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DK2819996T3 - 6-alkynylpyridiner som smac-mimetika. - Google Patents

6-alkynylpyridiner som smac-mimetika. Download PDF

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DK2819996T3
DK2819996T3 DK13705799.8T DK13705799T DK2819996T3 DK 2819996 T3 DK2819996 T3 DK 2819996T3 DK 13705799 T DK13705799 T DK 13705799T DK 2819996 T3 DK2819996 T3 DK 2819996T3
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alkyl
optionally
phenyl
independently
mmol
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DK13705799.8T
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Ulrich Reiser
Gerd Bader
Walter Spevak
Andreas Steffen
Alastair L Parkes
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Boehringer Ingelheim Int
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Claims (32)

1. Forbindelse ifølge formel (I)
hvor R1 er -H eller -Ci-5-alkyl; R2, R2a er uafhængigt af hinanden valgt blandt -H eller -Ci-5-alkyl eventuelt substitueret med én eller flere -F; R3 er valgt blandt -C6-io-aryl, 5-14-leddet heteroaryl, hver af disse grupper kan, eventuelt og uafhængigt af hinanden, være substitueret med én eller flere, uafhængigt af hinanden valgt, R5; eller R3 er valgt blandt -Ci-6-alkyl, -C4-7-cycloalkyl, -C4-7-cycloalkenyl, eller 5-14-leddet aromatisk ringsystem, hver af disse grupper kan eventuelt og uafhængigt af hinanden være substitueret med én eller flere, uafhængigt af hinanden valgt, R6a; R5 er valgt blandt -CN, halogen, -Ci 3-alkyl, -O-Ci 3-alkyl, -C(0)-R12, 5-6-leddet heteroaryl, hvor den 5-6-leddede heteroarylgruppe eventuelt kan være substitueret med -Ci-3-alkyl; eller R6 er phenyl, hvor phenyl eventuelt kan være substitueret med -0-Ci-3-alkyl R6a er valgt blandt =0, -CN, halogen, -Ci-3-alkyl, -O-Ci-3-alkyl, -C(0)-R12, 5-6-leddet heteroaryl, hvor den 5-6-leddede heteroarylgruppe eventuelt kan være substitueret med -Ci-3-alkyl; eller RSa er phenyl, hvor phenyl eventuelt kan være substitueret med -O-C1-3-alkyl; R12 er valgt blandt -NFI2, -NFI-Ci-3-alkyl, 5-7-leddet ikke-aromatisk heterocyclyl, eller -0-Ci-3-alkyl, hvor de -Ci-3-alkylgrupper eventuelt kan være substitueret med en 5-7-leddet ikke-aromatisk heterocyclyl; R4 er valgt blandt -H, -C6-io-aryl, 5-14-leddet heteroaryl, hver af disse grupper er eventuelt og uafhængigt af hinanden substitueret med én eller flere, uafhængigt af hinanden valgt, R7, eller R4 er valgt blandt Ci-6-alkyl, 5-14-leddet aromatisk ringsystem, -C5-7-cycloalkyl, hver af disse grupper er, eventuelt og uafhængigt af hinanden, substitueret med én eller flere, uafhængigt af hinanden valgt, R7a, eller R4 er valgt blandt -N(R8,R9), hvor R8, R9 er uafhængigt af hinanden valgt blandt H, -Ci-3-alkyl, -C(0)-R10 -S(0)2-Rn R10, R11 er uafhængigt af hinanden valgt blandt 5-7-leddet ikke-aromatisk heterocyclyl, -Cs-7-cydoalkyl, -C610-aryl, 5-10-leddet heteroaryl; R7 er valgt blandt -CN, halogen, -CF3, -NO2, -Ci-3-alkyl, -S-Ci-3-alkyl, -NH-Ci-3-alkyl, -N(Ci-3-alkyl)2, -NHC(0)-Ci-3-alkyl, -C(0)-R13, -OCi-3-alkyl, 5-14-leddet heteroaryl, -0-phenyl, -CFh-phenyl, phenyl, hver af disse phenylgrupper kan eventuelt være substitueret med halogen, eller 5-6-leddet ikke-aromatisk heterocyclyl, hvor den 5-6-leddede ikke-aromatiske heterocyclyl eventuelt kan være substitueret med -Ci-3-alkyl; R7a er valgt blandt =0, -CN, halogen, -CF3, -N02/ -Ci-3-alkyl, -S-Ci-3-alkyl, -NH-C1-3-alkyl, -N(Ci-3-alkyl)2, -NHC(0)-Ci.3-alkyl, -C(0)-R13, -O-Ci-3-alkyl, 5-14-leddet heteroaryl, -O-phenyl, -CH2-phenyl, phenyl, hver af disse phenylgrupper kan eventueltvære substitueret med halogen, eller 5-6-leddet ikke-aromatisk heterocyclyl, hvor den 5-6-leddede ikke-aromatiske heterocyclyl eventuelt kan være substitueret med -Ci-3-alkyl; hvor R13 er valgt blandt -OH, -NH2, -NH-Ci 3-alkyl, -Ci-3-alkyl; R5 er valgt blandt -H, halogen, -Ci-3-alkyl, -O-Ci-3-alkyl, hvor -Ci-3-alkylgrupperne eventuelt kan være substitueret med én eller flere halogener; eller R4 og R5 sammen danner en -C6-io-aryl eller 5-14-leddet heteroaryl, og, hvor forbindelserne ifølge formel (I) eventuelt kan være foreliggende i form af salte.
