ifølge et hvilket som helst af kravene 1-5, hvor R6 er -S(0)bRa eller azido, hvori b er 0, 1 eller 2, og Ra er Ci-C6alkyl eller C3-Cscycloalkyl; og Z er NR7R8, hvori R7 er Cs-Cscycloalkyl eller en 4 til 14-leddet heterocycloalkyl, der hver eventuelt er substitueret med en eller flere -Qs-Ts; og Rs er H eller Ci-C6alkyl.
9. Forbindelse ifølge et hvilket som helst af kravene 1-5, hvor forbindelsen har formel (II):
hvor n er 0, 1 eller 2; U er 0, S, N-Q5-T5 eller CH-Q5-T5; og R12 er Cl, Br eller methyl, og fortrinsvis U er CH-Q5-T5, og n er 0 .
10. Forbindelse ifølge et hvilket som helst af kravene 1-5 eller 9, hvor forbindelsen har formel (IIA):
hvor n er 0, 1 eller 2; U er O, S, N-Q5-T5 eller CH-Q5-T5; og R12 er Cl, Br eller methyl, og fortrinsvis U er CH-Q5-T5, og n er 0.
11. Forbindelse ifølge krav 10, hvor (i) Q5 er en binding, og T5 er H, Ci-C6alkyl, C3-Cscycloalkyl, en 4 til 12-leddet heterocycloalkyl, en 5 eller 6-leddet heteroaryl, amino, mono-Ci-C6alkylamino eller di-Ci-C6alkylamino, hvor T5 eventuelt er substitueret med en eller flere substituenter udvalgt fra gruppen, der består af halogen, hydroxyl, Ci-C6alkoxyl eller C3-C8cycloalkyl; (ii) Q5 er CO, S (0)2 eller NHC(0); og T5 er Ci~ Cgalkyl, Ci-C6alkoxyl, C3-Cscycloalkyl eller en 4 til 12-leddet heterocycloalkyl, (i i i) Q5 er en Ci-C3alkyllinker, og T5 er H eller C6-Cioaryl, (iv) Q5 er en Ci-C3alkyllinker, og T5 er C3-Cscycloalkyl, en 4 til 12-leddet heterocycloalkyl eller S(0)qRq, (v) Qs er NHC(O), og T5 er Ci-C6alkyl eller Ci-C6alkoxy, eller (vi) en eller flere -Q5-T5 er oxo.
12. Forbindelse ifølge et hvilket som helst af kravene 1-11, hvor en eller flere -Q6-T6 er oxo, eller når Q6 er en binding eller C(0), så er T6 Ci-C6alkyl eller Ci-C6alkoxy.
13. Forbindelse ifølge krav 1, der er udvalgt blandt
og farmaceutisk acceptable salte deraf.
14. Farmaceutisk sammensætning, der omfatter en forbindelse ifølge et hvilket som helst af kravene 1-13, N-(5-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl) methyl)carbamoyl)-2-methylphenyl)furan-2-carboxamid, N,N'-(5-(((4,6-dimethyl-2- oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1,3-phenylen)diacetamid, N-((4,6-dimethyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)-3-pivalamidobenzamid, 3-(3,4- dihydro-2H-benzo[b][1,4]dioxepin-7-sulfonamido)-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)benzamid, N- ((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3,5-dimethoxybenzamid, N-((4, 6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3,4,5-trimethoxybenzamid, 3-allyl-N-( (4,6- dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl)-4,5-dimethoxybenzamid, 4-(2-amino-2-oxoethoxy)-3-chlor-N- ( (4,6- dimethyl-2-oxo-l,2-dihydropyridin-3-yl) methyl)-5-methoxybenzamid, 3-chlor-N-((4,6-dimethyl-2-oxo-l,2- dihydropyridin-3-yl) methyl)-4-hydroxy-5-methoxybenzamid eller 3-brom-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-5-methoxy-4-propoxybenzamid eller et farmaceutisk acceptabelt salt deraf og et farmaceutisk acceptabelt bæremateriale.
15. Forbindelse ifølge et hvilket som helst af kravene 1-13 til anvendelse i en fremgangsmåde til behandling eller forebyggelse af cancer.
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EP2697198B1 (en) 2016-06-08
RU2017126990A (ru) 2019-02-01
HK1202534A1 (en) 2015-10-02
ES2590489T3 (es) 2016-11-22
IL228746A0 (en) 2013-12-31
HUE030722T2 (en) 2017-05-29
IL228746B (en) 2019-08-29
PT2697198T (pt) 2016-09-13
US9376422B2 (en) 2016-06-28
AU2017218920A1 (en) 2017-09-07
WO2012142513A1 (en) 2012-10-18
EP3470396A1 (en) 2019-04-17
MX2013011922A (es) 2014-04-10
TW201305107A (zh) 2013-02-01
CA2832846C (en) 2022-04-19
BR112013026308A2 (pt) 2022-07-19
EP3165520B1 (en) 2018-08-15

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