2. Forbindelse ifølge krav 1, hvor R1 er valgt blandt -CH3, -CH2-CH3.
3. Forbindelse ifølge krav 1 eller 2, hvor R2 og R2a er uafhængigt af hinanden valgt blandt -H,-CH3, -CH2-CH3. -CH-(CH3)2, -(CH2)2-CH3.
4. Forbindelse ifølge et hvilket som helst af kravene 1 til 3, hvor R5 er valgt blandt -H, -Cl, -F, -CF3,-OCH3, -CH3.
5. Forbindelse ifølge et hvilken som helst af kravene 1 til 4, hvor R3 er valgt blandt -C6-io-aryl, 5-14-leddet heteroaryl, hver af disse grupper kan, eventuelt og uafhængigt af hinanden, være substitueret med én eller flere, uafhængigt af hinanden valgt, R6, eller R3 er valgt blandt -C5-7-cycloalkenyl, 5-14-leddet aromatisk ringsystem, hver af disse grupper kan, eventuelt og uafhængigt af hinanden, være substitueret med én eller flere, uafhængigt af hinanden valgt R5a, eller R3 er -CH2-phenyl, hvor phenyl eventuelt kan være substitueret med -O-Ci-3-alkyl, og hvor R6 og R6a er som defineret ifølge krav 1.
6. Forbindelse ifølge et hvilket som helst af kravene 1 til 5, hvor R3 er valgt blandt -C6-io-aryl, 5-14-leddet heteroaryl, hver af disse grupper kan, eventuelt og uafhængigt af hinanden, være substitueret med én eller flere, uafhængigt af hinanden valgt, R6, eller R3 er valgt blandt 5-14-leddet aromatisk ringsystem, hvor grupperne eventuelt og uafhængigt af hinanden kan være substitueret med én eller flere, uafhængigt af hinanden valgt, R6a, hvor R6 og R6a er som defineret ifølge krav 1.
7. Forbindelse ifølge et hvilket som helst af kravene 1 til 5, hvor R3 er valgt blandt -CH2-phenyl,
hver af disse grupper er eventuelt substitueret ifølge krav 1.
8. Forbindelse ifølge et hvilket som helst af kravene 1 til 7, hvor R4 er valgt blandt -H, -Ce-io-aryl, 5-14-leddet heteroaryl, hver af disse grupper er eventuelt og uafhængigt af hinanden substitueret med én eller flere, uafhængigt af hinanden valgt, R7, eller R4 er valgt blandt -Ci-6-alkyl, 5-14-leddet aromatisk ringsystem og -Cs-7-cycloalkyl, hver af disse grupper er eventuelt og uafhængigt af hinanden substitueret med én eller flere, uafhængigt af hinanden valgt, R7a, eller R4 er valgt blandt -N(R8,R9), hvor R7, R7a, R8 og R9 er som defineret ifølge krav 1.
9. Forbindelse ifølge et hvilket som helst af kravene 1 til 8, hvor R4 er valgt blandt -C6-io-aryl, 5-14-leddet heteroaryl, hver af disse grupper er eventuelt og uafhængigt af hinanden substitueret med én eller flere, uafhængigt af hinanden valgt, R7, eller R4 er valgt blandt 5-14-leddet aromatisk ringsystem, -Cs-7-cycloalkyl, hver af disse grupper er eventuelt og uafhængigt af hinanden substitueret med én eller flere, uafhængigt af hinanden valgt, R7a, eller R4 er valgt blandt -N(R8,R9), hvor R7, R7a, R8 og R9 er som defineret ifølge krav 1.
10. Forbindelse ifølge et hvilket som helst af kravene 1 til 9, hvor R4 er valgt blandt -C6-io-aryl, 5-14-leddet heteroaryl, hver af disse grupper er eventuelt og uafhængigt af hinanden substitueret med én eller flere, uafhængigt af hinanden valgt, R7, eller R4 er 5-14-leddet aromatisk ringsystem, hver af disse grupper er eventuelt og uafhængigt af hinanden substitueret med én eller flere, uafhængigt af hinanden valgt, R7a, hvor R7 og R7a er som defineret ifølge krav 1.
11. Forbindelse ifølge et hvilket som helst af kravene 1 til 9, hvor R4 er valgt blandt -H, -Ci-3-alkyl,-CH2-phenyl, -N(CH3)-S02-phenyl, -N(CH3)CO-R10; -NH-CO-R10, hvor R10 er uafhængigt valgt blandt morpholin, cyclopentyl, phenyl, eller R4 er valgt blandt
hver af disse grupper er eventuelt substitueret ifølge krav 1.
12. Forbindelse ifølge et hvilket som helst af kravene 1 til 11, hvor R6 er valgt blandt -F, -CI,-CN -CH3, -O-CHs, -C(0)NHCH3, -C(0)NH2, C(0)0CH3, -C(0)-morpholinyl, -C(0)-0-CH2-tetrahydropyran, phenyl,
eller R5a er valgt blandt =0, -F, -Cl, -CN -CH3, -0-CH3, -C(0)NHCH3, -C(0)NH2, C(0)0CFI3, -C(0)-morpholinyl, -C(0)-0-CFl2-tetrahydropyran, phenyl,
13. Forbindelse ifølge et hvilket som helst af kravene 1 til 12, hvor R7 er valgt blandt -CN, -F, - Cl, -CF3, -NO2, -CH3, -CH2CH3, -CH2(CH3)2, -S-CH3, -NH-CH3, -N(CH3)2, -C(0)0H,-C(0)NH2, -C(0)NH-CH3, -NHC(0)CH3, -0-CH3, -0-CH2CH3, pyridyl, phenyl, -Ο-Phenyl, -CH2-phenyl,
eller R7a er valgt blandt =0, -CN, -F, -Cl, -CF3, -N02, -CH3, -CH2CH3, -CH2(CFI3)2, -S-CH3, -NH-CH3, -N(CH3)2, -C(0)0H, -C(0)NH2, -C(0)NH-CH3, -NHC(0)CH3, -o-ch3, -0-CH2CH3, pyridyl, phenyl, -0-Phenyl, -CH2-phenyl,
14. Forbindelse ifølge et hvilket som helst af kravene 1 til 3 og 5 til 7, hvor R4 og R5 sammen danner en phenyl.
15. Forbindelser ifølge et hvilket som helst af kravene 1 til 14, hvor R3 er valgt blandt
16. Forbindelse ifølge et hvilket som helst af kravene 1 til 13 og 15, hvor R4 er valgt blandt
17. Forbindelse ifølge krav 1, valgt blandt
18. Forbindelse ifølge krav 1 (26),
hvor forbindelsen eventuelt kan være foreliggende i form af et salt.
19. Forbindelse ifølge krav 1 (35),
hvor forbindelsen eventuelt kan være foreliggende i form af et salt.
20. Forbindelse ifølge krav 1 (28),
hvor forbindelsen eventuelt kan være foreliggende i form af et salt.
21. Forbindelse ifølge krav 1 (29),
hvor forbindelse eventuelt kan være foreliggende i form af et salt.
22. Forbindelse ifølge krav 1 (30),
hvor forbindelsen eventuelt kan være foreliggende i form af et salt.
23. Forbindelse ifølge krav 1 (47),
hvor forbindelsen eventuelt kan være foreliggende i form af et salt.
24. Forbindelse ifølge krav 1 (88),
hvor forbindelsen eventuelt kan være foreliggende i form af et salt.
25. Forbindelse ifølge krav 1 (89),
hvor forbindelsen eventuelt kan være foreliggende i form af et salt.
26. Forbindelse ifølge krav 1 (174),
hvor forbindelsen eventuelt kan være foreliggende i form af et salt.
27. Forbindelse ifølge krav 1 (185),
hvor forbindelsen eventuelt kan være foreliggende i form af et salt.
28. Forbindelse ifølge et hvilket som helst af krav 1 til 27, til anvendelse i behandling af cancer.
29. Forbindelse ifølge et hvilket som helst af krav 1 til 27 til anvendelse i behandlingen og /eller forebyggelsen af karcinom i brystet, prostataen, hjernen eller æggestokken, ikke-småcellet lunge karcinomer (NSCLC), melanomer og kronisk lymfatiske leukæmier (CLL).
30. Farmaceutisk sammensætning omfattende en forbindelse ifølge et hvilket som helst af krav 1 til 27.
31. Farmaceutisk sammensætning omfattende en forbindelse ifølge et hvilket som helst af krav 1 til 27 til anvendelse i behandlingen og/eller forebyggelsen af cancer.
32. Farmaceutisk sammensætning omfattende en forbindelse ifølge et hvilket som helst af krav 1 til 27 til anvendelse i behandlingen og /eller forebyggelsen karcinom i brystet, prostataen, hjernen eller æggestokken, ikke-småcellet lunge karcinomer (NSCLC), melanomer og kronisk lymfatiske leukæmier (CLL).
DK13705799.8T 2012-02-27 2013-02-25 6-alkynylpyridiner som smac-mimetika. DK2819996T3 (da)

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